Home-based Transcranial Direct Current Stimulation (tDCS) for Apathy in Alzheimer's Disease and Related Dementias (ADRD)
Phase: NA
Conditions: Alzheimer Disease and Related Dementias
Sponsor: The University of Texas Health Science Center, Houston

IRB NUMBER: HSC-MS-21-0089 
IRB APPROVAL DATE: 11/08/2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Home-based tDCS for apathy in Alzheimer’s disease and related dementias 
 
NCT04855643 
 
Version Date: 11/08/2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

IRB NUMBER: HSC-MS-21-0089 
IRB APPROVAL DATE: 11/08/2021 
 
Protocol Title: Home-based tDCS for apathy in Alzheimer’s disease and related 
dementias 
Principal Investigator: Professor Antonio Teixeira, UTHealth 
Co-Investigators: 
Dr Holly Holmes, UTHealth 
Dr Hyochol Ahn, UTHealth 
Dr Laís Bhering Martins, UTHealth 
Dr Robert Suchting, UTHealth 
Lijin Jose, UTHealth 
General Information 
Study Title 
Home-based tDCS for apathy in Alzheimer’s disease and related 
dementias (ADRD) 
Short Title 
tDCS for apathy in ADRD 
Study Design 
This is a randomized, experimenter- and participant-blinded trial 
to assess feasibility, acceptability, and safety of providing 
transcranial direct current stimulation (tDCS) to Alzheimer’s 
disease and related dementia (ADRD) patients with apathy. 
Participants will be randomized 1:1 to either treatment condition. 
Half of the participants will receive active (constant current 
intensity of 2mA), while half will receive sham tDCS. Anode and 
cathode electrodes will be placed over the left and right 
dorsolateral prefrontal cortexes, respectively, with the use of the 
Omni-Lateral-Electrode system. Caregivers will set up and 
administer tDCS for participants with ADRD at home. All sessions 
will be remotely supervised by trained research staff through 
video conferencing software (e.g., WebEx). Participants will be 
assessed at baseline, treatment day 14, treatment day 28, 
treatment day 42, and 6 weeks post-treatment. 
For our primary goal, we will collect clinical data related to 
feasibility, acceptability, and safety of providing tDCS to ADRD 
patients with apathy. 
Regarding our secondary goal (i.e., efficacy), the primary clinical 
outcome measure will be change on the Apathy Evaluation Scale 
score. The secondary clinical outcome measures will include: (1) 
total score on the Brief Dimensional Apathy Scale (bDAS); (2) 
total score on the Neuropsychiatric Inventory (NPI-Q) which 
evaluates 12 discrete neuropsychiatric symptoms; (3) depressive 
symptoms as assessed by the Cornell Scale for Depression in 
Dementia and (4) cognition as evaluated by the Mini-Mental State 

IRB NUMBER: HSC-MS-21-0089 
IRB APPROVAL DATE: 11/08/2021 
 
Examination (MMSE). Clinical and demographic data will also be 
collected at baseline. 
Study Participants 
Patients with ADRD and apathy will be recruited at the UTHealth 
Geriatric Neuropsychiatry Clinic, the Harris County Psychiatric 
Center (HCPC) (Dr. Teixeira) and the UT Physicians Center for 
Healthy Aging (Dr. Holmes). 
Planned Sample Size 
40 (1:1 for two groups). 
Planned Study Period 
12 weeks 
Objectives 
Outcome Measures 
Primary Goal 
To 
assess 
feasibility, 
acceptability, and safety of 
providing tDCS to ADRD 
patients with apathy. 
Feasibility measures will include 
recruitment rate (per month), 
randomization 
success, 
blind 
success, retention, and attrition 
rates. 
Acceptability will be evaluated 
using 
Likert 
scale 
(from 
0 
[strongly disagree] to 10 [strongly 
agree]) 
to 
answer 
ten 
affirmatives regarding the use of 
home-based tDCS. 
Safety will be assessed with a 
questionnaire about side effects 
that include itching, burning, 
headache, fatigue, and 
dizziness. 
Secondary Goal 
To assess the efficacy of 
tDCS 
for 
ADRD-related 
symptoms, with a primary 
focus on apathy. 
Neuropsychiatric 
symptoms 
evaluated 
through 
validated 
questionnaires. 
 
Background Information 
Alzheimer’s disease (AD) is the main cause of dementia and one of the great 
challenges of the 21st century (1). An estimated 40 million people, mostly older than 60 
years, have dementia worldwide, and this number is expected to increase significantly in 
the next decades. Despite ongoing advances in the understanding of the pathogenesis 
of Alzheimer’s disease and related dementias (ADRD), no treatment available can 
prevent or delay the cognitive decline that characterizes the condition (1). Besides 
cognitive impairment, nearly all patients with ADRD present behavioral and psychological 
symptoms, also called neuropsychiatric symptoms (NPS). 

IRB NUMBER: HSC-MS-21-0089 
IRB APPROVAL DATE: 11/08/2021 
 
NPS have been associated with negative outcomes in ADRD, including decrease of 
patient and caregiver quality of life, increased risk of institutionalization, higher costs and 
risk of mortality (2). The expression ‘NPS’ is an umbrella expression that encompasses 
different types of behavioral problems, such as agitation, apathy, delusion, insomnia, 
among others (3, 4). Due to the potential complications associated with the use of 
psychotropic drugs (e.g. increased risk of cerebrovascular events with antipsychotics, 
increased risk of falls and cognitive decline with benzodiazepines) and the limited 
evidence of their efficacy, clinical guidelines, medical organizations and expert groups 
recommend non-pharmacological strategies as the first-line treatment for NPS (5, 6). 
Apathy, which is defined as the loss or reduction of interest and goal-directed 
behaviors, is the most common NPS in ADRD, with a 5-year prevalence over 70% in this 
population (7, 8). Apathy has been associated with greater functional impairment, greater 
caregiver burden, increased risk of institutionalization and higher costs (9, 10). Because 
of its prevalence and clinical meaning, apathy is an important target in the management 
of ADRD. Standard pharmacological approach for apathy in ADRD uses cholinesterase 
inhibitors such as donepezil, with evidence of either no or very small effectiveness (10, 
11). The stimulant methylphenidate was also shown to be effective in reducing apathy in 
ADRD in open studies and two double-blind randomized controlled trials (12). However, 
the use of methylphenidate was associated not only with reduction in apathy but also with 
greater anxiety and weight loss (13). Another concern with the use of stimulants is their 
potential cardiovascular effects, a fact particularly relevant in older adults with multiple 
medical comorbidities (14). Studies investigating non-pharmacological strategies for 
apathy in ADRD, such as music, art therapy and psychomotor activity, have modest 
effects and only in patients in early stages of dementia (15). Therefore, there is a great 
need to develop effective and safe strategies for the treatment of apathy in ADRD. 
Transcranial direct current stimulation (tDCS) is a relatively novel non- 
pharmacological method of neuromodulation that has been evaluated in several 
neuropsychiatric conditions, showing promising results in depression and negative 
symptoms (including apathy) of schizophrenia (16, 17). tDCS modulates brain activity 
through low-intensity electrical currents applied over the scalp, and has been associated 
with significant changes in network connectivity involving the prefrontal cortex and the 
cingulate cortex, regions implicated in the neural basis of apathy (18-20). 
In ADRD, a few controlled studies have been conducted to evaluate the role of tDCS 
on cognitive functioning. A recent systematic review and meta-analysis of these studies 
found that tDCS improved cognitive function in mild to moderate ADRD, but the 
stimulation parameters (multiple sites; single vs. repeated; lower vs. higher current) were 
very different among studies, not allowing definite conclusions (21). After this systematic 
review, two interesting studies were published on the matter. Khedr et al. (2019) observed 
cognitive improvement, as assessed by general cognitive measures (i.e., Montreal 
Cognitive Assessment and Mini-Mental State Examination), in patients with ADRD 

IRB NUMBER: HSC-MS-21-0089 
IRB APPROVAL DATE: 11/08/2021 
 
submitted to 2 mA anodal tDCS for 20 minutes on each left and right temporal lobes (22). 
Each patient received five sessions/week for two consecutive weeks totaling 10 sessions. 
Im et al. (2019) investigated changes in cognitive performance, as assessed by the Mini 
Mental State Examination and other specific neuropsychological tests, after home-based 
2 mA tDCS with anodal on the left dorsolateral prefrontal cortex (PFC) and cathodal on 
the right dorsolateral PFC for 30 minutes daily for 6 months in patients with early ADRD 
(23). Besides showing the feasibility of long-term home-based tDCS, these researchers 
found that daily tDCS sessions improve or stabilize cognitive decline in patients with 
ADRD. This clinical effect was associated with changes in regional cerebral metabolic 
rate for glucose in the left temporal lobe as assessed by 18F-fluoro-2-deoxyglucose 
positron emission tomography (23). Altogether these studies suggest that tDCS is a 
promising tool for cognitive stabilization in ADRD. Only one study investigated the effect 
of tDCS on NPS in ADRD (24). Suemoto et al. (2014) studied 40 patients with ADRD who 
were randomized to receive either anodal tDCS (2 mA constant current for 20 minutes) 
or sham-tDCS over the left dorsolateral prefrontal cortex (DLPFC) for six sessions during 
two weeks (25). While tDCS was safe in this population, there was no evidence of efficacy 
of tDCS on apathy nor on other NPS assessed. The lack of efficacy was attributed to 
several factors, especially the low number of sessions and the short period of intervention. 
One important aspect of this study – and highlighted by the authors – was the challenge 
to engage subjects in the trial mainly due to issues related to transportation to the medical 
center for tDCS application (25). Since patients with ADRD usually cannot drive safely, 
caregivers and/or family members need to be available to bring them into medical 
appointments. Home-based therapy would be very useful in this regard, as patients would 
not need to attend clinic as often. 
Given the clinical relevance of apathy in ADRD, the equivocal results of the 
therapeutic resources available to address it, and the emerging evidence of safety and 
efficacy of tDCS in ADRD, our proposal aims to test the feasibility, safety and efficacy of 
home-based tDCS for the treatment of apathy in ADRD. Home-based tDCS circumvents 
critical problems observed in previous trials (25), including the need of multiple visits to 
medical centers for tDCS application, allowing a more intensive application (e.g. 5 x per 
week) for prolonged periods. 
 
Objectives 
Objectives 
Outcome Measures 
Primary objective 
To assess feasibility, acceptability, and 
safety of providing tDCS to ADRD patients 
with apathy. 
Feasibility 
measures 
will 
include 
recruitment 
rate 
(per 
month), 
randomization success, blind success, 
retention, and attrition rates. 
Acceptability will be evaluated using Likert 
scale  (from  0  [strongly  disagree]  to  10 

IRB NUMBER: HSC-MS-21-0089 
IRB APPROVAL DATE: 11/08/2021 
 
[strongly agree]) to answer ten affirmatives 
regarding the use of home-based tDCS. 
Safety 
will 
be 
assessed 
with 
a 
questionnaire about side effects that 
include itching, burning, headache, 
fatigue, and dizziness. 
Secondary objectives 
To assess the efficacy of tDCS for ADRD- 
related symptoms, with a primary focus on 
apathy. 
Neuropsychiatric symptoms and cognitive 
measures evaluated through validated 
tools. 
 
Study Design 
We will carry out a randomized, experimenter- and participant-blinded trial comparing 
home-based active tDCS and home-based sham tDCS. Participants will be randomized 
1:1 to either treatment condition. Half of the participants (n=20) will receive active 
(constant current intensity of 2mA), while half (n=20) will receive sham tDCS. No changes 
to the patient's standard care medication will be made. Participants will continue to 
receive standard treatment for their individual health problems. Anode and cathode 
electrodes will be placed over the left and right dorsolateral prefrontal cortexes, 
respectively, with the use of the Omni-Lateral-Electrode system. Caregivers will set up 
and administer tDCS for participants with ADRD at home. tDCS will be applied for 30 min 
at an intensity of 2mA, with 30 s ramping up and down. The same procedure will be used 
for sham stimulation, but in this case, electric current will be applied only in the first 30s 
tDCS. All patients, caregivers and clinicians will be blinded to the type of stimulation 
delivered. We will use bi-hemispheric stimulation (anode F3/cathode F4) based on the 
facts that bilateral frontal circuits have been implicated in apathy, and bilateral stimulation 
may have wider effects on brain 
networks (18, 23, 26). The stimulation 
will last 30 min according to previous 
studies (17, 23, 27). According to our 
previous home-based tDCS protocols 
(28, 29), all sessions will be remotely 
supervised   by   trained   research staff 
(RA),  therefore,  the  sessions  will run 
from Monday to Friday. The remote 
Fig. 1 Illustrative image of home-based tDCS. 
supervision of the sessions will be possible through video conferencing software (e.g., 
WebEx), and will ensure the use of proper technique and compliance to the study 
schedule, also monitoring any adverse events (Fig.1). The devices (tDCS & sham tDCS) 
will be programmed and cannot be tampered. Participants will be assessed at baseline, 

IRB NUMBER: HSC-MS-21-0089 
IRB APPROVAL DATE: 11/08/2021 
 
treatment day 14, treatment day 28, treatment day 42, and 6 weeks post-treatment (Fig. 
2). The device will be returned in person at the end of the treatment (week 6). 
 
Fig. 2 Proposed outline of the study. 
 
 
 
Analyses. Inferential Paradigm and Bayesian Analyses. Following recommendations in 
the clinical trial literature analyses we will proceed using parallel frequentist and Bayesian 
statistical inference (30, 31). The Bayesian inferential paradigm can provide probabilistic 
estimates of effects irrespective of sample size. Bayesian analyses will focus on posterior 
probabilities ≥ 0.75 (equivalent to a Bayes factor = 0.33 or 3.0) that parameter estimates 
are greater or less than zero to emphasize the value in discerning treatment effects in a 
small trial. Power calculations for the frequentist analyses are derived using G*Power v. 
3.1.9.2 and focus on the residual change model described in Hypothesis 2a. As noted, 
the Bayesian analyses will provide the primary inferential results; sample size 
considerations for the frequentist analyses are limited by the small sample size and 
provided as due diligence. Given alpha = 0.05, a sample size N = 40 provides 80% power 
to detect a Cohen's f = 0.45. Frequentist analyses will provide conventional interpretation 
of the relationships between predictors and outcomes: the probability of the data, given 
the null hypothesis. Bayesian analyses will incrementally update specified prior 
information regarding effects to directly yield the probability of an alternative hypothesis. 
Bayesian analyses will employ informative priors as they develop in the literature; 
otherwise, weakly informative priors will be used as a default (e.g., for regression 
coefficients: ~N[µ=0,σ2=100]; for non-linear outcome variables this prior applies to the 
coefficient within the link-function). Sensitivity analyses using optimistic and pessimistic, 
skeptical priors will evaluate prior assumptions. Assessing the convergence of Bayesian 
analyses on the posterior distributions via Monte-Carlo Markov chain (MCMC) will use 
diagnostic evidence including effective sample size and scale reduction factors. 
Evaluation of posterior distributions will permit statements regarding the probability that 
effects of varying magnitudes exist, given the data, even with a small sample size. 
Descriptive statistics will evaluate measures of central tendency and frequencies for all 
continuous and categorical variables (respectively) measured in the study. Correlation 
analyses (i.e., Pearson’s r, Spearman’s rho) will be used to evaluate broad patterns of 
relationships across variables. Preliminary data analyses will inspect relationships 
between sample characteristics (e.g., demographics), experimental group (e.g., active vs. 

IRB NUMBER: HSC-MS-21-0089 
IRB APPROVAL DATE: 11/08/2021 
 
sham tDCS), and specified outcome variables (e.g., Apathy) via traditional statistical tests 
(e.g., chi-square; Mann-Whitney; t-tests). Any sample characteristic variables that 
demonstrate a relationship with both predictor and outcome variables in a given model 
meet criteria for being a potential confounder (32, 33) and will be included as a covariate 
in such models for hypothesis testing. 
Statistical modeling will primarily use generalized linear modeling (GLM) with multilevel 
components (GLMM) for correlated observations. Potentially nonlinear relationships 
between predictors and outcomes will be evaluated via inclusion of polynomial or spline 
effects. Continuous, dichotomous, and count-distributed data will utilize linear, logistic, 
and Poisson/negative binomial regression, respectively (each with a canonical link 
function). Evaluation of distributional assumptions will use residual plots, formal statistical 
tests, and posterior predictive checking. Violations of assumptions will be addressed via 
transformation, robust estimation, stratification, and/or coefficient scaling where 
appropriate. Statistical analyses will be performed using the R statistical computing 
environment via packages lme, rstan, and brms. 
Missing data will be addressed via maximum likelihood, explicit modeling of missingness, 
or imputation where appropriate. Each approach is robust to ignorable missingness (i.e. 
MCAR and MAR). Sensitivity analyses will permit evaluation of the robustness of findings 
to missing data assumptions. While Bayesian analyses are not influenced by traditional 
concerns of multiplicity, for the frequentist analyses, all primary outcome variables (those 
specified by name in the hypothesis statements) will be evaluated at the α = 0.05 
statistical significance level, while any secondary or otherwise post hoc analyses will 
employ false discovery rate (FDR) to control for Type I error. 
 
Study Population 
We will randomize 40 patients aged 60 or older with ADRD and apathy to either 
active home-based daily (Monday to Friday) tDCS or sham tDCS for 6 weeks (1:1 for two 
groups). This sample size is set to maximize the number of participants that may be 
enrolled over the time period of the proposal assuming a credible average recruitment 
rate, given the financial parameters of the funding mechanism. 
Inclusion criteria will be: (1) diagnosis of possible or probable ADRD according 
to the National Institute of Aging – Alzheimer’s Association diagnostic criteria (34); (2) 
mild or moderate dementia, as defined by a MMSE score between 14 and 26 (35, 36); (3) 
clinically meaningful apathy for at least four weeks, clinically diagnosed according to 2018 
Apathy Diagnostic Criteria (37) or defined as Neuropsychiatric Inventory (NPI-Q) apathy 
score equal or above 4 (i.e., severity of ‘moderate’ or greater and caregiver distress ‘mild’ 
or greater) (38-40); (4) stable doses of cholinesterase inhibitors, memantine and other 
psychotropic medications for at least three months. 

IRB NUMBER: HSC-MS-21-0089 
IRB APPROVAL DATE: 11/08/2021 
 
Exclusion criteria will be: (1) unstable medical conditions; (2) history of epilepsy; 
(3) metallic objects in the brain; (4) diagnosis of major depression and/or a score higher 
than 18 on the Cornell Scale for Depression in Dementia (41). 
Recruitment and Retention. Subjects will be recruited at the UTHealth Geriatric 
Neuropsychiatry Clinic, the Harris County Psychiatric Center (HCPC) (Dr. Teixeira) and 
the UT Physicians Center for Healthy Aging (Dr. Holmes). As serious adverse effects and 
problems with the device use are not anticipated, it is expected a high retention rate. The 
remote supervision of the tDCS or tDCS sham daily sessions by trained research staff 
will contribute to the retention of subjects during the trial. 
Training plan. Patients will be instructed on treatment at baseline, when they will 
receive the device. A trained research staff will instruct the participant's caregiver on how 
to handle the equipment. All sessions will be remotely supervised by trained research 
(RA) staff, who will be able to answer questions during the sessions and verify that the 
device is being used correctly. 
 
Study Procedures 
Feasibility measures will include recruitment rate (per month), randomization 
success, blind success, retention and attrition rates. Overall consent and completion rates 
will be evaluated via descriptive statistics. Generalized linear modeling (GLM) will 
evaluate treatment group differences in consent and completion rates. We expect that a 
high proportion of participants will consent to participate (> 80%) and complete the study 
(> 70%). 
Acceptability will be evaluated using the method proposed by Ahn et al. (2019) 
(29). Participants and/or their caretakers will be asked to apply a Likert scale (from 0 
[strongly disagree] to 10 [strongly agree]) to answer ten affirmatives regarding the use of 
home-based tDCS. For example, question 1: “It was easy to prepare the device and 
accessories”, question 7: “I felt confident using the device.” Overall acceptability across 
groups will be evaluated by descriptive measures of satisfaction ratings. GLM will model 
participant satisfaction ratings as a function of treatment group (active vs. sham tDCS). 
We expect that participant satisfaction ratings at the end of treatment will demonstrate 
high acceptance of tDCS treatment in the present sample. 
Safety will be assessed with a questionnaire about side effects that include itching, 
burning, headache, fatigue, and dizziness (29). Descriptive statistics will describe raw 
frequencies of AEs and side effects. Treatment group differences in AEs and side effects 
will be evaluated via Chi-square and Fisher’s exact test of contingency tables. We expect 
that adverse events and side effects will be rare, and any that may occur will be mild. 
The primary clinical outcome measure will be change on the Apathy Evaluation 
Scale score (42), the best-validated scale for measuring apathy in AD, which consists of 
18 items phrased as questions that are to be answered by the caregiver on a four-point 
Likert scale, with higher scores indicating greater severity of apathy. Apathy will be 

IRB NUMBER: HSC-MS-21-0089 
IRB APPROVAL DATE: 11/08/2021 
 
assessed at baseline, during treatment (weeks 2, 4 and 6) and 6 weeks post-treatment. 
Our hypothesis is that active tDCS group will demonstrate lower apathy scores at the end 
of treatment relative to sham tDCS. GLM will evaluate residual change by modeling 
apathy at the end of treatment as a function of treatment group, controlling for apathy at 
the beginning of treatment. This analysis is a regression-based analogue to ANCOVA 
that permits non-normally distributed outcome distributions. Follow-up analyses will 
evaluate change over time across groups via GLM with multilevel components (GLMM) 
as well as cross-sectional analyses within each measurement time point via GLM. 
The secondary clinical outcome measures will include: (1) total score on the Brief 
Dimensional Apathy Scale (bDAS) (43); (2) total score on the NPI-Q which evaluates 12 
discrete NPS considering their severity and the related caregiver distress (38-40); (3) 
depressive symptoms as assessed by the Cornell Scale for Depression in Dementia (41); 
(4) cognition as evaluated by the Mini-Mental State Examination (MMSE), which includes 
memory, language, praxis and orientation tasks, yielding a global cognition score ranging 
0 to 30, with higher scores indicating better performance (35). 
Our hypothesis is that active tDCS group will demonstrate lower scores on the 
bDAS, NPI-Q and Cornell Scale for Depression, and higher scores on the MMSE at the 
end of treatment relative to sham tDCS. GLM will evaluate residual change in each 
outcome (in separate models) by modeling scores at the end of treatment as a function 
of treatment group, controlling for baseline. 
Sociodemographic data (gender, age, marital status and education) will be 
collected at the baseline. Clinical (health history, use of medication and life habits) and 
anthropometric data will be collected at the baseline and after the treatment period. These 
data will be control variables for the study. 
 
Table 1. Timetable for Collection of Data 
 
Assessment 
Baseline 
Week 2 
Week 
Week 
Week 12 
4 
6 
Medical History Questionnaire 
X 
MMSE 
X 
X 
X 
AES (primary outcome) 
X 
X 
X 
X 
X 
NPI-Q 
X 
X 
X 
X 
X 
bDAS 
X 
X 
X 
X 
X 
Cornell Scale for Depression 
X 
X 
X 
tDCS experience questionnaire 
X 
X 
X 
X 
Side effects questionnaire 
X 
X 
X 
X 

IRB NUMBER: HSC-MS-21-0089 
IRB APPROVAL DATE: 11/08/2021 
 
Data and Safety Monitoring 
Data will be collected from 40 human participants, and all information will be de- 
identified in order to protect their confidentiality. All clinical information will be stored in 
dedicated files at UTHealth Department of Psychiatry. We will maintain full control over 
the data and resources for 1 year following the completion of data collection. This will 
allow sufficient time for data cleaning, validation and analysis, and subsequent publication 
of the primary findings that address the proposed specific aims of the project. After this 
time, de-identified datasets with full data dictionaries will be made publicly available. The 
investigators are aware of and agree to abide by the principles for sharing research 
resources, as expected by TARCC-funded research. Before the data become publicly 
available, individual requests for data sharing will be considered by the PI, Co-Is, and the 
TARCC staff on a case-by-case basis. Evaluation of these requests will be based on the 
scientific validity of the proposal as well as the adequacy of plans for maintaining the 
security and confidentiality of the data. The data generated in this grant will be presented 
at national or international conferences and published in a timely fashion. 
 
Statistics 
Inferential Paradigm and Bayesian Analyses. Following recommendations in the 
clinical trial literature analyses we will proceed using parallel frequentist and Bayesian 
statistical inference (30, 31). The Bayesian inferential paradigm can provide probabilistic 
estimates of effects irrespective of sample size. Bayesian analyses will focus on posterior 
probabilities ≥ 0.75 (equivalent to a Bayes factor = 0.33 or 3.0) that parameter estimates 
are greater or less than zero to emphasize the value in discerning treatment effects in a 
small trial. Power calculations for the frequentist analyses are derived using G*Power v. 
3.1.9.2 and focus on the residual change model described in Hypothesis 2a. As noted, 
the Bayesian analyses will provide the primary inferential results; sample size 
considerations for the frequentist analyses are limited by the small sample size and 
provided as due diligence. Given alpha = 0.05, a sample size N = 40 provides 80% power 
to detect a Cohen's f = 0.45. Frequentist analyses will provide conventional interpretation 
of the relationships between predictors and outcomes: the probability of the data, given 
the null hypothesis. Bayesian analyses will incrementally update specified prior 
information regarding effects to directly yield the probability of an alternative hypothesis. 
Bayesian analyses will employ informative priors as they develop in the literature; 
otherwise, weakly informative priors will be used as a default (e.g., for regression 
coefficients: ~N[µ=0,σ2=100]; for non-linear outcome variables this prior applies to the 
coefficient within the link-function). Sensitivity analyses using optimistic and pessimistic, 
skeptical priors will evaluate prior assumptions. Assessing the convergence of Bayesian 
analyses on the posterior distributions via Monte-Carlo Markov chain (MCMC) will use 
diagnostic  evidence  including  effective  sample  size  and  scale  reduction  factors. 

IRB NUMBER: HSC-MS-21-0089 
IRB APPROVAL DATE: 11/08/2021 
 
Evaluation of posterior distributions will permit statements regarding the probability that 
effects of varying magnitudes exist, given the data, even with a small sample size. 
Descriptive statistics will evaluate measures of central tendency and frequencies for all 
continuous and categorical variables (respectively) measured in the study. Correlation 
analyses (i.e., Pearson’s r, Spearman’s rho) will be used to evaluate broad patterns of 
relationships across variables. Preliminary data analyses will inspect relationships 
between sample characteristics (e.g., demographics), experimental group (e.g., active vs. 
sham tDCS), and specified outcome variables (e.g., Apathy) via traditional statistical tests 
(e.g., chi-square; Mann-Whitney; t-tests). Any sample characteristic variables that 
demonstrate a relationship with both predictor and outcome variables in a given model 
meet criteria for being a potential confounder (32, 33) and will be included as a covariate 
in such models for hypothesis testing. 
Statistical modeling will primarily use generalized linear modeling (GLM) with 
multilevel components (GLMM) for correlated observations. Potentially nonlinear 
relationships between predictors and outcomes will be evaluated via inclusion of 
polynomial or spline effects. Continuous, dichotomous, and count-distributed data will 
utilize linear, logistic, and Poisson/negative binomial regression, respectively (each with 
a canonical link function). Evaluation of distributional assumptions will use residual plots, 
formal statistical tests, and posterior predictive checking. Violations of assumptions will 
be addressed via transformation, robust estimation, stratification, and/or coefficient 
scaling where appropriate. Statistical analyses will be performed using the R statistical 
computing environment via packages lme, rstan, and brms. 
Missing data will be addressed via maximum likelihood, explicit modeling of 
missingness, or imputation where appropriate. Each approach is robust to ignorable 
missingness (i.e. MCAR and MAR). Sensitivity analyses will permit evaluation of the 
robustness of findings to missing data assumptions. While Bayesian analyses are not 
influenced by traditional concerns of multiplicity, for the frequentist analyses, all primary 
outcome variables (those specified by name in the hypothesis statements) will be 
evaluated at the α = 0.05 statistical significance level, while any secondary or otherwise 
post hoc analyses will employ false discovery rate (FDR) to control for Type I error. 
Ethics/Protection of Patient Confidentiality 
The sample of this study consists of 40 older adults aged 60 years-old and over 
with ADRD and apathy. Study participants or their legally authorized representatives will 
give informed consent. Moreover, caregivers and/or relatives will be required to be 
present during the clinical assessments and tDCS sessions to ensure reliable information 
and proper use of the device. Participants will be recruited without any specific regard to 
sex, race, religion or ethnicity. Patients will be recruited at the UTHealth Geriatric 
Neuropsychiatry Clinic, the HCPC, and UTHealth Center for Healthy Aging. We will recruit 
ADRD patients whose dementia is of mild to moderate severity (CDR 1 and 2). Adults 

IRB NUMBER: HSC-MS-21-0089 
IRB APPROVAL DATE: 11/08/2021 
 
younger than 60, adolescents and children are excluded as we are focusing on dementia, 
an age-related disorder that usually affects individuals aged 60 and older. No other 
special classes of vulnerable individuals will be included. It is anticipated that the subject 
demographic profile will mirror the larger population of individuals with ADRD from which 
they are recruited. 
Informed Consent and Assent. Potential subjects and their caregivers/relatives will 
be informed about the study purpose, procedures, risks and benefits. They will be 
informed that participation in the research study is voluntary and that they are free to 
decline to be in the study, or to withdraw from it at any point. Study records will be kept 
confidential. Study information will be coded, and only study personnel will have access 
to the files. 
Protection Against Potential Risks. The risks to the subjects involved in this study 
are minimal. To ensure this, we will take necessary steps to reduce risk for all study 
participants. We will try to create an atmosphere of security and trust prior any clinical 
assessment in order to minimize any discomfort with the research questions. In addition, 
subjects are always given permission to not answer questions with which they feel 
uncomfortable. A number of procedures (e.g. use of identifying numbers instead of 
names) will be implemented to protect subjects against loss of confidentiality. Side effects 
related to active tDCS application are uncommon, and mild when present, including: 
itching and burning sensation on the scalp, mild headache, dizziness, and fatigue. No 
serious adverse effects have been reported with tDCS. 
Potential Benefits to Research Participants. If our hypothesis is correct, subjects 
in the active arm of the study might benefit from the study participation. Importantly, the 
results will be relevant to the field of AD and neuromodulation. 
Significance 
Our proposal will address a frequent and sometimes overlooked clinical problem 
in patients with ADRD, i.e. apathy. The proposal can advance the field of non- 
pharmacological strategies for NPS, also presenting a great potential for clinical 
translation. Home-based intervention with real-time monitoring through a secure 
conferencing platform is a new modality for improving symptom management in ADRD. 
Moreover, home-based, remotely supervised tDCS has advantages over clinic-based 
sessions, considering the time and cost associated with attending multiple sessions over 
several days. Caregivers will be trained at the in-person baseline visit, and all the tDCS 
sessions will be remotely supervised via secure videoconferencing software by trained 
research staff for the entire duration of each session to ensure the use of proper technique 
and to monitor any adverse events. 

IRB NUMBER: HSC-MS-21-0089 
IRB APPROVAL DATE: 11/08/2021 
 
Costs and Compensations 
Subjects will not be charged for tests, procedures or other costs incurred solely for 
the purposes of this research. Patients will receive a voucher of US 50.00 for their time 
dedicated to each evaluation (total number of assessments = 5). 
This project was approved to receive financial support from Texas Alzheimer’s 
Research and Care Consortium (TARCC) 2020 Grant Program. 
Publication Plan 
This study will represent an original contribution to the areas of non- 
pharmacological approaches for NPS in ADRD and neuromodulation in ADRD, also 
fostering home-based interventions. More importantly, we expect to have enough 
evidence on the feasibility, acceptability, safety and efficacy of tDCS for apathy in AD so 
we can adjust and/or expand the protocol, ultimately, aiming its translation into the clinical 
practice. This project, if granted, will also strength emerging clinical research groups at 
UTHealth working with novel technologies that can be applied to ADRD and other 
neuropsychiatric conditions. 
 
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