Biomarker Predictors of Memantine Sensitivity in Patients With Alzheimer's Disease
Phase: PHASE4
Conditions: Alzheimer Disease
Sponsor: University of California, San Diego

Biomarker Predictors of Memantine Sensitivity in Patients With Alzheimer's Disease 
NCT03703856 
Study Protocol and Statistical Analysis Plan 
12/05/2025 

PI: SWERDLOW, NEAL R
Title: Biomarker Predictors of Memantine Sensitivity in patients with Alzheimer's
Disease
Received: 10/02/2017
FOA: PAR16-365
Council: 05/2018
Competition ID: FORMS-D
FOA Title: PILOT CLINICAL TRIALS FOR THE SPECTRUM OF ALZHEIMERS
DISEASE AND AGE-RELATED COGNITIVE DECLINE (R01)
1 R01 AG059640-01
Dual: NR
Accession Number: 4092026
IPF: 577507
Organization: UNIVERSITY OF CALIFORNIA, SAN DIEGO
Former Number: 
Department: Psychiatry
IRG/SRG: ZRG1 BBBP-Z (55)R
AIDS: N
Expedited: N
Subtotal Direct Costs
(excludes consortium F&A)
Year 1:      250,000
Year 2:      250,000
Year 3:      250,000
Year 4:      250,000
Year 5:      250,000
Animals: N
Humans: Y
Clinical Trial: Y
Current HS Code: 30
HESC: N
New Investigator: N
Early Stage Investigator: N
Senior/Key Personnel: 
Organization:
Role Category: 
Neal Swerdlow
The Regents of the Univ. of Calif., U.C.
San Diego
PD/PI
Gregory Light
The Regents of the Univ. of Calif., U.C.
San Diego
Co-Investigator
Lisa Delano-Wood
The Regents of the Univ. of Calif., U.C.
San Diego
Co-Investigator
Jairo Romero
The Regents of the Univ. of Calif., U.C.
San Diego
Co-Investigator
Brinda Rana
The Regents of the Univ. of Calif., U.C.
San Diego
Co-Investigator
Michael Thomas
The Regents of the Univ. of Calif., U.C.
San Diego
Co-Investigator

Abstract
 
This application responds to PAR-16-365: Pilot Clinical Trials for the Spectrum of Alzheimers Disease 
..., and its calls for Studies to define and refine the target population and address heterogeneity of 
response identification of specific individuals more [vs.] less likely to benefit from the intervention(s). 
 
Alzheimers Disease (AD) is a severe neurodegenerative brain disorder, with limited therapeutic 
options. The NMDA receptor antagonist, memantine (MEM) is approved for treatment of moderate-to-severe 
AD; its mechanisms are not well understood, but may include a blunting of glutamate-mediated neurotoxicity. 
While meta-analyses confirm MEMs effectiveness in delaying the progression of cognitive and behavioral 
disturbances in AD, the clinical response to MEM is modest, short-lived and highly heterogeneous, with many 
AD patients showing no gains even with an extended MEM trial. The utility of MEM in AD might be greatly 
enhanced if patients could be identified as MEM-sensitive vs. MEM-insensitive in advance of a therapeutic 
trial, using a predictive biomarker.
 
For the past decade, the PI has studied the acute neurophysiological effects of MEM in laboratory 
animals, healthy human subjects (HS) and schizophrenia (SZ) patients. These studies demonstrated that a 
single challenge dose of MEM (20 mg) significantly enhanced specific laboratory measures of early auditory 
information processing (EAIP) in HS and SZ patients: prepulse inhibition (PPI), mismatch negativity (MMN) and 
gamma band auditory steady-state response (ASSR; including gamma power and synchronization). This
application will determine whether the EAIP response to an acute MEM-challenge can be used to 
predict a positive therapeutic response to MEM in patients with mild-to-moderate AD, over a 24 week trial.  
 
Aim 1 tests the hypothesis (H1) that a single dose of MEM (20 mg vs. placebo (PBO)) will significantly 
enhance EAIP measures in patients with mild-to-moderate severity AD (n=88). Assessed across the full cohort 
of patients, PPI, MMN and ASSR should be significantly greater after MEM vs. PBO. However, the magnitude 
of this MEM effect (MEM minus PBO) will vary across measures and patients. Aim 2 will leverage this 
response heterogeneity to test the hypothesis (H2) that patients exhibiting a larger MEM effect on EAIP will 
experience a significantly greater clinical response to MEM, compared to patients with a smaller MEM effect 
on EAIP. After Aim 1 testing, MEM treatment will be initiated and titrated to 10 mg bid in all patients. Clinical 
outcome measures will be assessed at baseline, 8, 16 and 24 weeks. Analyses will determine whether MEM 
effects on EAIP measures (individually, and in composite scores) predict the magnitude of the clinical response 
to MEM in these patients. Moderating factors will be tested, including specific single nucleotide polymorphisms 
known to moderate MEM sensitivity. This application leverages a unique set of empirical laboratory findings 
with MEM to develop a novel biomarker predicting sensitivity to MEMs therapeutic impact in patients with AD.  
Contact PD/PI: Swerdlow, Neal
Project Summary/Abstract
 Page 6

Specific Aims: This application responds to PAR-16-365: Pilot Clinical Trials for the Spectrum of Alzheimers 
Disease..., and its calls for Studies to define and refine the target population and address heterogeneity of 
response identification of specific individuals more [vs.] less likely to benefit from the intervention(s). 
Specifically, this application develops a laboratory-based biomarker that predicts clinical sensitivity to the 
NMDA receptor antagonist, memantine, in patients with mild-to-moderate severity Alzheimers Disease.
Alzheimers Disease (AD) is a severe neurodegenerative brain disorder, with limited therapeutic options. The 
low-affinity, voltage-dependent, uncompetitive NMDA receptor antagonist, memantine (MEM) is FDA-approved 
for treatment of moderate-to-severe AD; its mechanisms are not well understood, but may include a blunting of 
glutamate-mediated neurotoxicity. While meta-analyses confirm MEMs effectiveness in delaying the 
progression of cognitive and behavioral disturbances in AD, the clinical response to MEM is modest, short-
lived and highly heterogeneous, with many AD patients showing no gains even with an extended MEM trial. 
The utility of MEM in AD might be greatly enhanced if patients could be identified as MEM-sensitive vs. 
MEM-insensitive in advance of a therapeutic trial, using a predictive biomarker.
For the past decade, the PI has studied the acute neurophysiological effects of MEM in laboratory animals, 
healthy human subjects and schizophrenia patients. These studies demonstrated that a single challenge 
dose of MEM (20 mg) significantly enhanced laboratory measures of early auditory information processing 
(EAIP) in healthy subjects and schizophrenia patients: prepulse inhibition (PPI), mismatch negativity (MMN) 
and gamma band auditory steady-state response (ASSR; gamma power and synchronization). MEM-induced 
increases in these EAIP measures after one pill provides evidence that MEM is bioactive in cognition-relevant 
brain circuitry; conceivably, such a brain signal might also identify individuals most likely to benefit from 
MEMs therapeutic effects. This application tests whether the EAIP response to an acute MEM-challenge 
can predict a therapeutic response to MEM in patients with mild-to-moderate AD, over a 24-week trial.  
This application has two phases: 1. Biomarker assessment; and 2. Therapeutic trial. Phase 1 will test the acute 
effects of MEM (20 mg po) vs. placebo (PBO) on EAIP measures in 88 carefully characterized patients with 
mild-to-moderate severity AD who are not currently taking AD medications. From this challenge test, a set of 
EAIP MEM sensitivity measures will be derived for each patient. In Phase 2, all patients will begin an open-
label trial of MEM monotherapy, titrated to 10 mg bid, with outcome measures collected after 8, 16 and 24 
weeks of treatment. Medication adjustments are not restricted, and response heterogeneity is anticipated. 
Phase 1 and Phase 2 measures will be used to achieve 2 Specific Aims:
Aim 1. To assess the acute effects of MEM (0 vs. 20 mg) on measures of early auditory information processing 
(EAIP) in patients with mild-to-moderate severity AD. Measures of PPI, MMN and ASSR will be assessed in 88 
individuals with mild-to-moderate severity AD after placebo (PBO) and 20 mg MEM po, in a double-blind, 
randomized order cross-over design. Hypothesis 1: Assessed across the full cohort of patients, PPI, MMN 
and ASSR will be significantly greater after MEM vs. PBO. However, the response to MEM will be 
heterogeneous: the magnitude of this MEM effect (MEM minus PBO) will vary across the dependent 
measures, and across patients, with some patients demonstrating robust increases in EAIP measures after 
MEM, and other demonstrating little response or reduced EAIP performance.  
Aim 2. To determine the ability of MEM-induced alterations in EAIP in AD patients to predict their clinical 
response to MEM. The magnitude of the MEM effect will be calculated for each patient and each EAIP 
measure. MEM treatment will be initiated and titrated to 10 mg bid in all patients. Clinical severity will be 
assessed at baseline, 8, 16 and 24 weeks using the ADAS-cog as a primary measure. Analyses will determine 
whether the MEM effect on some or all EAIP measures moderates the magnitude of the clinical response to 
MEM. Hypothesis 2: Patients exhibiting a larger MEM effect on EAIP measures will exhibit a more robust 
positive clinical response to MEM, compared to patients exhibiting a smaller MEM effect on EAIP measures. 
This hypothesis will be tested empirically for each of the primary EAIP measures, and for regression-derived 
composite scores from multiple EAIP measures. 
Analyses (linear mixed-effects model) will test the hypothesis (H2) that EAIP MEM sensitivity (in Phase 1) 
predicts the clinical response to MEM (in Phase 2). Moderating roles of specific variables on MEM sensitivity 
will be assessed, including demographic/clinical variables, baseline neuropsychological measures and 
genotypes associated with MEM sensitivity or AD. Source localization will identify anatomical substrates 
associated with MEM effects on EAIPs, and enable us to test structure- and circuit-based mediation models. 
In total, this application: 1. identifies measures that detect changes in cognition-relevant circuitry after a single 
pill of MEM in AD patients, and 2. determines whether patients most sensitive to such acute MEM effects are 
ultimately most sensitive to MEMs therapeutic effects, including its ability to delay cognitive decline and 
behavioral disturbances in AD. Developing an acute challenge test to identify MEM-sensitive patients could 
be an important step towards a personalized medicine approach for AD.  
Contact PD/PI: Swerdlow, Neal
Specific Aims
 Page 49

Research Strategy. A. Significance: Alzheimers Disease (AD) is a severe neurodegenerative brain disorder 
affecting about 50 million people worldwide. Its cost to society is well documented (2), as are stories of
suffering among AD patients and their families. Despite significant advances in the identification and 
characterization of mild cognitive impairment (MCI) and pre-MCI risk factors, many millions of individuals will 
continue to manifest the cognitive and behavioral symptoms of AD for the foreseeable future. Even as scientific 
efforts focus increasingly on preventative strategies, both the prevalence of the AD and its negative impact on 
society are expected to rise.  Thus, identifying effective treatments for the cognitive and behavioral 
disturbances of AD is  and will continue to be - of paramount importance. 
Enhancing treatment effectiveness by using predictive biomarkers: Four medications are approved for 
the treatment of AD worldwide: three cholinesterase inhibitors (AChE-Is) and the noncompetitive N-methyl-D-
aspartate (NMDA) receptor antagonist, memantine (MEM) (as well as a combination of an AChE-I + 
memantine). MEM is approved for treatment of moderate-to-severe AD, though it is frequently used in earlier 
stages of AD and even in Mild Cognitive Impairment (MCI) (86). A retrospective analysis of 5200 patients with 
newly diagnosed AD started on monotherapy, MEM was initiated in roughly 16% of these patients, and 1-year 
discontinuation rates and subsequent non-adherence rates were the lowest among all treatments (including 3 
AChE-Is) (4). MEMs mechanisms of action are not well understood, but may include its ability to reduce
glutamate-mediated neurotoxicity (66). While meta-analyses have confirmed that MEM monotherapy reduces
cognitive impairment (3,14,93,119) and behavioral disturbances (40-1) in AD, these salutary effects are 
generally modest is magnitude and duration. Moreover, the clinical response to MEM is highly heterogeneous, 
with many AD patients showing little or no gains even with an extended MEM trial (14).  
Both AD and MCI are heterogeneous in terms of presumed etiologies and symptom profiles (9,11). One way to 
enhance treatment efficacy is to narrow the target population from a broader, heterogeneous patient group to 
more selective "sensitive" clinical subgroups, identified through the use of laboratory-based biomarkers. In this 
approach to precision medicine, biomarkers are used to stratify patients into subgroups for whom a 
medication would be more vs. less likely to be effective. Conceivably, a biomarker predicting MEM sensitivity 
could identify AD patients for whom MEM would be most protective against the progression of cognitive and 
behavioral disturbances; conversely, patients lacking a positive biomarker response might be counseled 
towards other treatments, to avoid the loss of time and resources at a critical phase of illness progression. 
 
This application responds to PAR-16-365: Pilot Clinical Trials for the Spectrum of Alzheimers Disease and 
Age-related Cognitive Decline, and to this FOAs specific calls for Studies to define and refine the target 
population and Studies that address heterogeneity of response identification of specific 
individuals [who] are more likely or less likely to benefit from the intervention(s).  
For the past decade, the PI has assessed the acute neurophysiological effects of MEM, first in laboratory 
animals (107), and then in healthy human subjects (HS) and schizophrenia (SZ) patients (5,65,99,107), with 
the goal of using MEM or related drugs as pro-cognitive interventions in SZ. [Note: no investigators in this 
application have any financial relationship with the commercialization of MEM.] In the past 4 years, supported 
by the NIMH, these studies assessed the effects of acute MEM challenge (placebo (PBO), 10, 20 or 30 mg, 
po) on measures of early auditory information processing (EAIP) and neurocognition in SZ patients and 
HS. Prepulse inhibition (PPI), mismatch negativity (MMN) and gamma band auditory steady-state response
(ASSR) were used as dependent measures because they: 1) are neurophysiological measures of EAIP, i.e. of 
the brains automatic response to a simple sensory event proximal to, or independent of, a point at which it 
engages conscious or volitional processing; 2) are reliable, objective and quantitative; 3) consistently detect 
deficits in neuropsychiatric populations; 4) reflect automatic vs. volitional processes and are relatively 
insensitive to motivational or effort-based artifact; 5) are suited to repeated testing in a cross-over design 
without significant order or carry-over effects, and 6) are each regulated by NMDA activity, with at least some 
evidence for enhanced performance associated with MEM (29,44,107), including the PIs studies demonstra-
AChE-I: acetylcholinesterase inhibitor; AD: Alzheimers Disease; ADAS: Alzheimers Disease Assessment Scale;  
AP: antipsychotic; ASSR: auditory steady state response; EAIP: early auditory information processing;  
GBS: gamma band synchronization; HS: healthy subjects; MCI: mild cognitive impairment; MEM: memantine;  
MMN: mismatch negativity; PBO: placebo; PPI: prepulse inhibition; RON: reorienting negativity; SZ: schizophrenia 
Fig. 1. Schematic showing the 
idealized impact of adding a bio-
marker to a heterogeneous 
population defined by a clinical 
phenotype to enhance the likeli- 
hood of treatment response.  
 = treatment-sensitive patient.    
Contact PD/PI: Swerdlow, Neal
Research Strategy
 Page 50

ting MEM-enhanced PPI in HS (107), and those of others reporting MEM-enhanced MMN (44) in HS. 
Via a placebo (PBO)-controlled within-subject cross-over design, we detected statistically significant effects of 
MEM (20 mg) on PPI, MMN and ASSR (65,99) (Fig. 2A-D). In each case, one pill of MEM significantly en-
hanced EAIP. These changes were not explained on the basis of AP medication interactions, or other factors 
related to treatment or illness chronicity, since similar changes were detected in both patients and HS, as we 
had previously reported in HS with PPI (107), and as others had previously reported in HS with MMN (44).  
This is the first demonstration that deficient PPI, MMN and ASSR in SZ patients  widely viewed to reflect 
fixed, heritable abnormalities in brain mechanisms regulating auditory information processing  can be 
significantly enhanced (i.e. brought significantly closer to normal values) via an acute intervention in chronically 
ill SZ patients. These findings of MEM-enhanced EAIP are novel and important, as they demonstrate
significant plasticity in brain mechanisms that are thought to contribute to core neurocognitive deficits in SZ.
Because EAIP are known to mediate neurocognition and function in these patients (111), in a separate 
application, we hope to use these findings to identify novel therapeutic strategies for SZ and related disorders. 
Ironically, this approach has faced some headwinds, based on a concern that use of an NMDA antagonist in 
SZ patients might lead to symptom exacerbation; this concern persists in peer review despite numerous 
controlled trials and meta-analyses of the use of MEM as an adjunctive therapy in SZ, all showing that it is 
well-tolerated, and most demonstrating clinical benefits (cf. 127). Clearly, this pattern of safety and tolerability 
parallels the clinical experience with MEM in AD populations (37-8). 
Of greater relevance to the development of AD therapeutics, our findings show that it is possible to detect 
robust neurophysiological effects of MEM after a single 20 mg pill. These neurophysiological signals reflect 
the fact that MEM is reaching the brain and acting on neural mechanisms that we know are highly relevant to 
neurocognition (111). Importantly, as with clinical responses to MEM, while the groups show statistically
significant increases in EAIP after MEM, there is heterogeneity in this MEM response, with some HS and 
patients exhibiting robust EAIP increases after MEM, and others showing little change, or even small EAIP 
reductions (Fig. 3). This heterogeneity is critically important to our ability to identify individuals who are more 
vs. less sensitive to MEM effects on EAIP, and by extension, to ultimately using biomarkers to stratify patients 
into subgroups for assessing a differential clinical response to MEM. 
Conceivably, AD patients in whom MEM most readily accesses the brain, and positively impacts 
cognition-relevant brain circuitry as detected by enhanced EAIP, will ultimately be most sensitive to its 
therapeutic effects, including its ability to slow cognitive decline and behavioral disturbances in AD. We 
propose to test this hypothesis in the present application. 
We hypothesize that evidence for MEM sensitivity that identifies an optimal candidate for MEM treatment will 
be provided by gains in EAIP in response to a MEM challenge. This personalized medicine approach 
Fig. 2. Effects of MEM on A: PPI; B: MMN; C, D: ASSR in HS and SZ patients. Patients and HS (ns=42 & 42) were 
tested after 1 pill of either PBO or MEM (10 or 20 mg po; 20 mg shown here) in a double-blind, balanced cross-over 
design. Tests were 7d apart. Compared to HS, patients had deficits in MMN (B) and ASSR (C,D). MEM (20 mg) 
significantly enhanced PPI (99) (A; p<0.04 for 10-120 ms; p<0.01 for 60 ms), MMN (99) (B; p<0.014; stimulus 
mismatch: Duration; Pitch; Combined) and ASSR (65) (C: evoked power, 40 Hz *p<0.025; D: gamma phase locking, 
*p<0.002). An identical test design is proposed for the present study, to identify MEM-sensitive patients with AD. 
Fig. 3. Distributions of MEM effect (MEM (20 mg) minus PBO) on EAIP 
performance, for (L to R): PPI (60 ms), MMN, gamma power and gamma 
coherence, in HS and SZ patients (pooled, since there were no group 
differences in MEM effects). This application tests the hypothesis that AD 
patients defined as MEM-sensitive based on these MEM effects will exhibit a 
superior clinical response to MEM in a 24 week trial. Different criteria for MEM-
sensitivity will be empirically assessed, based on discrete distributional criteria 
(eg. median split) and continuous (linear mixed-effects model) approaches, and 
using individual EAIPs vs. composite (weighted) indices (see text).   
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 %PPI              μV                   μV2                 PLF      
   PPI               MMN          γ Power          γ Coher     
MEM Effect (MEM minus PBO) 
Contact PD/PI: Swerdlow, Neal
Research Strategy
 Page 51

parallels the use of a test-dose to predict clinical benefits from treatments ranging from hormones (7) to anti-
Parkinsonian drugs (34) to bronchodilators (20). Evidence for enhanced EAIP in response to MEM challenge 
suggests that MEM is accessing neural circuitry relevant to neurocognition, and furthermore, that such circuitry 
has yet been spared, and remains plastic and hence a viable target for pharmacotherapy. Conceivably, via this 
approach, in the span of two office visits separated by one week (see Methods) subgroups of AD patients will 
be stratified as MEM-sensitive vs. MEM-insensitive, based on their physiological responses (eg. gain in 
EAIP) to an acute MEM challenge-dose. This personalized medicine approach has been used in other fields
(7,20,34) and attempted for some psychotherapeutics (cf. 19,22), but has not yet been developed for AD.  
B. Innovation: The primary innovation in this application is the development of a clinically feasible test to 
predict sensitivity to the therapeutic response to MEM in AD patients based on the biomarker of MEM-
enhanced EAIP. As described in the PAR, mediators of the therapeutic intervention will also be identified.  
Specifically, we hypothesize and will test in Aims 1-2 that in AD patients, evidence of MEM-enhanced EAIP
will predict a superior clinical response to MEM. Prior to starting a standardized MEM treatment regimen, 
subjects not currently receiving AD medications will be tested to their EAIP response to placebo or a single pill 
of MEM (20 mg). They will then be followed clinically during MEM monotherapy, consisting of a titration to a 
daily dose of 10 mg bid for 24 weeks. Clinical indices will be assessed at baseline, weeks 8, 16 and 24. Clinical 
responses will then be compared across groups stratified by the magnitude of MEM-enhanced EAIP (Fig. 3), 
and the relationships of MEM-enhanced EAIP measures to the magnitude of clinical gains will be tested using 
both discrete (ANOVA) and continuous (linear mixed-effects model) approaches. Secondary analyses will be 
used to optimize criteria for EAIP MEM sensitivity, to determine whether EAIP MEM sensitivity also predicts
the rapidity and durability (in addition to the magnitude) of MEMs clinical benefits, and whether specific 
demographic, clinical and genetic factors moderate the predictive strength of MEM EAIP sensitivity. If our 
hypothesis is supported by these findings, we plan to expand our tests in future applications to include 
combination therapies (MEM+AChE-I) vs. AChE-I monotherapy, and MCI / early AD patients, with the 
prediction that combined regimens (but not AChE-I monotherapy) will also produce superior gains among 
subgroups exhibiting the greatest MEM-enhanced EAIP response. Positive findings in this application may also 
justify tests with other AD therapeutics for which an acute EAIP-based laboratory biomarker is available. 
Summary: Current therapeutics for AD are suboptimal. In particular, clinical response to MEM in AD is variable 
and modest. One strategy to enhance treatment efficacy is to prospectively identify drug-sensitive subgroups, 
based on the presence of predictive biomarkers for drug response (Fig. 1). MEM enhances neurophysiological 
measures of EAIP in healthy subjects as well as patients with SZ (Fig. 2). We now propose to determine if 
greater sensitivity to MEM-enhanced EAIP (Fig. 3) predicts a superior therapeutic impact of MEM in AD 
patients. This application is thus responsive to PAR-16-365, and its specific calls for Studies to define and 
refine the target population and Studies that address heterogeneity of response. 
Measures of EAIP: The 3 measures of EAIP to be used in this application are reviewed below. The clear 
experimental rationale for their use in this present application is that they are known to be sensitive to an acute 
20 mg dose of MEM in both patients and HS, independent of the presence of a disease-related EAIP 
deficiency (Fig. 2 and citations below) or the concomitant use of psychotropic medications. Furthermore, 
inspection of Figure 3 reveals that the distributions of MEM effects on these EAIP measures (MEM minus 
PBO) show inter-individual heterogeneity, which is important if these measures are to serve as biomarkers 
predicting a heterogeneous clinical response to MEM. Measuring these EAIP will enable us to test the 
primary hypothesis of this application. In brief, these measures are:  
1. PPI: PPI is an operational measure of sensorimotor gating (108). In PPI, a weak lead stimulus inhibits the 
magnitude of a startle response to an intense, abrupt stimulus occurring 30-120 ms later (Fig. 4). On average, 
the amount of reflex inhibition caused by the prepulse is reduced in patients with one of several brain disorders
(108); of the 3 reports testing PPI in MCI and AD samples, however, two detected no deficits, and one reported 
mixed results (26,78,89,115). The PI of this application has been instrumental in understanding the 
neurobiology and clinical relevance of PPI, starting with his first contribution to this literature in 1982 (95), and 
continuing in roughly 200 peer-reviewed data papers on these topics. 
Fig. 4. PPI is the automatic inhibition of a startle response to an intense, abrupt 
stimulus or pulse (A. P-Alone, top), when this startling stimulus is preceded by 
a weaker prepulse (A. pp+P, bottom). In our studies, PPI is assessed using 
EMG of orbicularis oculi (blink response). B. At right are two superimposed EMG 
responses to either a P-Alone (solid black) or pp+P (open, white area). The % 
reduction in EMG amplitude produced by the prepulse is the operational measure 
of sensorimotor gating, and is regulated by well-studied neural circuitry (101,108). 


Contact PD/PI: Swerdlow, Neal
Research Strategy
 Page 52

PPI is generally viewed as a measure of automatic, preattentional inhibition (17). It is regulated by circuits
connecting portions of the prefrontal and mesial temporal cortex, with subcortical systems extending from the 
basal ganglia to the pons (101). Drugs acting at prominent nodes in this circuitry have potent effects on PPI
(108). For example, PPI is increased in HS by the NMDA antagonists ketamine (1,15), amantadine (105) and 
MEM (107). We first reported the PPI-enhancing effects of MEM (20 mg po) in HS (107); these findings were 
extended as seen in Fig. 2. MEM (20 mg) significantly increased PPI in SZ patients (Fig. 2A), across 10-120 
ms prepulse intervals; comparable effects were detected in HS at 60 ms intervals, which is a critical sensitive 
temporal window for therapeutic drug effects (103). Interestingly, these potent MEM effects in SZ patients were 
evident despite the fact that, as a group, these patients were not deficient in PPI, consistent with the fact that 
90% were taking PPI-normalizing second generation antipsychotics (SGAPs) (48,103,123).   
MEM effects on PPI are moderated by age and baseline PPI level, but not by AP load, anticholinergic load or 
demographic or clinical variables (5,99). These findings support the strong prediction that PPI will be a potent 
signal of MEM bioactivity in this application  a quantifiable measure of MEMs activity within the brain, and 
specifically within PPI-regulatory circuitry that includes elements relevant to the pathophysiology of AD - and 
might conceivably serve as a biomarker predicting therapeutic response to MEM among AD patients. 
2. MMN is an auditory event-related potential (ERP) component 50-150 ms after a deviant, "oddball" stimulus
is presented within a sequence of repetitive standard sounds (Fig. 5: shown, from mild-to-moderate AD 
patients, n=20 (G. Light)); it reflects the properties of automatic, memory-based comparison processes (cf. 74).
It is rapidly assessed, and while it is highly stable in normal and impaired patient populations across the 
lifespan (63), studies of this form of MMN in AD patients have reported inconsistent results, with many studies 
reporting no differences vs. age-matched HS (21,76-7). MMN is largely automatic and preattentional, yet it is 
strongly associated with neurocognition and psychosocial function, even in HS (64). 
MMN is regulated by forebrain circuitry, and is sensitive to NMDA activity: it is 
disrupted in infrahuman primates by 
PCP (cf. 36), and in HS by ketamine
(23), but is increased in HS by an 
acute 30 mg dose of MEM (d=0.87) 
(44). The PI and Co-PI (Dr. Light) 
have published extensively on MMN 
and its deficits in patient vs. HS 
cohorts (57-8,63-4,84).  
We reported significant MEM-induced increases in MMN in both HS and SZ patients after a single oral dose of 
20 mg (99). As seen in Fig. 2B, compared to HS, SZ patients exhibited MMN deficits (p<0.007). MEM (20 mg) 
significantly increased MMN across both groups (p<0.014); this effect was highly consistent within subjects, 
and across each of 3 different deviant conditions (27). Others report MEM-enhanced MMN in rodent models 
(112), and in HS after 30 mg po (44). 
Exploratory measures of EAIP in this application include P3a and reorienting negativity (RON) (84-5), which 
were root causes of neurocognition and functional outcome in our study of 1415 SZ patients (111). MMN, P3a
and RON are automatically elicited as a 3-peak waveform complex in response to unattended oddball stimuli
(Fig. 5).  MMN is the primary dependent variable based on evidence that it is MEM-sensitive (27,44,112); P3a 
and RON will also be carefully assessed as their sensitivity to MEM has not been previously studied. The P3a 
ERP is thought to reflect the transition from perception and sensory registration to focal attention or orienting to 
the stimulus; RON is thought to reflect reorienting of attention after distraction. Together with MMN, these 
components reflect processes underlying auditory perception, auditory learning and memory and other 
complex cognitive functions (84). MMN, P3a and RON arise from broadly distributed patterns of neural 
activation (85) and are regulated by NMDA activity (88). Thus, it is conceivable that these measures will be 
sensitive to MEM, and that this sensitivity may serve as a biomarker for clinical response to MEM, either as 
stand-alone measures, or in regression-derived composite measures (below). In addition to assessing the 
magnitude of these potential biomarkers, source localization (12-13,109,124) will be used to identify anatom-
ical substrates associated with MEM-induced changes in EAIP in AD patients, as a first step towards
understanding the neural mechanisms underlying the predictive value of these potential biomarkers. Using 
these same source localization strategies, we previously reported that deficits in different ERP components 
(eg. MMN vs. P3a) map onto distinct frontal and temporal regions (39,85); here, we propose to use similar 
strategies to localize sources of MEM-induced changes that best predict clinical response.  
3. ASSR: Synchronous neural oscillations centered at 40-Hz appear to reflect brain resonance that is critical 
for cortico-cortical communication and large-scale integration of distributed neural functions (18,49,71,96,116). 
The automatic entrainment of gamma band oscillations to 40-Hz auditory steady-state stimulation (ASSR) is 
Fig. 5. Mismatch Negativity in AD patients (n=20): 
negative-going ERP component 50-150 ms after a 
sequence of repetitive standard' stimuli (S, 
above) is interrupted by infrequent oddball deviant 
stimuli (above). Also shown: P3a, RON (see text). 
Y-axis: μV; X-axis: ms post-stimulus.  
ms 
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0 
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deficient in SZ (49), even at first episode (96); in contrast, the literature on ASSR in AD patients is inconsistent, 
reflecting a lack of standardized paradigms for eliciting ASSR across these studies (eg. 75,116,118).  Gamma 
oscillations are enhanced by MEM in rodent models (29,67) and by ketamine in both rodents and HS
(31,33,50). Our recent studies (Fig. 2) detected deficits in ASSR gamma evoked power and phase locking in 
SZ patients, that were significantly corrected by MEM. However, MEM-enhanced gamma power and phase 
locking was also detected in HS (Fig. 2C-D) (65). These findings support the strong prediction that ASSR 
metrics will be a potent signal of MEM-sensitivity in this application. The PI and Co-
PI (Dr. Light) have published extensively on the characterization of the ASSR and its 
deficits in patients vs. HS (39,59-62). 
The extant literature does not make a strong prediction regarding levels of baseline EAIP performance 
in AD patients. It is thus important to emphasize that the prediction of MEM-enhancement of these EAIPs in 
AD patients is independent of the presence of any AD-related EAIP deficiency. For example, MEM enhances 
PPI, MMN and ASSR in HS (65,99,101) (who by definition do not have EAIP deficits), and MEM enhances PPI 
in SZ patients whose PPI has been normalized by SGAPs (103,123).  Furthermore, MEM-enhanced EAIP 
was detected in patients despite the presence of a variety of psychotropic medications (including SGAPs) that 
potentially will also be used by the AD patients in this application. Thus, the ability to detect the proposed 
biomarker for MEM-sensitivity in this application should not be impeded by the presence (or absence) of 
abnormalities in baseline EAIP levels or the use of psychotropic medications in the AD patient group. 
High Risk / Low Cost: Genetic biomarker(s)? Cross-species studies report a connection between MEM 
effects and genetic variations in glutamate ionotropic receptor subtypes (GRIN2A, GRIN2D); these variations 
are associated with sensitivity to anticonvulsant effects of MEM (51-2,80). While no SNPs in GRIN2A or 2D 
were tested in our previous studies with MEM, of the 4 SNPs tested, one in GRIN3A (rs1337697) moderated 
MEM effects on both neurocognition and PPI (n=19) (5). Interestingly, other SNPs in GRIN2B (rs10845840) 
and 3A (rs3739722) are reported to be associated with AD (54,97). Based on these findings with GRIN2A 2D
and 3A (51,52,54,80,126), this application will test the potential contribution to MEM sensitivity of functional 
SNPs in GRIN2A, 2B, 2D and 3A (MAFs=0.32-0.43), as a high-risk / low-cost exploratory aim. Assessing 
genetic predictors of a therapeutic MEM response in AD patients responds to PAR-16-365s request to identify 
specific individuals according to genetic profiles more likely or less likely to benefit from the intervention(s). 
Though not part of the primary or exploratory aims, we will also assess APOE genotype (rs7412, rs429358) to 
further characterize MEM-sensitive vs. -insensitive patients. Subjects will be divided in two groups: carrier 
subjects (ε4+) with one or two ε4 alleles, and non-carrier subjects (ε4−) without any ε4 allele. Because we have 
no a priori predictions that these biomarkers will identify MEM-sensitive patients, or moderate the impact of 
EAIP sensitivity on MEM clinical response (but see (53)), analyses assessing such relationships will be 
undertaken only on a post-hoc, exploratory basis. As recommended in this FOA, this application will store 
blood for future genomic and other analyses aimed at interrogating treatment responsiveness... 
C. Approach: This application will test the acute effects of 20 mg MEM (po) on EAIP in patients with mild-to-
moderate severity AD (Mini-Mental State Examination score between 10-22 at screening), and determine 
whether sensitivity to MEM-induced changes in primary EAIP measures predicts the clinical response to MEM 
in these patients over a 24-week trial. The primary clinical outcome measure will be the Alzheimers Disease 
Assessment Scale (ADAS-cog) (87), as described below. Secondary analyses will assess alternate potential 
biomarkers, alternate outcome measures, and moderating roles of specific patient characteristics (including 
genotype), as well as the anatomical localization of the MEM-induced changes in EAIP measures.  
Aim 1. To assess the acute effects of MEM (0 vs. 20 mg) on measures of early auditory information processing 
(EAIP) in patients with mild-to-moderate severity AD. Measures of PPI, MMN and ASSR will be assessed in 88 
individuals with mild-to-moderate severity AD after placebo (PBO) and 20 mg MEM po, in a double-blind, 
randomized order cross-over design. Hypothesis 1: Assessed across the full cohort of patients, PPI, MMN 
and ASSR will be significantly greater after MEM vs. PBO. However, the response to MEM will be 
heterogeneous: the magnitude of this MEM effect (MEM minus PBO) will vary across the dependent 
measures, and across patients, with some patients demonstrating robust increases in EAIP measures after 
MEM, and other demonstrating little response or reduced EAIP performance.  
Fig. 6. ASSR in AD patients (n=20): (γ
power, phase locking (PL)): 40 Hz clicks/ 
tones (left) drive γ power and PL in the 
EEG; this may reflect capacity of the 
auditory system to generate oscillations 
in synchrony with the stimuli. At right, γ 
PL time-frequency plot: x-axis: time in 
ms; y-axis: frequency. Color = PL factors.  
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of 20 clicks 
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Aim 2. To determine the ability of MEM-induced alterations in EAIP in AD patients to predict their clinical 
response to MEM. The magnitude of the MEM effect will be calculated for each patient and each EAIP 
measure. MEM treatment will be initiated and titrated to 10 mg bid in all patients. Clinical severity will be 
assessed at baseline, 8, 16 and 24 weeks using the ADAS-cog as a primary measure. Analyses will determine 
whether the MEM effect on some or all EAIP measures moderates the magnitude of the clinical response to 
MEM. Hypothesis 2: Patients exhibiting a larger MEM effect on EAIP measures will exhibit a more robust
positive clinical response to MEM, compared to patients exhibiting a smaller MEM effect on EAIP measures.
This hypothesis will be tested empirically for each of the EAIP measures, and for regression-derived composite 
scores from multiple EAIP measures.               
Design Overview: The general study design is modeled after that 
employed by Peskind et al. (79) and Pomara et al. (81). These authors 
conducted a 24-week, multi-site placebo-controlled randomized trial of 
MEM monotherapy (10 mg bid) in mild-to-moderate AD, demonstrating 
significant gains in cognitive, global and behavioral measures. The present 
study will differ from that of Peskind et al. (79) in 3 major ways: 1. Patients 
will be characterized at baseline to assess their EAIP response to a MEM 
challenge dose (20 mg); 2. This is a single site study; 3. All patients will 
receive MEM treatment; to test the key hypothesis (H2), analyses will 
compare groups stratified by the magnitude of their EAIP response to 
MEM. Other minor methodological differences will be described below.  
88 AD patients who consent to participation undergo a full neurocognitive 
characterization and medical evaluation.  Patients also receive baseline 
ADAS-cog assessment and secondary outcome measures (described 
below) by Dr. Lisa Delano-Wood (Neuropsychologist; Clinic Director: 
UCSD Memory, Aging and Resilience Clinic [MARC]; Co-I).  
Patients will then be tested in a PBO-controlled double-blind within-subject cross-over study of the effects of 20 
mg MEM po on EAIP measures (PPI, MMN, ASSR). This proposed N is adequate to be stratified into low 
vs. high MEM sensitivity using discrete criteria, eg. median split, for categorical analyses (eg. ANOVA) and to
detect medium effect size (d=0.5) differences in outcome between MEM-sensitive vs. -insensitive patients (see 
"Power Considerations"). Inclusion and exclusion criteria are seen in Table 2. 
Clinical Evaluations: Based on the above inclusion / exclusion criteria, patients will be recruited through: 1) 
the UCSD MARC and Medicine for Seniors Clinic, under the supervision of Lisa Delano-Wood, PhD and Jairo 
Romero, MD (Geriatric Internal Medicine physician; Co-I), (typical clinic flow: 8 new AD patients/week); 2) the 
UCSD ADRC (see below and accompanying letter; typical evaluation of new AD cases = 5/week); and 3) 
community providers within a network affiliated with the UCSD ADRC (eg., Glenner Center; Alzheimers San 
Diego; Southern Caregivers Resource Center). Importantly, this target population is in relatively less research 
demand, based on the current UCSD research focus on MCI and pre-MCI. 
Patients who agree to participate undergo an initial screening session, during which inclusion and exclusion 
criteria are confirmed, patients provide study consent (see Human Subjects) and undergo a full clinical and 
neurocognitive characterization as well as baseline ADAS-cog and secondary outcome measures (described 
below). A structured history is obtained of the onset, course, and nature of cognitive and other symptoms, 
medical history (and review of medical records to investigators by the participant, including copies of clinical 
neuroimaging studies) and system review, family history, documentation of current and past medications.  
After enrollment in the study, the ADAS-cog will be administered under the direction of Dr. David Salmon 
(clinical psychologist; Director of Neuropsychology, UCSD ADRC; see letter). The standard ADAS-cog scores 
range from 0-70; higher scores indicate greater impairment. The validity and factor-derived subscales of the 
ADAS-cog are described in (79). For this study, the ADAS-cog will also have an added delayed recall subtest, 
and will be administered using newly standardized instructions (per D. Salmon). This ADAS-cog administration 
Table 1. Inclusion and exclusion criteria
Inclusion: 1. ADRC-confirmed diagnosis of AD; 2. MMSE score 10-22; 3. Age 50-70 y; 4. Knowledgeable caregiver; 
5. Ambulatory; 6. Medically stable; 7. Audiometric testing (detection < 40 db(A) at 1000 Hz); 8. Informed consent. 
Exclusion: 1. Active systemic illness (eg. heart disease, liver or renal failure, cancer, HIV, tuberculosis, Hepatitis C); 
2. Current psychiatric or neurologic illness other than AD; 3. History of vascular disease, MI, CVA, TIA, seizure, head 
injury with loss of consciousness; substance dependence (including EtOH and Opioid); 4. Past treatment with MEM; 5. 
AChE-I or investigational drug treatment within 30 d of screening; 6. Current medication: amantadine, riluzole, other 
pro-cognitive medication, opioids; 7. Positive urine toxicology for non-prescribed psychoactive substance; 8. Actively 
enrolled in cognitive remediation therapy.
Fig. 7. From Pomara et al. (81). 
MEM (10 mg bid) significantly 
improved ADAS-cog scores after 8-
24 weeks in patients with mild-to-
moderate AD. LS = least squares; 
SE = standard error. Total n = 394.  
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provides the primary baseline (week 0) assessment metric; alternate list versions are used in subsequent 
(week 8-24) tests. Secondary assessment measures are behavioral symptoms documented by the 
Neuropsychiatric Inventory (NPI-Q) and the Geriatric Depression Scale. An RA administers the Clinical 
Dementia Rating (CDR), Montreal Cognitive Assessment (MoCA), Functional Activity Questionnaire (an IADL 
scale), Health & Safety and Managing Money subscales of the Independent Living Scales, and the modified 
Lawton physical self-maintenance schedule (a basic ADL scale). Blood is collected at baseline for exploratory 
genetic biomarkers (described above). A physical examination (≈ 40 min) is performed by a study physician, 
including a neurological examination under Dr. Galaskos direction, and an electrocardiogram (EKG). Unless 
already performed, blood tests will rule out other causes of cognitive impairment (eg., vitamin / metabolic 
deficiencies; endocrine disorders). Audiometric testing ensures that patients detect 40 dB(A) tones at 1000 Hz. 
A comprehensive neuropsychological evaluation is conducted under the supervision of Dr. Lisa Delano-
Wood (≈ 2h; see Human Subjects). This test battery is used to characterize MEM-sensitive vs. -insensitive 
subgroups, and includes sensitive measures of memory (California Verbal Learning Test-II, WMS-IV Visual 
Reproduction Test with delayed recall and recognition, WMS-IV Logical Memory with delayed recall and 
recognition), attention (WAIS-R Digit Span Forward and Backward), language (Boston Naming Test; Letter and 
Category Fluency Tests), problem solving and executive function (modified Wisconsin Card Sort Test, Digit 
Symbol Substitution Test; Trailmaking, Fluency Switching, and Color-Word Interference subtests of the Delis-
Kaplan Executive Functioning System [DKEFS]); constructional and visuospatial abilities (WASI-II Block 
Design Test, Clock Drawing Test, D-KEFS Visual Scanning), and global cognition (Mattis Dementia Rating 
Scale-2). Appropriate normative data are used for all tests (eg., Mayo Older American Normative Studies; 98). 
The number of prior cognitive assessments will be recorded for each subject to ensure that experimen-tal 
groups (MEM-sensitive vs. MEM-insensitive) do not differ in the number of prior assessment exposures. A
follow-up visit with the primary provider is scheduled for approximately 2-3 weeks after screening. All subjects 
are paid after screening, test days and 8, 16 and 24-week follow-ups (see Human Subjects). 
Test Days: Subjects who complete the screening session are scheduled for EAIP Test Days within 7 days. 
Transportation is provided. Urine toxicology is repeated on each test day. Test Days last from 08301600,
much of which is spent relaxing, watching television, reading or eating. In brief, EAIP are assessed as in
(59,99), 210 (PPI) and 345 min (MMN, ASSR) after administration of placebo or MEM (20 mg po), in a 
randomized order double-blind design. Vital signs (VS) and visual analog scale (VAS) measures of subjective 
self-ratings (99) are taken throughout the day. MEM pharmacokinetics are linear for single oral doses of 5-40 
mg; Tmax for a single 20 mg dose is 6.89 h; elimination T(1/2) is 60-80 h (94). Test days are ≈ 1 week apart. 
Intervention: Within 1 week of completing EAIP testing, subjects are seen by their primary provider, for 
initiation of MEM therapy. Many but not all patients will be treated through the UCSD MARC and Medicine for 
Seniors Clinics, where they were recruited. MEM is initiated at 5 mg/d and titrated with 5 mg weekly 
increments. During this time, subjects / caregivers are contacted weekly by study staff to assess adherence.
Intervention Week 1 will begin when dosing reaches 10 mg bid.  
 
  
Outcome measures:  At the end of Intervention Weeks 8, 16 and 24, subjects will be evaluated with the 
ADAS-cog, the NPI-Q and Geriatric Depression Scale.  
Analytic strategy: This study is not designed to test whether MEM monotherapy leads to clinical gains in mild-
to-moderate severity AD: this has already been studied in large, multi-site trials (3,14,79,81). Rather, this 
study will determine whether laboratory-based biomarkers predict which patients will benefit most from a 
therapeutic trial of MEM. This hypothesis can only be tested using patients who complete a nominally 
therapeutic trial. Based on previous findings (Fig. 7), we plan to include in our full analyses all subjects who 
complete at least 8 weeks of MEM monotherapy (10 mg bid). Dose adjustments are permitted during weeks 3-
8, but subjects unable to tolerate 10 mg bid by the end of week 7 will be characterized as incomplete 
C. Test Days a.m. 
830: Brkfst, vital signs, UTox 
900: Pill (PBO or MEM) 
VS q 30 min, VAS q 60 min 
1130: Lunch 
A.≈Day 
Screen Day      1 
Test Day 1        8 
Test Day 2       15 
B. Screen Day 
Consent, Structured history 
Baseline clinical metrics 
Physical exam, EKG, audiometry 
Neuropsychological testing 
D. Test Days p.m. 
VS, VAS contd 
1230: PPI (30 min) 
Break 
1445: EEG (50 min) 
Fig. 8. Schedule: A. 3 sessions over ≈2 weeks. B. Screen Day: C-D. Test Days: Total test time ≈80 min; 
vital signs (VS) and VAS ratings taken all day, and parameters are set to notify the on-site study MD. 
Fig. 9. Study flow chart. Screening, 
testing and dose titration take 5 
weeks. Starting from full dose (10 mg 
bid), ratings are completed at weeks 
8, 16 & 24. Final n = 88.  
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treatment in the final analyses. Importantly, separate analyses will consider incomplete treatment patients,
those who discontinue MEM use or add an AChE-I in testing H2, as described below.   
Detailed Methods: 
Stimulus parameters: The rationale for startle and ERP stimuli reflects both empirical and theoretical
considerations, as discussed in our published reports (99,103). Empirically, these stimuli and session designs 
detect consistent MEM effects on PPI, MMN and ASSR (Fig. 2), and thus afford us the strongest predictions in 
terms of MEM effects in this application. There are also pragmatic considerations specific to each measure; for 
example, weaker pulse intensities generate smaller startle responses, and with the habituation resulting from 
repeated testing (2 test days), this results in an unacceptable number of startle "non-responders. Space does 
not allow a full description of the many such decision points with each measure, which are supported by a rich 
literature and the PIs and Co-PIs > 30 years of published experience.  
Startle and PPI are assessed as in (99), with 42 trials, of 6 types: a 118 dB(A) 40 ms noise (pulse), and pulse
preceded 10, 20, 30, 60, or 120 ms by a prepulse 16 dB over a 70 dB(A) background. Primary measure: MEM 
effect (MEM minus PBO) on mean %PPI with 60 ms prepulse intervals. Total time: 30 min, with clean-up. 
EEG data are continuously recorded from 64 channels using a BioSemi ActiveTwo system with a sampling rate 
of 1 kHz. Subjects are assessed on EEG biomarkers in the same order: MMN/P3a/RON (20 min), ASSR (5 
min). Auditory stimuli are presented at 85 dB SPL via insert earphones. All setup and data acquisition take < 
60 min with breaks. Stimulation, recording and analysis techniques for MMN are as in (57,99), using binaural 
stimulation (1 kHz square wave stimuli, 5 ms rise/fall) with fixed stimulus onset-to-onset asynchrony of 500 ms. 
A pseudorandom sequence of tones, of which 82% are standards (50 ms, 1000 Hz) and 18% are deviants (6% 
per deviant type): duration deviants are 100 ms, 1000 Hz; frequency deviants are 50 ms, 1500 Hz; double-
oddball deviants are 100 ms, 1500 Hz. MMN, P3a and RON metrics are extracted as per (84,99) (primary 
measures: μV at Fz, 135-205 ms, 250-300 ms and 350-450 ms, respectively). For ASSR, gamma evoked 
power and phase locking are assessed in response to 250 1-ms clicks presented in 500-ms trains at a 
frequency of 40Hz, played with an inter-train interval of 1-s, as per (39,49,59). Evoked power (primary 
measure: mean μV2 at Fz (0-500 ms)) and phase locking (primary measure: mean PLF (0-500 ms)) are 
calculated using wavelet transformation of the segmented data across the 30-50 Hz frequency layer, as per
(59). Exact Low Resolution Electromagnetic Tomography Analyses (eLORETA) uses voxel-by-voxel
comparisons to localize significant drug effects on ERP neural sources, as per (109,124).  
Exploratory genetic analyses: Alleles in specific GRIN-2A, -2B, -2D and -3A SNPs are identified in DNA 
isolated from venous blood via RFLP after PCR amplification. Allele frequencies will be compared with
published reports (eg. 126), including our own study (5). The rationale for studying these genes is described 
above, based on their potential impact on MEM sensitivity in humans and animal models (5,52,80), and/or with 
AD (54,97). In addition to GRIN2B (rs10845840) and 3A (rs1337697, rs3739722), specific GRIN2A and 2D 
SNPs will be selected based on available functional and MAF data (eg. 51,52,80,126) and guidance from B. 
Rana, and tested to determine if they moderate either MEM effects on EAIP, or the impact of the "MEM-
sensitive" EAIP phenotype on clinical measures (below). We recognize that glutamate-related genotypes are 
implicated across normal and aberrant cognitive phenotypes; the rationale for interrogating these genes is 
based specifically on empirical findings described above, and otherwise is viewed as "agnostic" to
mechanisms of MEM action or the role of glutamate in the pathology of AD. If data support a moderating role 
for any SNP(s), this information will be viewed in the broader context of potential neurochemical interactions, 
and of glutamate as a moderator of neurocognitive function and dysfunction.   
Statistical Analyses - General Approach: All analyses are conducted in the general linear model and mixed 
model frameworks (32). Consistent with standard recommendations (10), violations of statistical assumptions 
will be identified using statistical tests and diagnostic plots. When appropriate, robust standard errors will be 
Fig. 10. Schematized overview of study design.   
Aim 1 tests EAIP MEM sensitivity in patients with mild-
to-moderate severity AD, in a double blind, within-
subject cross-over design of MEM (20 mg po) vs. PBO. 
The primary result of Aim 1 is a biomarker character-
ization of EAIP MEM-sensitivity for each subject. 
Patients are also screened for baseline outcome and 
neurocognitive measures. In Aim 2, all patients titrate to 
10 mg MEM bid, and outcome measures are collected 
at 8, 16 and 24 weeks. Analytic strategies are then 
used to test the hypothesis (H2) that greater EAIP MEM 
sensitivity predicts greater clinical MEM sensitivity.  
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used to derive test statistics. Outliers will be detected using Cooks distance. Missing data over time will be 
handled by analyzing all available data (assuming data are missing at random) and by using full information 
maximum likelihood estimation, or through multiple imputation of data. Analyses are conducted using R.  
Statistical tests for each hypothesis:  
Aim 1: Repeated measure (Rm)-ANOVAs will determine whether PPI, MMN and ASSR significantly differ after 
MEM vs. PBO (Hypothesis 1). Primary variables for each EAIP, as well as exploratory secondary measures, 
are identified above. Based on a recruited sample of 88 total participants, we will have 80% power to detect 
effect sizes of d = 0.35 (small) using a Bonferroni corrected α = .05/3 (2-tail). Heterogeneity of response will be 
characterized using variance components expressed as intraclass correlation coefficients (ICCs).  
Aim 2: Linear mixed-effects models regressing change in ADAS-cog outcome scores (at 8, 16, and 24 weeks 
vs. baseline) onto a fixed effect of group defined by MEM sensitivity will test the hypothesis that patients 
exhibiting a larger MEM effect on EAIP measures will exhibit a larger positive clinical response to MEM. 
Groups will be defined by a median split of MEM effect (MEM minus PBO) on EAIP. Power was estimated 
using methods described by Hedeker et al. (25) solving for sample size with α = .05 (2-tail), test-retest 
correlations of .50, and 5% attrition at each time point. A sample of 88 total participants provides us with 80% 
power to detect a medium effect of d = 0.50. The primary outcome will be chosen based on effect sizes 
obtained as part of Aim 1. In exploratory analyses, we will also examine group by time interactions using 
orthogonal polynomial contrasts. We will also predict change in clinical outcomes as a function of all four 
candidate biomarkers in order to create an optimal prediction equation. We will perform ROC curve analyses 
using EAIP MEM sensitivity values as continuous variables and predict clinical improvement after MEM as a 
discrete outcome (responders vs. non-responders) in order to determine the clinical utility of this approach 
defined in terms of sensitivity and specificity. Secondary analyses will also be conducted with biomarker 
groups defined as MEM-sensitive vs. insensitive via specific thresholds for EAIP MEM sensitivity.   
Multiple analytic strategies: The critical test of H2 will utilize both continuous and discrete analyses. Treating 
EAIP MEM sensitivity as a continuous variable will enable us to identify moderating factors (i.e. factors 
moderating the relationship between EAIP MEM sensitivity and clinical MEM sensitivity) with greater power. By 
identifying these moderators, and their relative contributions to the biomarker-clinical response relationship, 
this continuous approach will potentially be more informative regarding the mechanisms by which EAIP MEM 
sensitivity is related to MEMs clinical impact. Compared to ANOVA, a linear mixed-effects model is also 
relatively less impacted by missing data. 
Treating MEM sensitivity as a discrete variable will enable us to divide the patient sample via a specific 
threshold, eg. median split, based on EAIP MEM sensitivity (Fig. 3). Exploratory analyses will test more or less 
stringent thresholds, aiming to optimize the positive and negative predictive value of this discrete threshold. 
This approach has the potential practical value of establishing preliminary criteria for distinct MEM-sensitive 
and MEM-insensitive clinical subgroups.  
Secondary / Exploratory Analyses: To test H2, we will examine multiple metrics of EAIP MEM sensitivity:  
1. primary measures from each individual EAIP measure (described above);  
2. secondary composite variable based on these 4 primary measures, generated via multiple regression;  
3. exploratory measures of EAIP: P3a amplitude and RON (described above).  
An underlying premise of H2 is that the neurobiological bases of MEM effects on the Aim 1 EAIP measures 
share some amount of variance, and hence positive and negative predictive value, with the clinical therapeutic 
response to MEM in AD. However, MEM effects on these 4 EAIP primary measures likely reflects its actions on 
(overlapping but) non-identical neural substrates; this is consistent with findings that MEM sensitivities on 
these measures are positively correlated for some (MEM effects on MMN and ASSR (65)) but not other 
measures (MEM effects on PPI and MMN (99)). Which of these primary measures, or composite measure, 
provides the best prediction of MEM effects on AD-relevant neural substrates, and hence provides the best 
prediction of MEMs therapeutic sensitivity, is an important empirical question that we will address in Aim 2.  
Analyses to test H2 will also utilize primary, secondary and exploratory metrics of MEMs clinical effects: 
1. primary outcome measure: ADAS-cog, change from baseline; 
2. secondary outcome measures: NPI-Q and Geriatric Depression Scale (change from baseline);  
3. exploratory outcome measures: ADAS-cog factor-derived subscales (change from baseline) (eg. 81).  
Factors that moderate the relationship of the primary biomarkers (EAIP MEM sensitivity) and clinical outcome 
will also be explored, including: 1. Genetic markers (GRIN, APOE, described above); and 2. Patient 
characteristics (eg. age; past AD medications; baseline (T0) neuropsychological and outcome measures).  
Lastly, we will probe the specific anatomical basis of MEM effects on MMN and ASSR using source locali-
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zation techniques (109,124); conceivably, these analyses will provide information more generally relevant to 
the anatomical basis for MEMs therapeutic actions, i.e. the mediators of the therapeutic intervention, as 
described in this PAR. A simple model for such mediation might be: MEM action on structure X  EAIP 
change  enhanced therapeutic sensitivity, but more complex, circuit-based models will also be explored.  
For simplicity, this application associates greater EAIP MEM sensitivity with an EAIP-enhancing response to 
MEM challenge (eg. EAIP (MEM minus PBO) > median value); this approach is parsimonious because 
arithmetically larger EAIP values are generally associated with positive neurocognitive and functional change 
(21,56,58,64,111). However, one might rationally argue that any significant change in response to MEM 
challenge reflects MEM sensitivity, and thus directionality of the MEM response should not be assumed. 
Thus, while we represent arithmetically larger MEM responses as MEM-sensitive in this application, Aim 2 
analyses (linear mixed-effects model) make no assumptions of directionality; exploratory categorical analyses 
will also define MEM sensitivity based on the absolute change in EAIP amplitude (i.e., positive or negative).  
Important questions related to experimental design and analysis: 
Does Aim 2 depend on Aim 1? What if MEM does not significantly enhance EAIPs in the inclusive group of 
AD patients? While our strong a priori hypothesis is that MEM will significantly increase PPI, MMN and ASSR 
in AD patients, this prediction is based on findings in HS and SZ patients (29,44,65,99,107), and secondarily, 
from findings in rats (107). Conceivably, brain circuitries that mediate the EAIP response to MEM might be 
damaged in AD, and hence MEM effects on EAIP measures may be blunted and not reach statistical 
significance across the inclusive group of AD patients. Importantly, for testing H2, the key outcome of Aim 1 
will be a heterogeneous EAIP response to MEM, since the ability to detect significant moderating effects of 
MEM sensitivity on clinical response in Aim 2 relies on the shared variance between EAIP MEM sensitivity on 
the one hand, and clinical MEM sensitivity on the other. Thus, neither the ability to test H2, nor its importance, 
is diminished by an absence of a statistically significant effect of MEM in AD patients in Aim 1. In fact, a lack of 
MEM response in Aim 1 might be a particularly important (negative) predictor of MEM clinical sensitivity, 
precisely because it reflects AD-related damage to brain substrates required for MEMs therapeutic effects. 
Why test only 20 mg MEM vs. EAIP? The PI has tested the effects of 10, 20 and 30 mg MEM po in HS, and 
10 and 20 mg MEM po in SZ patients. Based on these studies, the 20 mg dose was selected for this 
application, because it produced significant increases in PPI (107) and MMN (44) in HS, and in PPI, MMN and 
ASSR in both HS and SZ patients (65,99) (Fig. 2).  A 10 mg dose of MEM was inactive in all 3 measures of 
EAIP (65,99) and 30 mg was associated with dizziness in HS (107). Thus, there is a strong prediction that a 20 
mg challenge dose will generate a significant effect of MEM on EAIP performance, and thereby confirm that 
the intervention is bioactive. We expect to find that 20 mg MEM (vs. PBO) produces EAIP-enhancing effects 
in AD patients this application; such a replication of our previous findings in HS and SZ patients will allow us 
to most easily interpret the relationship between MEM-induced changes in EAIP and clinical response to MEM 
in AD patients. However, even if no significant effect of MEM on EAIP performance is detected across the full 
AD cohort, it is possible that EAIP MEM sensitivity would still be predictive of a clinical response to MEM in a 
subgroup of patients (eg. those with MEM effects greater than a specific threshold), and that mixed effect 
models would still detect meaningful moderators of MEM clinical sensitivity.   
We will re-evaluate the choice of the 20 mg dose of MEM based on our experience with the first 6 test 
subjects. For example, despite its benign effects in HS and SZ patients (eg. no effect on vital signs; (99)) and 
other patient populations up to a 40 mg po challenge dose (24), it is conceivable that a single 20 mg pill of 
MEM might produce different effects (eg. sedation) in our AD cohort. If this occurs, after discussion with, and 
approval of, our NIA Program Officer, we may reduce the challenge dose to 10 mg MEM: this dose reduc-tion 
would be defensible since the effects of a challenge dose of MEM on EAIP might predict an individual 
patients clinical response to MEM, even if that dose does not significantly enhance EAIP performance across 
an inclusive group of patients. Body weight will also be used to calculate a precise mg/kg dose for each 
subject, for post-hoc correlations with the magnitude of MEM effects on each measure. Ultimately, to make this 
biomarker scalable to clinical practice, it will be important to streamline the challenge dose assessment, and 
to minimize dose requirements; such fine tuning would be the goal of a future application.  
Why test only 20 mg daily as a therapeutic dose? This dose is the one most commonly studied in AD trials 
(40); it has been shown to enhance, and/or slow the decline of, cognition in mild-to-moderate severity AD, 
using the primary outcome measure and treatment duration proposed for this study (3,14,79,81). This dose of 
MEM is generally well-tolerated, and while we anticipate non-serious adverse events (AEs), several large 
studies document that the rate of AEs at this MEM dose is not different from the placebo rate (3,14,40,82).  
Why MEM monotherapy?  MEM is often used clinically in combination with an AChE-I (eg. donepezil). This 
study excludes patients at study entry who are already taking an AChE-I for 3 reasons: 1. We have no 
evidence that the critical biomarkers  MEM-enhanced EAIP responses  will be present in patients who are 
Contact PD/PI: Swerdlow, Neal
Research Strategy
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taking an AChE-I; this would significantly complicate interpreting a negative finding in Aim 1. In fact, studies in 
laboratory animals and HS report complex and drug-dependent effects of AChE-I on each of the Aim 1 EAIP 
measures (27-9,42); 2. MEM added to an AChE-I in mild-to-moderate severity AD has failed to produce clinical 
gains (82); without evidence of positive therapeutic impact in the absence of biomarker stratification, it will be 
difficult to interpret a negative findings in the present study; 3. The mechanistic interpretation of any positive 
findings in the present study will be much more complex if patients are using a combination regimen. 
Nonetheless, we recognize that patients may opt to add an AChE-I to their MEM regimen in the course of this 
study. If this occurs, and patients also remain adherent to MEM, outcome measures will be collected analyzed 
with a grouping structure that distinguishes them from patients who remain on MEM monotherapy.  
Parenthetically, MEM significantly enhanced EAIP measures in SZ patients, despite their use of complex 
medication regimens, including antipsychotics, antihypertensives and anticholinergics (99). This suggests that 
complex medication regimens in AD patients should not obscure the primary biomarker, with the possible 
exception of AChE-Is, which are thus an exclusion criterion.  
Why 24 weeks of treatment? In several studies, MEM benefits vs. placebo in mild, moderate and severe AD 
first become evident by week 8; by week 24, clinical symptoms in MEM-treated patients have typically returned 
to pre-MEM baseline, though their progression is effectively delayed by 24 months, compared to placebo-
group patients (eg. 81). Thus, while our primary analyses will assess whether the clinical response to MEM is 
larger in EAIP-defined MEM sensitive vs. MEM-insensitive patients, a 24-week study should also enable us 
pursue secondary analyses to determine whether MEM-sensitive individuals experience clinical gains from 
MEM that are more rapid or more durable, compared to MEM-insensitive individuals.   
How will we address incomplete (MEM dose < 10 bid) or discontinued subjects? It is possible that the 
proposed biomarkers (eg. MEM-insensitive EAIP) will predict the likelihood to discontinue MEM treatment. All 
subjects who complete T0 outcome measures will be considered valid.  Based on published data (Fig. 7; 
(81)), subjects who complete at least 8 weeks (10 mg bid) will be considered complete, and included in the 
primary Aim 2 analyses. Data from all valid subjects will be used in separate analyses to understand how 
MEM EAIP sensitivity impacts the likelihood to complete the MEM trial, vs. remain at doses < 10 mg bid, 
discontinue MEM or add an AChE-I. MEM costs are budgeted through week 24 for all subjects.     
Why Mild-to-Moderate AD? This application is designed to test the hypothesis that, nested within a 
heterogeneous cohort is a subgroup that will be identified via the proposed EAIP measures as MEM-
sensitive, and that this enriched subgroup will exhibit a strong positive clinical response to MEM (Fig. 1). 
MEM is FDA-approved for use in patients with moderate-to-severe AD; the efficacy of MEM at these middle 
and late stages of AD has been demonstrated in several studies, without the use of predictive biomarkers. 
Testing our hypothesis (H2) will be most feasible in an AD population that is NOT maximally sensitive to MEM. 
At the other extreme, patients with MCI do not appear to benefit from MEM (186); it is likely that in the present 
study design, a low baseline level of symptoms in MCI could obscure a positive clinical response, even among 
a biomarker-defined sensitive subgroup. While MEM is commonly prescribed to patients with Mild-to-
Moderate AD, its benefits appear to be modest among cohorts that are not stratified by predictive biomarkers 
(eg. Cohens d in mild-to-moderate AD at 8 weeks = 0.3 (81)). We are thus proposing to test patients with mild-
to-moderate AD, based on the expectation that such a cohort will include a subgroup of MEM-sensitive 
individuals, and that detecting a clinical response in these patients will be facilitated by the fact that baseline 
symptoms are within a dynamic range, i.e. neither at extreme floor or ceiling levels.  Importantly, MEM is 
FDA-approved for use only in moderate-to-severe AD based on documented efficacy (rather than any 
increased risk of adverse events in mild-to-moderate severity patients). Thus, we anticipate that MEM 
use in Aim 2 will not incur any added risks to the well-being of the study participants. 
Why no control group? Two potential control groups are not included in this design. First, no parallel HS 
group is included to confirm the predicted effect of MEM on EAIP measures during laboratory testing. Because 
such findings in HS have already been reported by our group, and extended in various forms by other groups 
(discussed above), we view a re-replication as unjustifiable in terms of effort or cost, particularly because the 
outcome of HS testing would not directly alter the interpretation of the key results (prediction of clinical 
response in AD patients). Second, no parallel AD treatment group is proposed. Thus, it is conceivable that the 
EAIP response to MEM might reflect a degree of neuroplasticity or other biological characteristic within AD-
relevant brain substrates, that is a general predictor of a positive clinical response to other drugs, eg. AChE-Is, 
rather than a specific predictor of a therapeutic response to MEM. While we considered this possibility, we felt 
that the most cost-effective and biologically parsimonious approach was to test whether EAIP MEM sensitivity 
predicts clinical MEM sensitivity; a positive finding might justify studies in a future application, testing similar 
predictive value in combined regimens (MEM+AChE-I) as well as AChE-I monotherapy.    
FOA-specific information: The use of MEM in AD has been the focus of many large multi-site studies; this 
application will not broadly address MEMs therapeutic role, i.e. its mechanism of action, the role of NMDA in 
Contact PD/PI: Swerdlow, Neal
Research Strategy
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AD pathogenesis, or the predicted optimal disease stage for MEM use. The focus of this application is to test 
the predictive value of EAIP MEM sensitivity on its therapeutic impact in AD. Justification for experimental 
parameters is provided above, including treatment dose, duration and target population; we do not propose 
fundamental studies of MEMs clinical effects, eg. pharmacodynamics, because these are well established, 
though we plan to store blood for future tests of potential predictive biomarkers.  Our plans for future clinical 
development are described briefly above, and include: 1. Tests that include patients using combination 
regimens (MEM + AChE-I); 2. Tests with patients at earlier stages of illness; 3. Tests with other AD 
therapeutics for which an acute EAIP-based laboratory biomarker is available. 
Sex as a biological variable: Sex will be included as a grouping factor in all major analyses; groups will be 
sex balanced as described in Human Subjects. The PI was the first to report sex differences and menstrual 
cyclicity of PPI in HS (102), and some EAIP sex differences may persist into late life (48). No sex differences in 
MEM effects on PPI, MMN (99) or ASSR (65) were noted in our studies (Fig. 2). 
Timeline (Table 2): Screening 114 subjects/57 mo. (2 subjects / mo.) is well within the capacity of our referral 
sources in the UCSD Memory and Geriatric Medicine Clinics, ADRC and affiliated community network 
(cumulative flow >>15 new AD patients/wk). Proposed EAIP testing rate (< 4 tests / mo.) is well within our 
capacity (typical rate 16 tests / mo.). Thus, subject recruitment and test rate should meet the demands of the 
proposed N. EAIP methods are currently in use in our lab, so no new training, equipment or infrastructure is 
needed. At a rate of ≈1.5 completed subjects/mo., we will reach our target in 57 months, leaving 3 months for 
genotyping, data analysis and writing. Interim analyses at ≈6 months will confirm the fidelity of all measures 
and potentially adjust MEM test dose (see above), and at 36 months will guide a future NIA application. 
Key benchmarks of success will include: 1. Recruitment and clinical and neurocognitive assessment of 88 
individuals with Mild-to-Moderate AD (M:F ≈ 44:44). 2. Completion of two days of EAIP testing in study 
subjects, one week apart, in a double-blind, cross-over design using PBO vs. 20 mg MEM. 3. Titration of MEM 
to target dose (10 mg bid). 4. Repeated clinical and neurocognitive assessment after 8, 16 and 24 weeks of 
MEM treatment. 5. Completion of proposed analyses of EAIP and clinical data to test hypotheses, H1 and H2.  
Potential Limitations:  
1. Recruitment: One concern is the possible difficulty 
recruiting sufficient numbers of individuals with mild-to-
moderate severity AD. A strength of this application is its 
intimate ties to active AD clinics and ongoing studies with 
large samples of well-characterized older adults, many of 
who have been diagnosed with AD, through collaborations with the UCSD Memory Clinic and Geriatric 
Medicine Outpatient Clinic, the UCSD ADRC and its affiliated networks throughout San Diego. Recruitment 
needs for this application are ≈ 2 new subjects / mo. (see Timeline and Table 2), with a projected 10% 
attrition at screening, and 5% attrition at each of the subsequent points of study contact (EAIP testing, weeks 
8, 16 and 24), based on past experience and ongoing studies. The target population (mild-to-moderate AD) is 
not a focus of most ongoing UCSD studies, which prioritize MCI and Pre-MCI subjects; thus, availability of AD 
patients for this application will support much higher recruitment needs if attrition exceeds projected rates.    
2. EAIP measures in AD patients: Our published reports of MEM effects on EAIP measures involved HS and 
SZ patients, ages 18-55 (65,99). The present application proposes such measures in patients with mild-to-
moderate severity AD, ages 50-70 y; thus, both diagnosis and age of the proposed cohort differ from our past 
experience, and may present unexpected challenges. Importantly, our laboratory group has published 
extensively on EAIP measures across the full lifespan (eg. ages 18-88: (16)), and in populations with severe 
dementia and behavioral disturbances (eg. Huntingtons Disease (104)), and recently completed a study of 
EAIP measures in 20 patients with mild-to-moderate severity AD (G. Light, PI). Thus, neither the clinical 
symptoms nor age of the proposed cohort should limit the acquisition or interpretation of EAIP measures. 
3. Expertise: The PI was Co-Director of the UCSD GHPP Clinic for 10 years (serving patients with Hunting-
tons Disease (HD) and Hereditary Ataxias), and has been a clinically active Board Certified Psychiatrist for 24 
years. While he has never had a primary role in AD clinical research, the PI brings to Aim 1 over 30 years of 
studies of EAIP measures, including studies of MEM effects on EAIP measures in rodents, HS and patients 
with SZ, and EAIP studies in patients with HD, Tourette Syndrome and other brain disorders (100,104). He has 
published extensively on the development, validation, interpretation and conceptual implications of EAIP meas-
ures as biomarkers in HS and patient populations (cf. 60-3,108). Importantly, the PI has assembled a team 
with expertise in AD, its assessment and treatment, and the conduct of clinical trials in AD. This team includes 
active Co-Is of Drs. Greg Light, Michael Thomas, Lisa Delano-Wood and Jairo Romero, who collectively have 
significant expertise in these areas (see Biosketches) as well as the active collaboration of the leadership of 
the UCSD ADRC (Drs. Galasko and Salmon) and ADCS (Drs. Oltersdorf and Huisa-Garate) (see Letters).  
Table 2. Projected screening and completion n 
Study Month 
12 
24 
36 
48 
 57 
Screen  
24 
48 
72 
96         114 
EAIP Tests 
21 
43 
64 
86         103 
Wk 8  measures   20 
40 
60 
81           98 
Wk 16 measures 19 
38 
57 
77 
 93 
Wk 24 measures 18 
36 
54 
73 
 88  
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Research Strategy
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Protection of Human Subjects
(1) The final subject population for the present application will include approx. 88 adults, ages 50-70, 
carrying a diagnosis of AD, mild-to-moderate severity (based on a Mini-Mental Status Examination 
(MMSE) score of 10-22. Rationale for selection of this level of AD severity is discussed in the 
Research Strategy. The representation of males and females will be roughly equal; sample size is 
based on power analyses described above. We anticipate that, in order to complete testing in 88 
subjects, we will need to "consent" and screen approximately 114 subjects; the remaining subjects will 
be excluded based on specific screening results, or self-initiated study withdrawal. 
Subjects are recruited through: 1) the UCSD MARC and Medicine for Seniors Clinic, under the 
supervision of Lisa Delano-Wood, PhD and Jairo Romero, MD (Geriatric Internal Medicine physician; 
Co-I), (typical clinic flow: 8 new AD patients/week); 2) the UCSD ADRC (see below and 
accompanying letter; typical evaluation of new AD cases = 5/week); and 3) community providers 
within a network affiliated with the UCSD ADRC (e.g., Glenner Center; Alzheimers San Diego; 
Southern Caregivers Resource Center). Subjects are only approached for study participation if they 
express an interest in initiating MEM therapy to treat their symptoms of AD, they have not previously 
been treated with MEM, and they are not currently taking another medication for that purpose.  
In essence, for a patient who has decided to initiate a trial of MEM for treatment of their AD 
symptoms, this study involves the following added steps of: 1) a thorough screening evaluation; 2) 
Test days 1 and 2, for EAIP measures; 3) weekly calls by the Study Coordinator once MEM treatment 
is initiated, to assess adherence and off-target effects, and 4) three 2-hour symptom assessments 
(weeks 8, 16 and 24). Otherwise, once MEM titration has begun, all decisions regarding MEM use are 
made solely to address the clinical needs of the patient, based on the assessment of the treating 
physician. This use of flexible, individualized dosing and real life conditions to gauge MEM effects 
emulates features of a pragmatic clinical trial (PCT).
Screening assessments will exclude subjects for current substance abuse or history of other 
significant medical illness (e.g. cancer, diabetes, heart disease, HIV, seizures), open head injury or 
closed head injury with loss of consciousness > 1 min, or hearing impairment. A screening physical 
examination (with laboratory measures as needed) is conducted by a licensed physician to rule out 
significant medical illness, including EKG abnormalities and positive urine toxicology findings of 
recreational drugs. Audiometric testing is used to carefully assess hearing in all subjects, with strict 
exclusion criteria. These rigorous screening measures have been applied towards the testing of AD 
patients through the UCSD ADRC for decades. Appropriate subjects are scheduled to come to the 
UCSD Medical Center, Clinical Teaching Facility (CTF); once at the CTF, the study is described 
again. Females of childbearing potential will undergo a urine pregnancy test to rule out pregnancy; 
urine toxicology, and pregnancy testing in females, will be repeated in each subsequent visit for these 
patients. Payment is $15/hour: $60 for the Screen Day (approx. 4 hours), $120 for Test Day 1 
(approx. 8 h) and $120 for Test Day 2 (approx. 8 h), and $30 for clinical assessments (weeks 8, 16, 
24: approx. 2 hours). This payment is required to maintain subject flow and thereby avoid cost-
ineffective down time.  Study medications are provided through 24 weeks at the maximum proposed 
dose (10 mg bid). Subjects and their caregiver will be driven to and from Test days 1 and 2 at the 
UCSD Medical Center by an established patient transportation service, at no cost. 
(2) Records and data will be rigorously protected, as described below. Historical and questionnaire 
data and EAIP measures will be obtained; urine will be obtained for toxicological analysis as part of 
the subject exclusion process. Blood will be obtained by venopuncture for determination of the 
subjects' GRIN2A, 2B, 2D and 3A polymorphisms, and genotypes of APOE. Each subject is assigned 
a unique identification code and all data are entered into our database under this code number in 
order to protect privacy. The hard copy of the data (i.e., forms and source documents) is kept in a 
locked file in a secure room with access limited to study personnel. Medical information is made 
available to the subject's physician upon written request for release of information. 
Contact PD/PI: Swerdlow, Neal
Protection of Human Subjects
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(3) Subject recruitment and informed consent procedures follow the PIs established methods, 
approved by the UCSD Human Subjects IRB. In all cases, fully informed consent is obtained by a 
trained technician or the PI or Co-PIs (Drs. Romero or Delano-Wood), and the PI will be directly 
available to clarify questions. Signed and witnessed consents are kept on file with other subject data. 
The UCSD IRB has authorized no waivers or modifications of normal procedures.  
(4) Potential risks are minimal. Methods for MEM administration for EAIP testing have already 
been vetted and approved by an NIH clinical trials review committee (ITVA) for use in PIs 
studies in HS and SZ patients from MH093453 and MH94320. The rating scales and 
questionnaires are innocuous. Neuropsychological testing is standard for these research clinics and is 
not burdensome to patients or caregivers; it includes: the Clinical Dementia Rating (CDR), the 
Montreal Cognitive Assessment (MoCA), Functional Activity Questionnaire (an IADL scale), the 
Health & Safety and Managing Money subscales of the Independent Living Scales, and the modified 
Lawton physical self-maintenance schedule (a basic ADL scale).   
Startle and electroencephalographic testing exposes subjects to the application of skin tape 
electrodes and to brief loud sounds, which in >25 years of testing have caused no side-effects. 
Alternative measures have been considered; the selection of these specific EAIP measures reflects 
the significant advantages of applying towards these studies the substantial body of information 
generated by > 25 years of systematic studies of the startle reflex, MMN and ASSR in humans and 
laboratory animals. The drug (MEM) at the single dose (20 mg) in this proposal for EAIP testing 
carries a very small risk of toxicity or adverse effects. Based on our substantial experience with this 
and higher doses (170,178), and experience of others using 40 mg as a challenge dose (24), 
adverse reactions are not likely; such effects should be identified in initial tests, permitting dose 
reductions for subsequent tests. The only subjective effect associated with the 20 mg dose in healthy 
subjects (178) was a small increase in self-rated happiness; a similar trend was detected in SZ 
patients (170), with no other subjective effects detected.  No significant effects of MEM (20 mg) were 
detected on heart rate or blood pressure in our past studies with HS or SZ patients (170); this includes 
SZ patients who were in their early 50's, with complex medication regimens (typically 4-5 different 
medications, including 2-3 psychotropic meds, antihypertensives, a diuretic and an oral 
hypoglycemic), and the typical stigmata of the illness that include metabolic syndrome, hypertension, 
tobacco dependence and its accompanying medical sequelae. Alternative drugs have been 
considered, and the proposed drug was selected, based on: 1) existing data with this drug, dose and 
measures; 2) its effects on specific neurochemical substrates being investigated; 3) its lower 
likelihood of producing toxicity or significant side-effects, compared to other drugs with related 
pharmacological properties. 
The target MEM dose (10 mg bid) for Aim 2 is standard in terms of clinical use (see Research 
Strategy). MEM has been carefully studied in >120 NIH clinical trials (ClinicalTrials.gov). Its 
cumulative clinical sales exceed 1 billion dollars, with over 1 million prescriptions written, with an 
outstanding safety record (66,69).  
(5) The overall risks of this proposal are small. MEM will not be administered to subjects in whom it is 
contraindicated. Aim 1 studies will be conducted at the UCSD Medical Center, under the direct 
supervision of a licensed physician. To address the potential for MEM to produce changes in heart 
rate or blood pressure, all subjects vital signs will be carefully monitored, and subjects will not be 
released from the laboratory until their vital signs are within normal limits. To address the possible 
side effect of somnolence, subjects will arrange for their transportation from the hospital on test days. 
All women of child-bearing potential will 1) be tested in early follicular phase; 2) have negative urine 
pregnancy tests at each visit, and 3) agree to utilize double-barrier contraception throughout the 
duration of study participation. If a female of childbearing potential becomes pregnant during the 
study, the subject will be exited from the study. The investigator will determine whether the subject 
was exposed to active study drug or placebo, and notify the subject of this information (see also 
"Inclusion of Women and Minorities"). Drugs will be dispensed by a licensed physician or pharmacist, 
and a licensed physician will be present on the premises at all times during testing to assess and 
address potential adverse drug effects, and if needed, to administer medical assistance to the test 
Contact PD/PI: Swerdlow, Neal
Protection of Human Subjects
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subject. MEM effects on PPI, MMN and ASSR performance have been studied in > 120 HS and 
patients in the PIs laboratory without a single adverse event. Protection of subject confidentiality and 
privacy will be rigorously guarded by the assignment of coded numbers to each file in the computer 
analysis and database. The PIs UCSD psychophysiology research group has studied over 5000 HS 
and patients without any problems with confidentiality.  
The dose selected for use in these Aim 2 studies is the most common therapeutic dose for MEM 
when used clinically, and the proposed titration in 5 mg increments is also standard practice with 
MEM.  Clinical care will be managed by the patients usual physician; medication adjustments  
including dose of MEM, and addition of other medications  will not be altered by study participation. 
MEM is FDA-approved for use only in moderate-to-severe AD based on documented efficacy (rather
than any increased risk of AEs in the mild-to-moderate severity patients), and its use in mild-to-
moderate severity AD is standard practice in the community. Thus, we anticipate that MEM use in Aim 
2 will not incur any added risks to the well-being of the study participants. 
(6) It is anticipated that the proposed studies will yield important, new information about a new clinical 
intervention of direct relevance to several neuropsychiatric disorders. Thus, these studies have a 
significant potential for providing major gains in our understanding of the basis and optimal treatment 
strategies for a disorder (AD) that is severe and common. Because subjects in these studies will not 
be treated differently on the basis of their Aim 1-identified EAIP biomarkers, this information will not be 
of direct benefit to them. Nonetheless, due to the prevalence of AD in our community, it is anticipated 
that AD subjects will benefit indirectly - through a cascade of familial and societal benefits - from the 
information generated by these studies. Furthermore, based on their awareness of the potential 
importance of this work to their community, all subjects will benefit in areas of self-esteem and self-
understanding. Information from physical examinations, and screening measures, may also be of 
direct benefit to test subjects. The overall risks of the proposed studies are low, as described above. 
Thus, on balance, the risk/benefit ratio of the proposed studies is very low. 
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Data and Safety Monitoring Plan and Board:  
 
1. The Data Safety and Monitoring Plan (DSMP) for this application is commensurate with the low
risks and complexity of this study.   
 
It is important to note that the pragmatic treatment phase of the proposed study includes the 
following features, which in some cases obviate the typical role of a DSMB: 
 
1. All subjects receive treatment with the same FDA-approved treatment for AD 
(memantine (MEM)) using a dose titration schedule that is consistent with common clinical 
practice. Thus, the treatment phase is not blinded, and thus there is no opportunity to utilize 
a DSMB for purposes related to study blinding or unblinding; 
2. All adjustments to MEM dose and other medications are done by the treating physician, 
based on the clinical needs of the patient, and are not constrained by experimental 
design; 
3. No placebo control or other patient comparison group is utilized: analyses rely on 
groups distinguished by biomarkers identified prior to initiation of MEM therapy; 
4. The study is not designed to test the therapeutic benefits of MEM in AD per se, as this 
issue has already been repeatedly addressed in large, multi-site clinical trials. 
 
 
While the proposed therapeutic intervention is not experimental, and has had longstanding FDA 
approval in AD, this application nonetheless meets NIH criteria for a Clinical Trial, defined in Notice 
of Revised NIH Definition of Clinical Trial. Thus, a DSMP is described below, and a DSMB is 
available through faculty within the UCSD ADCS. Plans for implementing this DSMB, should this 
application be funded, are described below and in a supportive letter from the ADCS faculty 
(attached). 
 
Potential Risks
 
The potential risks to study participants include: 
 
1. Venopuncture:  During the initial assessment phase, blood will be collected for assessing patients 
health status, and for study-related genetic markers. With any venopuncture procedure, there may be 
temporary slight discoloration of the skin. 
 
2. Aim 1 test dose of placebo or MEM, 20 mg po: The drug (MEM) at the single dose (20 mg) in this 
proposal for EAIP testing carries a very small risk of toxicity or adverse effects. Based on our 
substantial experience with this and higher doses (99,107), adverse reactions are not likely; such 
effects should be identified in initial tests, permitting dose reductions for subsequent tests. The only 
subjective effect associated with the 20 mg dose in healthy subjects (107) was a small increase in 
self-rated happiness; a similar trend was detected in SZ patients (age range: 18-55) (99), with no 
other subjective effects detected.  No significant effects of MEM (20 mg) were detected on heart rate 
or blood pressure in our past studies with HS or patients (99). Significantly higher challenge doses of 
MEM have been studied in other patient populations without adverse effects (eg. 40 mg po (24)). 
Alternative drugs have been considered, and the proposed drug was selected, based on existing data 
with this drug, dose and measures, including its effects on specific biomarkers being investigated. 
Subjects will be driven to and from test days by an established patient transport service, at no cost. 
 
3. Aim 1 electroencephalographic (EEG) and electromyographic (EMG) measures: EEG and EMG 
testing exposes subjects to the application of skin tape electrodes and to brief loud sounds, which in 
>25 years of testing have caused no side-effects. Alternative measures have been considered; the 
selection of these specific EAIP measures reflects the significant advantages of applying towards 
these studies the substantial body of information generated by > 25 years of systematic studies of the 
startle reflex, MMN and ASSR in humans and laboratory animals.  
 
4. Aim 2 titration and ongoing treatment with MEM: The dose selected for use in these Aim 2 studies 
is the most common therapeutic dose for MEM when used clinically, and the proposed titration in 5 
mg increments is also standard practice with MEM. Importantly, this dose and titration schedule is not 
associated with adverse event rates in excess of placebo rates in several large AD studies (eg. 3). 
Clinical care will be managed by the patients usual physician, with medication adjustments  
Contact PD/PI: Swerdlow, Neal
Data Safety Monitoring Plan
 Page 65

including dose of MEM, and addition of other medications  unaffected by study participation. MEM is 
FDA-approved for use in moderate-to-severe AD, and its use in mild-to-moderate severity AD is 
standard practice in the community.  
 
Potential Benefits
 
The potential benefits to study participants include: 
 
1. A thorough diagnostic assessment to identify alternative, potentially treatable etiologies of cognitive 
decline. 
2. Careful symptom monitoring at weeks 8, 16 and 24 of MEM treatment might identify clinically 
relevant changes in symptoms. 
3. Because subjects in these studies will not be treated differently on the basis of their Aim 1-identified 
biomarkers, this information will not be of direct benefit to them. Nonetheless, due to the prevalence of 
AD in our community, it is anticipated that AD subjects will benefit indirectly - through a cascade of 
familial and societal benefits - from the information generated by these studies. Furthermore, based 
on their awareness of the potential importance of this work to their community, all subjects will benefit 
in areas of self-esteem and self-understanding. Information from physical examinations, and 
screening measures, may also be of direct benefit to test subjects. 
 
Adverse Event (AE) and Serious Adverse Event (SAE) Monitoring and Reporting 
 
AE and SAE Monitoring:  
 
Aim 1: For EAIP testing, subjects are monitored during their study sessions at the UCSD Medical 
Center, as described in Research Strategy. While on the premises during the remainder of the 
screen day and both testing days, subjects are accompanied by a trained laboratory assistant, who 
regularly inquires about their subjective well-being and is trained to observe subjects for any changes 
in behavior; the protocol calls for the on-site covering MD to be notified if the subject either complains 
of discomfort or is noted to have a change in behavior. Both vital signs (heart rate, blood pressure) 
and subjective ratings (visual analog scale) are obtained at regular intervals on test days; the protocol 
calls for the covering MD to be notified if vital signs fall outside of established parameters. Subject are 
not discharged from the test days until their vital signs are within parameters established within the 
IRB-approved protocol.   
 
In tests using this identical design with over 100 subjects to date in our laboratory, including this drug 
and dose (or higher dose), there has not been any adverse changes in behavior or vital signs in any 
test subject.  
 
Aim 2: Primary and secondary outcome measures will be assessed at study weeks 8, 16 and 24 at 
clinic visits, including the ADAS-cog, the Neuropsychiatric Inventory (NPI-Q) and the Geriatric 
Depression Scale. 
 
2. Frequency of monitoring, including any plans for interim analysis and stopping rules (if applicable). 
 
Aim 1: Monitoring can theoretically occur at different frequencies, based on circumstances. Vital signs 
and visual analog scales (VAS) data of subjects subjective states are assessed approximately hourly 
throughout the test day. In the event that the covering MD is contacted by the study technician and 
deems it necessary, the subject will be examined immediately. A protocol is established for contacting 
the study pharmacy and unblinding the MD to the study drug if viewed as necessary by the study MD. 
In the absence of an AE, the results of each test are monitored by the PI within one week of testing, 
during weekly laboratory meetings. More generally, as described in the Research Strategy, interim 
analyses of study results are planned as described below.  
 
Aim 2: Subjects will be treated by their primary physician, who will make all medication adjustments 
according to the clinical needs of the patient. Patients will be contacted weekly by the Study 
Coordinator to confirm and record medication adherence. Scheduled monitoring for primary outcome 
measures will be conducted by the Study Coordinator / RA at 8, 16 and 24 weeks; at that time, the 
Study Coordinator will also record any changes in MEM dose or addition of other medications, and the 
reasons for such changes.  
Contact PD/PI: Swerdlow, Neal
Data Safety Monitoring Plan
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3. The process by which Adverse Events (AEs), including Serious Adverse Events (SAEs) will be 
managed and reported as required: 
 
Aim 1: In the acute presentation, any AE or SAE is managed first by the study technician, per our 
existing IRB-approved protocol. The on-site study MD is contacted immediately, and personally 
assesses the subject to determine the appropriate management; because the laboratory is located at 
the UCSD Medical Center, approximately 50 yards from the UCSD Medical Center Emergency Room, 
subjects can be escorted to this facility for evaluation and management in the event of a more serious 
AE.  
 
Aim 2: During the treatment phase, patients will be monitored primarily by their treating physician and 
will be instructed to follow all recommendations of the primary physician in the context of clinical 
deterioration, including AEs and SAEs. In addition, patients will be contacted weekly by the Study 
Coordinator as described above, and any concerns related to the patient well-being  and specifically 
any increased symptoms of depression or suicidality - will be reported to the PI, who will contact the 
patient, caregiver, and if warranted, the treating physician.  
 
In the aftermath of an AE or SAE (or any other unexpected event), the PI will contact the UCSD IRB 
by phone, and (in the event of a non-acute event) via submitting a written report to our eIRB service. 
The UCSD IRB and Research Compliance Program decision tree for reporting procedures is found 
at: https://irb.ucsd.edu/Decision_tree_UPRs.pdf 
 
Reporting of AE or SAE to other agencies, including the OBA and FDA, is accomplished as directed 
by the UCSD IRB, and described in UCSD Human Research Protections Program IRB Standard 
Operating Policies and Procedures Reporting Adverse Events and Unanticipated Problems. Section 
3.13 ; Version Date: 3/21/2017. Specifically,  
 
The Director, Human Research Protections Program, is responsible for reporting  
unanticipated problems involving serious risks to subjects, instances of serious or  
continuing noncompliance with regulations or committee requirements, and any  
suspension or termination or committee approval, to the US Food and Drug  
Administration, OHRP and appropriate institutional officials, in compliance with  
guidance provided by federal regulations and University policy.  
 
4. The individual(s) or group that will be responsible for trial monitoring and advising the appointing  
entity.  
 
Given the low risk and complexity of this trial, the default approach is that the PI will responsible for 
trial monitoring and advising the appointing entity. This DSMP is consistent with our existing 
approved omnibus UCSD IRB protocol for human psychophysiological studies, and will be 
confirmed with our UCSD IRB in advance of enrolling any R01 study subjects for this renewed 
application.
However, as noted below, Drs. Tilman Oltersdorf and Branko Huisa of the UCSD ADCS are available 
to serve as DSMB Safety Specialist and Medical Monitor, respectively, for this study, should NIA 
program determine that a DSMB is required for this project. 
 
Protection Against Study Risks 
 
All subjects are carefully screened to rule out significant medical illness, and MEM is not administered 
to any individual for whom it is contraindicated. In Aim 1, subjects receive a single pill of MEM (20 mg) 
prior to laboratory testing, and all dependent measures are experimental rather than health-related 
per se. As described in Protection of Human Subjects, The MEM dose (20 mg) is a standard daily 
dose for clinical use. MEM has been carefully studied in >120 NIH clinical trials (ClinicalTrials.gov). Its 
cumulative clinical sales exceed 1 billion dollars, with over 1 million prescriptions written, with an 
outstanding safety record (35). In clinical trials in AD patients, with a daily dose of 20 mg, MEM is not 
associated with increased risk for serious adverse events; non-serious adverse event rates do not 
generally exceed placebo levels, and are described in Protection of Human Subjects. Based on our 
substantial experience in acute drug challenge studies with 20-30 mg of MEM (99,107), adverse 
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Data Safety Monitoring Plan
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reactions are not likely; such effects should be identified in initial tests, permitting dose reductions for 
subsequent tests. The only subjective effect associated with the 20 mg dose in healthy subjects (107) 
was a small increase in self-rated happiness; a similar trend was detected in schizophrenia patients 
(up to age 55) (99), with no other subjective effects detected.  No significant effects of MEM (20 mg) 
were detected on heart rate or blood pressure in HS or patients (99). Higher (40 mg) oral doses 
produced no adverse effects in other reports (24). 
 
Also as described in Protection of Human Subjects, Startle and electroencephalographic testing 
exposes subjects to the application of skin tape electrodes and to brief loud sounds, which in >25 
years of testing have caused no side-effects. 
 
Importantly, all study-related assessment and testing is conducted in a safe, hygienic environment by 
experienced clinicians and laboratory staff. Supervising investigators and staff have many years, and 
in some cases decades, of experience with the proposed measures in clinical populations. 
 
Aim 2 involves treatment of all subjects with MEM monotherapy, in a manner (titration rate, final dose) 
that is common practice in clinical settings. This medication regimen has had longstanding FDA 
approval for use in moderate-to-severe AD; its use in mild-to-moderate severity AD as proposed here 
is both common community practice, and has been the focus on many large, multi-site studies (eg. 
3,14,40-1,79,81,86). There is no placebo control group or blinding during this phase, and no 
restrictions on medication adjustments based on clinical need, and thus none of the 
procedures are viewed to carry any added experimental risk beyond that encountered in 
standard community clinical practice. Events that would preclude a participant from continuing with 
the intervention are based entirely on the clinical judgment of the patients physician in consultation 
with the patient. There are no constraints on this process imposed by the study design. Subjects who 
finish baseline (T0) and biomarker (Aim 1) testing will be considered valid, and subjects who finish 8 
weeks of MEM treatment and week 8 outcome measures will be considered complete. 
 
Informed Consent Process: Informed Consent is conducted according to standard ADRC protocol, 
supervised by Dr. Delano-Wood. The consent process informs a subject about the study, indicates the 
participation is voluntary and he/she has the right to stop at any time. Risks are enumerated in the 
informed consent form and described orally during the consent process. The PI has successfully 
conducted Informed Consent with study subjects for over 25 consecutive years of NIH-funded studies. 
INTERIM ANALYSIS 
Interim analyses after 6 subjects will assess visual analog scales for subjective drug effects during 
Aim 1 and potentially adjust MEM test dose as described in the Research Strategy should 
unanticipated effects (e.g. sedation) be evident. Interim analyses of Aim 1 biomarker data at § 6 
months (expected n=18) will confirm the fidelity of all EAIP measures, and at § 36 months (expected 
n=54) will guide a future NIA application. Because the critical test of H2 does not involve an 
absolute magnitude of clinical change in the subject group, or even a statistically significant 
group change, there are no plans to stop the study based on an interim analysis 
demonstrating either outcome. 
DATA AND SAFETY MONITORING  
The Principal Investigator (PI) will be responsible for ensuring participants safety on a daily basis. As 
a single-site, minimal risk clinical trial, data and safety monitoring will be accomplished by a Safety 
Officer (SO): either Tilman Oltersdorf MD, Director, Medical and Safety Core of the UCSD ADCS, or 
Branko Huisa MD, ADCS Medical Monitor, unless instructed otherwise by NIA Program (see letter 
attached). The SO will act in an advisory capacity to the NIA Director to monitor participant safety, 
evaluate the progress of the study, to review procedures for maintaining the confidentiality of data, the 
quality of data collection, management, and analyses.  To accomplish this, the SO will conduct annual 
reviews of all safety reports, study procedures, and test results as summarized in annual NIA 
Progress Reports.  
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Data Safety Monitoring Plan
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Frequency of Data and Safety Monitoring  
The PI will be informed of serious adverse events as soon as they occur and will notify the NIA and 
Safety Officer within 24 hours of notification. The PI and Safety Officer (SO) will meet annually, either 
in-person or by teleconference call to review study progress, data quality, and participants safety. 
Safety reports are sent to the SO annually and will include a detailed analysis of study progress, data 
and safety issues. 
Content of Data and Safety Monitoring Report  
The content of the data and safety monitoring report will include: study status, recruitment records, 
participant descriptive information, safety information, study data.  
Proposed Safety Officer (see letter attached): Tilman Oltersdorf MD, Director, Medical and Safety 
Core of the UCSD ADCS, or Branko Huisa MD, ADCS Medical Monitor.  
Conflict of Interest for SO 
The SO has no direct involvement with the study investigators or intervention. The SO will sign a 
Conflict of Interest Statement which includes current affiliations, if any, with pharmaceutical and 
biotechnology companies (e.g., stockholder, consultant), and any other relationship that could be 
perceived as a conflict of interest related to the study and / or associated with commercial interests 
pertinent to study objectives.  
Protection of Confidentiality  
Data will be presented in an anonymized manner in meetings with the SO and in reports to the SO; 
data and discussion are confidential. Participant identities will not be known to the SO. 
 
The Data and Safety Monitoring Board (DSMB) is an independent group of UCSD experts 
established through our UCSD ADCS, based on a Data and Safety Monitoring Plan (DSMP) specific 
to a clinical trial application. The DSMB will operate under a charter, according to NIA guidelines 
(https://www.nia.nih.gov/research/dgcg/clinical-research-study-investigators-toolbox/data-and-safety-
monitoring). 
 
Aim 1 of this application is an experimental medicine study rather than a phase-associated clinical 
trial per se, and while it meets the NIH definition of clinical trial via the involvement of humans, the 
study endpoints are experimental rather than health-related measures. Aim 2 of this application 
involves an open trial of an FDA-approved medication, in a manner that is common practice in the 
community; as noted above, there is no proposed placebo control group or blinding during this phase, 
and no restrictions on medication adjustments based on clinical need, and thus none of the 
procedures are viewed to carry any added risk beyond that encountered in standard community 
clinical practice. 
 
If convened, the DSMB will consist of 2-3 ADCS multidisciplinary leaders, free from any conflicts of 
interest or direct involvement with the academic or other credit resulting from this study, who advise 
both the PI and the NIA, based on their expertise. The primary responsibilities of the DSMB are 
enumerated below; they include to periodically review and evaluate the accumulated study data for 
participant safety, study conduct and progress, and efficacy, and to make recommendations to the 
NIA concerning the continuation, modification, or termination of the R01 protocol. The DSMB 
considers study-specific data as well as relevant background knowledge about the treatments 
(memantine) and patient population under study (mild-to-moderate severity AD).  
 
The DSMB is also responsible for maintaining the confidentiality of its internal discussions and 
activities as well as the contents of reports provided to it. During this application, the DSMB will review 
cumulative study data to evaluate safety, study conduct, and scientific validity and integrity of the trial. 
Our approved IRB protocol describes timely reporting requirements by the PI related to any adverse 
events (AEs), serious adverse events (SAEs) or unanticipated problems (UPs). DSMB members must 
be satisfied that the timeliness, completeness, and accuracy of the data submitted to them for review 
are sufficient for evaluation of the nature of the event and the safety and welfare of the study 
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Data Safety Monitoring Plan
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participants. The DSMB will also assess the performance of overall study operations and any other 
relevant issues, as necessary. A letter of support from Tilman Oltersdorf MD, Director, Medical 
and Safety Core of the UCSD ADCS, and Branko Huisa MD, ADCS Medical Monitor is attached, 
indicating their readiness to convene and oversee a DSMB for this study. Nominally, the 
primary responsibilities of this DSMB include:
1. Conducting an initial review of the proposed research protocol, informed consent documents and 
plans for data safety and monitoring, to assure quality study conduct;  
2. Reviewing study procedures to assure quality of study conduct, including SOPs for data 
management and quality control procedures, and when satisfied, recommend subject recruitment be 
initiated;  
3. Evaluating the quality of the ongoing study conduct by performing quarterly evaluations of the study 
accrual, compliance with eligibility, participant adherence to study requirements, and accuracy and 
completeness of data;  
4. Considering factors external to the study when relevant information becomes available, such as 
scientific or therapeutic developments that may have an impact on the safety of the participants or the 
ethics of the study;  
5. Protect the safety of the study participants: recommending appropriate study review or temporary 
halting for any SAE, and termination due to the occurrence of 3 SAEs (e.g. symptom exacerbation or 
suicidality associated specifically with MEM treatment), or inability of PI to provide necessary 
assessment information or to answer study questions;  
6. Recommending continuation of ongoing studies at quarterly reviews;  
7. Ensure the confidentiality of the study data and the results of monitoring; and, 
8. Assist the NIA by commenting on any problems with study conduct, enrollment, sample size, and/or 
data collection. 
9. Considering the overall picture, including need to pursue both primary and appropriate secondary 
analysis, and making these recommendations during the data analysis phase of the project;  
10. Reviewing final results, via DSMB report by PI within 90 days of completion of final study subject.  
 
 
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Data Safety Monitoring Plan
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Inclusion of Women and Minorities  
Inclusion of women: Women will be included in this study. One key dependent measure (PPI) exhibits clear sexual 
dimorphism; previous studies of memantine effects detected no interactions of sex with drug or diagnosis for 
any of the proposed measures of early auditory information processing (PPI, MMN or ASSR). Importantly, it is 
possible that a significant effect of memantine on auditory processing measures, or an interaction between 
memantine sensitivity and potential moderating factors (e.g. age, baseline performance, single nucleotide 
polymorphisms) will be evident in only one or the other sex, or that relationships among specific measures might be 
sex-specific. Thus, there is a strong rationale for assessing the predicted drug effects in both men and women, to 
test specific predictions of drug-behavior relationships.  
To avoid exposure of any fetus to memantine, subject recruitment is limited to individuals > 50 years of age; 
subjects will be excluded if they are pregnant, nursing, imminently planning pregnancy or have a positive urine 
pregnancy test on screen day or any test day will be excluded from this study. Second, pre-menopausal women will 
be tested only in the early follicular phase of their menstrual cycle. Third, female subjects of childbearing potential 
(defined here as any female who has not had a total hysterectomy and/or bilateral oophorectomy, or who has had a 
menstrual cycle within the past year) will have urine pregnancy tests on each visit. The pregnancy test is able to 
detect the pregnancy hormone hCG (Human Chorionic Gonadotropin) in urine. HCG will be measured by a urine 
"dip-stick" ("Surecheck Early Pregnancy Test"). This test is a midstream format test for the detection of the 
pregnancy hormone in urine. Fourth, in all subjects of childbearing potential, drug testing will occur within days 1 - 
10 of menses onset. Fifth, to participate in this study, females of childbearing potential must agree to use a double-
barrier method of contraception when participating in sexual intercourse (regardless of other methods of 
contraception). If a female of childbearing potential becomes pregnant during the study, the subject will be exited 
from the study. The investigator will determine whether the subject was exposed to active study drug or placebo, 
and notify the subject of this information.  
Typically, the gender distribution for our studies is roughly equal for men and women. Regarding our most recent 
San Diego county US Census Bureau statistics, 49.8% of San Diego countys population are women. Within the 
ADRC, the gender distribution is 55% women. 
Inclusion of minorities: Ethnic representation is based on recruitment response, with every effort made to include 
minority groups. Exclusion criteria are not based on ethnicity. Based on our experience, the following ethnic 
percentages are expected in the AD patient study sample, based on patient demographics at the UCSD ADRC: 
Caucasian = 74%; Black, not of Hispanic origin = 3%; Latino = 13%; Other (Asian American, Native American) = 
10%. Thus, prospective recruitment efforts for this renewal period will attempt to buttress those percentages to be 
more comparable with the US Census Bureaus percentages for San Diego county (approximately 65% White, 5% 
African American, 11% Asian American or Pacific Islander, 1% Native American, and 32% reporting of Hispanic or 
Latino origin; 5% reporting two or more races). This recruitment goal of increasing racial and ethnic minority 
representation will initially be accomplished through a campaign of advertisements in various media sources (i.e., 
local newsletters, newspapers, periodicals, and radio) and lectures by the candidate and/or co-investigators to local 
groups and independent living residential facilities as well as with other outreach efforts targeting racial and ethnic 
minority senior groups (eg., local chapters of the Advisory Committee on Minority Veterans, California Black Health 
Network, UCSD ADRC Hispanic Program, etc). Our targeted/planned enrollment table numbers reflect this goal of 
increasing racial and ethnic minority representation to be more comparable to the UCSD ADRC as well as with the 
US Census Bureaus statistics for San Diego county. 
Any ethnic differences in MEM-sensitive vs. MEM-insensitive groups recruitment will be explored in post-hoc 
analyses. The source of recruitment information is recorded for each subject, providing us with ethnic success 
rates for particular means of recruitment. Ethnic representation is then reviewed with annual progress reports. 
Recruitment efforts are adjusted, based on success rates of specific recruitment means, to respond to any 
significant deviation from the projected ethnic recruitment rates. The UC San Diego Health System is an equal 
opportunity employer; pursuant to state legislation, the University of California no longer applies affirmative action 
criteria in the student application process. 
Contact PD/PI: Swerdlow, Neal
Inclusion of Women and Minorities
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Resource Sharing 
All biomarker data will be shared with the National Database for Clinical Trials (NDCT) related to 
Mental Illness, with descriptive and raw data submitted semi-annually, and complete data and 
analyses within 6 months of study closure, via the Global Unique Identifier (GUID) and Data 
Dictionary technology. Language will be included in all study consent forms to address this plan. 
Budgeting for data management support will account for this activity in the final months of 
PY5, when experimental activity will be completed (month 57), and effort from research staff 
will be shifted to support these data sharing requirements at the time when they will be most 
critical (see Justification, Ms. Talledo).  
Results will also be shared via presentations to the relevant scientific community. The PI and Co-PIs 
are active members of many professional organizations where the proposed science will hold great 
interest, including the American College of Neuropsychopharmacology, Society of Biological 
Psychiatry and Society for Neuroscience, and will present data from these studies at the meetings for 
those societies. When data are ready for peer review, they will be disseminated to the scientific 
community via publications in high impact journals.  
It is anticipated that this application will generate at least five distinct types of resources: 
1. Raw data, both descriptive and quantitative, will be disseminated as described above; 
2. Processed and analyzed data will be disseminated via presentations and data-based publications, 
as described above; 
3. Conclusions will be reached from the above data regarding a range of topics, from new biomarkers 
to opportunities for new therapeutic interventions in our field, and will be disseminated as #2, above, 
in addition to higher profile symposia; 
4. Conceptual ideas related to bigger picture issues, from study design to novel ways to understand 
treatment algorithms, will be reported in review articles and book chapters;  
5. With patient release, all genomic information will be shared with NIH via the procedures and 
timelines described in the NIH Genomic Data Sharing Policy (NOT-OD-14-124).
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Resource Sharing Plan(s)
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