Evaluation of Brain and Cognitive Changes in Older Adults With MCI Taking Lithium to Prevent Alzheimer Type Dementia
Phase: PHASE4
Conditions: Mild Cognitive Impairment
Sponsor: Ariel Gildengers, MD

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Study Protocol  
 
 
 
 
 
 
Official Title: Lithium As a Treatment to Prevent Impairment of Cognition in Elders 
(LATTICE) 
  
 
 
ClinicalTrials.gov ID (NCT number): NCT03185208 
 
 
 
Protocol Date: March 12, 2025 
 
 
 
 

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Scientific Background 
 
Alzheimer’s disease (AD) is the most common cause of dementia in adults 65 years and older.1 
AD is a terminal illness that in the run up to death leads to a complete loss of memory and 
independent function. Unchecked, the disease will reach epidemic proportions in the United 
States and worldwide by 2050, and presently, there is no intervention that has shown a clear 
effect on AD progression.2 The Alzheimer’s Association’s 2015 trajectory report estimates that a 
treatment delaying onset by five years and beginning to show its effect by 2025 would decrease 
the total number of older Americans with AD from 8.2 to 5.2 million by 2030.3 Additionally, a 
treatment that slows disease progression will also result in far fewer AD patients in the most 
severe stage that requires the highest level of care with the greatest cost.3 Hence, there is an 
urgent need to find treatments from pre-symptomatic to symptomatic AD to meet this looming 
challenge. This work aims to meet this challenge.  
 
Over the past several years, there has been increasing interest in repurposing the use of lithium 
for diseases involving neurodegeneration.4 Lithium treatment has been associated with 
neurogenesis in the hippocampus,5 up-regulation of important neurotrophic factors such as B-cell 
lymphoma 2 (Bcl-2) and brain-derived neurotrophic factor (BDNF),6 and, relevant to this project, 
inhibition of glycogen synthase kinase 3 (GSK-3) isoforms α and β. In particular, GSK-3α interacts 
with gamma-secretase playing a critical role in the conversion of amyloid precursor protein (APP) 
to amyloid-beta (Aβ); lithium has been shown to reduce Aβ production and memory deficits in AD 
transgenic mouse models.7 GSK-3β phosphorylates tau, a critical step in the formation of 
neurofibrillary tangles, and lithium has been shown to reduce tau phosphorylation in vivo and in 
vitro.8 That lithium may alter the AD trajectory is supported by numerous observational reports 
showing delay of dementia onset in those treated with it.9-13 However, the results of the few human 
lithium trials conducted have been mixed.14-17 At this time, it is difficult to draw definitive 
conclusions and make recommendations for widespread use of lithium based on the current 
evidence as well as the unclear risk/benefit profile of lithium treatment in older adults at risk for 
developing AD. Research is needed to determine whether lithium has a role as an anti-dementia 
agent. In contrast to previous studies, we will implement an RCT with a more integrative, 
comprehensive approach than done before involving state-of-the-art ultra-high field (7T) human 
MRI, neurocognitive assessment, and blood-/CSF- based biomarker measurement to investigate 
the role of lithium as an anti-dementia agent. 
 
The rate of conversion to dementia among older adults with mild cognitive impairment (MCI) is 
15% per year in clinic samples.18 Accordingly, we will enroll older adults who meet criteria for MCI 
in which we will assess whether lithium can alter the AD trajectory.19 Enrolling individuals who 
exhibit no cognitive impairment would be the basis of a different, much larger and longer study 
given the lower rates of AD conversion compared with individuals with MCI. Conversely, enrolling 
individuals with established AD is likely too far in the disease process for lithium to make a 
significant difference. 
 
 
 

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Study Objectives 
 
Specific Aim: To examine the potential disease modifying properties of lithium in 
individuals with MCI in delaying conversion to dementia. 
 
H1: a) Participants randomized to take lithium for two years, compared to placebo, will better 
maintain cognitive function, primarily in memory, which b) will be associated with changes in 
biomarkers (e.g., GSK-3β activity, BDNF). 
 
H2: a) Participants randomized to take lithium for two years, compared to placebo, will have larger 
hippocampal volumes and lower total gray matter thinning, which b) will be associated with 
changes in biomarkers (e.g., GSK-3β activity, BDNF) and c) better cognitive function, primarily in 
memory. 
 
Exploratory Aim: To examine whether lithium is related to additional markers of enhanced 
brain integrity (e.g., lower level of microbleeds, higher white matter integrity, better 
network connectivity, or decreased CSF phospho tau levels). 
 
 
 
 

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Study Design & Methods 
 
Enroll and randomly assign 80 individuals 60 years and older with MCI to take lithium, titrated as 
tolerated to a blood level of 0.6 to 0.8 mEq/L, or placebo for two years to assess lithium’s effects 
on preserving cognition and delaying conversion to dementia. Participants will receive annual 
neurocognitive assessment, ultra-high field (7T) brain MRI (e.g., high-resolution imaging of 
hippocampal and total cortical gray volumes, white matter integrity, dynamic imaging), blood- 
(e.g., GSK-3β, BDNF, cytokines) and CSF-based (e.g., Aβ, total tau, and phospho tau) biomarker 
measurement. All subjects will undergo baseline PET imaging of Aβ on which to stratify 
randomization. This study is powered to detect medium/large effect sizes for H1-2, and will serve 
as the “go/no-go” for a subsequent, larger-scale, confirmatory study. 
 
 
 
 

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Eligibility Criteria  
 
Inclusion criteria: 
1. 60 years or older 
2. Diagnosis of Mild Cognitive Impairment 
 
Exclusion criteria: 
1. Major psychiatric illness (mild psychiatric illness may be included) 
2. Major neurologic illness (e.g., multiple sclerosis) 
3. Contraindication to lithium (e.g., renal insufficiency) 
4. Unable to complete neuropsychological testing due to non-remediable impairment (e.g., 
blindness) 
 
 
 
 
 
 

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Statistical Considerations 
 
HYPOTHESIS TESTING. All statistical analyses will be conducted starting with basic descriptive 
techniques and two sample testing (t-tests, Wilcoxon tests, chi-square tests) for testing the 
difference between the intervention and control groups. Statistical tests will be two-sided and 
interpreted at the 0.05 level. We have also performed all of our power computations and have 
provided effect sizes for all adjusted analysis (p<0.01) due to multiple testing. Additionally, all of 
our voxel-wise analyses results will be corrected using FWE. These analyses will then inform the 
next step in the analysis process that will include statistical modeling. First, adherence will be 
assessed over time by intervention group using a Kaplan-Meier approach where non-adherence 
is considered to be an "event.” For all modeling, we will use regression diagnostics to identify 
potential outliers or influential observations. Additionally, the analyses will be assessed for the 
impact of missing data. For the initial reporting of all results, we will follow the guidelines outlined 
in the CONSORT statement and follow intention to treat principles: subjects will continue to be 
followed and analyzed according to the original randomized assignment.134, 135 Tests of whether 
missingness is at random will be performed. Should missing data prove to be an issue, we will 
rely on inverse probability weighting or imputation as part of the analysis.  
 
Specific Aim: H1-2. This analysis focuses on assessing the effect of lithium on: (H1) cognitive 
performance and, (H2) neuroimaging measures of hippocampal volumes and total gray matter 
and cognition. Outcomes are measured at three time points, and our primary analysis will consist 
of linear mixed effects models. These models will include a term for time, group and a time-by-
group interaction. We will test for lithium effect by testing the significance of the coefficient 
associated with the interaction term in the model as well as by a likelihood ratio test between the 
models with and without interaction. First, we will fit these basic models for each of the outcomes 
of interest and test for the time-by-group interaction as an assessment of the effect of lithium. 
Second, we will include potential covariates (e.g., age, education, sex, etc.) and exploratory 
covariates (e.g., physical activity) that may influence the group effect and test for a time-by-group 
interaction in this context. We will examine the biomarker trajectories across the two groups. If 
the assays used to measure the biomarkers produce results outside of the detectable limits, we 
will use tobit model and mixed model extensions of the tobit model to test for differences between 
the two groups. 
 
POWER ANALYSIS. For H1a/H2a, where 80 subjects will be randomized to one of two groups 
with 64 completers (32 in each cell), we computed power based on the following assumptions: a 
two-sided significance level of 0.05, a power of 0.80 and measurements at three time points for a 
repeated measures model. Based on these assumptions, we are powered to observe an effect 
size (Cohen’s d) of 0.57 (i.e., medium) when the observations are correlated at a level of 0.5 
across time. The effect size ranges from 0.45 to 0.60, a little over a half standard deviation 
difference in the outcome variable, as the correlation between repeated observations ranges from 
0.1 to 0.6. We also computed the effect size for a two-sided significance level of 0.01, a more 
conservative alpha for testing multiple outcomes, and power of 0.80 as above and found that the 
effect size ranged from 0.54 to 0.72 as the correlation between repeated observations ranged 
from 0.1 to 0.6. 
 
 
 
 

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