A Randomized-Controlled Trial Targeting Cognition in Early Alzheimer’s Disease by Improving Sleep with Trazodone (REST)

Abstract

Alzheimer’s Disease (AD) is a leading cause of mortality and morbidity among aging populations worldwide. Despite arduous research efforts, treatment options for this devastating neurodegenerative disease are limited. Sleep disturbances, through their link to changes in neural excitability and impaired clearance of interstitial abnormal protein aggregates, are a key risk factor for the development of AD. Research also suggests that the neuroprotective effects of sleep are particularly active during slow wave sleep. Given the strong link between sleep disturbance and AD, targeting sleep in the prodromal stages of AD, such as in mild cognitive impairment (MCI), represents a promising avenue for slowing the onset of AD-related cognitive decline. In efforts to improve sleep in older individuals, several pharmacologic approaches have been employed, but many pose safety risks, concern for worsening cognitive function, and fail to effectively target slow wave sleep. Trazodone, a safe and widely used drug in the older adult population, has shown promise in inducing slow wave sleep in older adults, but requires more rigorous research to understand its effects on sleep and cognition in the prodromal stages of AD. In this review, we present the rationale and study design for our randomized, double-bind, placebo-controlled, crossover trial (NCT05282550) investigating the effects of trazodone on sleep and cognition in 100 older adults with amnestic MCI and sleep complaints.

Introduction

Alzheimer’s Disease (AD) is a leading cause of mortality and morbidity among aging populations worldwide. [1] Sleep disturbances are a key risk factor for the development of AD and commonly present along with other neuropsychiatric symptoms in its prodromal stages, such as in mild cognitive impairment (MCI). [2] Moreover, there is evidence of a bidirectional relationship between sleep disturbance and AD, wherein impaired sleep may initiate brain changes that accelerate AD pathogenesis, which in turn further disrupt normal sleep patterns. [3,4] We are presenting the rationale and study design for the use of a commonly prescribed sleep medication (trazodone) to improve sleep and cognition in older persons with amnestic MCI (aMCI) and sleep complaints.

Currently, treatment options for AD are limited, and targeting sleep represents a promising avenue for slowing the onset of AD-related cognitive decline. Healthy sleep has been shown to be associated with hippocampal-dependent memory consolidation. [3] Conversely, sleep disturbances are linked to deleterious effects on vigilance, attention, and memory, mediated in part by disruptions in synaptic pruning and homeostasis. [3,5] Two primary mechanisms – changes in neural excitability and clearance of interstitial amyloid-β (Aβ), tau and other metabolites – may link disturbed sleep to pathogenic pathways in AD. First, wakefulness increases neural excitability in insects, rodents, and humans that is renormalized during sleep, particularly slow wave sleep (SWS). We have observed increased hippocampal activation in individuals with amnestic mild cognitive impairment (aMCI) during a memory task involving hippocampal encoding. [6,7] Because poor sleep may be associated with increased hippocampal activation, improving sleep is a potential target for positively affecting cognition and disease progression in AD. Second, in animal model studies, amyloid-β and tau are cleared from brain interstitial fluid and cerebrospinal fluid (CSF) during SWS and accumulate when SWS is reduced, which has been proposed to occur via sleep-related glymphatic mechanisms. Analogous mechanisms may be involved in humans that coincide with sleep-related changes in neural activity. Thus, improving sleep in aMCI may improve cognition and AD pathologic mechanisms.

The glymphatic system has been well-characterized in murine models. Flow through this system is composed of para-arterial cerebrospinal fluid (CSF) that moves intracellularly through a trans-astrocytic pathway to mix with interstitial fluid before being cleared along para-venous pathways. [8] Evidence from animal models suggests that heightened SWA clears amyloid-β and tau proteins from brain interstitial fluid and CSF through sleep-related glymphatic mechanisms. [9–11] For example, a mouse model of AD showed evidence of glymphatic impairments leading up to the significant accumulation of amyloid-β (Aβ) [12], suggesting that impaired glymphatic clearance could be a key mechanism underlying development of AD-related pathology.

The existence of analogous hemodynamic mechanisms in humans are speculated to exist but require further study. In cognitively normal older adults, age-related medial prefrontal cortex volume decreases were shown to be associated with reduced SWA, which mediated reduced overnight sleep-dependent memory retention, increased hippocampal activation, and reduced functional connectivity between the hippocampus and prefrontal cortex during an episodic memory task. [13] These data support an association between reduced SWA, increased hippocampal activation, and long-term memory impairment. Thus, increasing SWA may decrease hippocampal hyperactivity, which can serve to improve memory consolidation in cognitively normal individuals and in those with aMCI.

In efforts to improve sleep in older individuals, several pharmacologic approaches have been employed, including melatonin, second-generation antipsychotics, and sedating antidepressants. However, many of these medications have high safety risks or pose concern for worsening cognitive function. [14] Suvorexant, a recently approved dual orexin receptor antagonist with a promising safety profile, was shown to increase total sleep time, decrease wake after sleep onset, and even reduce tau phosphorylation and amyloid-β concentrations in the central nervous system. [16] However, suvorexant did not impact time spent in slow wave sleep (SWS), emphasizing the need for a safe, pharmacological agent that improves SWS in older adults with aMCI/AD.

Trazodone (TRZ) is a generic antidepressant widely used off-label to treat sleep disturbance, particularly enhancing SWS. Reduced hippocampal excitability is one potential mechanism for this effect. While TRZ has been demonstrated to improve sleep in AD and potentially mitigate the risk of developing aMCI, its effect on sleep has not been rigorously studied in aMCI. TRZ, originally approved by the FDA as a treatment for major depressive disorder (MDD), is a widely used off-label sleep aid among patients with AD. [15,17,18] Low doses of TRZ have been shown to be sufficient to induce its sleep promoting effects, and TRZ is distinct among sleep medications in its ability to induce SWS [18, 19–21]. Due to its favorable side effect profile, lack of anticholinergic activity, and low potential for dependence, TRZ is a promising therapy for older adults, who are at high risk of adverse drug reactions. [22]

Findings from several studies provide support for the efficacy of TRZ in treating insomnia in older adults, with evidence supporting positive impacts on AD pathogenesis. A large retrospective cohort study followed 6,000 participants over 3–4 years and found that baseline sleep complaints were associated with an increased risk of incident MCI, but that this association was not present in TRZ users. [18] In a small randomized-controlled trial, Camargos et al. (2014) found that TRZ use improved total sleep time in patients with AD compared to placebo. [23] Beyond its effects on sleep, TRZ has also been shown to slow cognitive decline in older adults. For example, La et al. (2019) reported that regular TRZ users had a 2.6-fold decreased rate of decline on Mini Mental Status Exam performance compared to non-TRZ users, which was associated with subjective improvement of sleep. [24] Conversely, a UK cohort study found that TRZ prescription use in 406 individuals with MCI did not significantly improve cognition. [25] However, only approximately 25% of subjects in this study reported sleep complaints at baseline, suggesting that the beneficial effects of TRZ on cognition may be particularly suited to those with sleep difficulties.

Together, these results suggest that TRZ, through its induction of SWS, may improve sleep in older adults and potentially affect AD pathophysiology. However, more rigorous research is needed to understand the effects of TRZ on sleep and cognitive functioning in individuals in the prodromal stages of AD, such as those with amnestic mild cognitive impairment (aMCI). Thus, we present the methods for a rigorous double-blind, randomized-controlled crossover trial of TRZ in 100 subjects with prodromal AD/aMCI and sleep complaints. Thus, to investigate trazodone’s effects on sleep, hippocampal-dependent memory and hippocampal excitability, and supported by its benign safety profile, we are conducting a rigorous randomized double-blind, placebo-controlled, crossover trial in 100 subjects with aMCI and sleep complaints.

Our primary aim is to assess the effect of TRZ on sleep parameters as measured by polysomnography (PSG), actigraphy, and self-report. We hypothesize that TRZ will improve total sleep time and proportion of time in SWS. To measure associated changes in cognition, we will administer a cognitive battery that assesses domains of cognition affected by aMCI and poor sleep. [24,26,27] Additionally, given findings that aMCI patients show performance deficits on dentate gyrus (DG)/cornu ammonis-3 (CA3)-mediated memory tasks in functional magnetic resonance (fMRI) analyses [6,7,28], participants will also complete three fMRI sessions that will assess hippocampal activation during performance a behavioral task. With this data, our secondary aim is to examine the effect of TRZ on hippocampal hyperactivity and performance on the Behavioral Pattern Separation Objects task, which is designed to test hippocampal-dependent episodic memory function. We will also assess a broader range of cognitive domains and neuropsychiatric symptoms as tertiary outcomes. Finally, we will perform exploratory analyses to assess the impact of TRZ on changes in plasma biomarkers relevant to AD-related pathology and whether the relationships between TRZ and biomarker changes are mediated by increases in SWS. [29]

Methods

Study Design

Our study, RCT targeting cognition in Early Alzheimer’s Disease by Improving Sleep with Trazodone (REST, NCT05282550), was approved by the Johns Hopkins Medicine Institutional Review Board (IRB). REST is a randomized, placebo-controlled, double-blind crossover study of TRZ in 100 participants with aMCI who report sleep complaints. The study is being conducted at the Johns Hopkins University of Medicine and at the Kennedy Krieger Institute in Baltimore, Maryland. Participants are randomized to receive either TRZ (50 mg at bedtime, provided in opaque capsules) or placebo (matching capsules containing inert filler) for 4 weeks each. Following completion of the four-week treatment phases, both groups will undergo a four-week intervening washout period, sufficient to allow elimination of TRZ given a half-life of 10–12 hours. [30,31] After the washout period, groups will be crossed-over such that participants who received TRZ for the first treatment phase will then receive placebo, and vice versa, for another 4 weeks. The crossover design will allow for subjects to act as their own controls and reduce the need for additional recruitment.

Prior to initiating in-person procedures, a telephone-based screening will be conducted during which the Hopkins Verbal Learning Test–Revised Version (HVLT-R) will be administered to assess potential eligibility of participants. [32] Individuals who qualify (see below) will be invited for a series of five in-person study visits (Figure 1). Cognitive testing and neuropsychiatric assessment will be collected on all participants at the baseline visit (visit 1) and upon completion of both treatment phases (visits 3 and 5). After visit 1, eligible participants will complete an MRI session at visit 2, and again upon completion of both treatment phases (visits 3 and 5). Sleep measures including polysomnography (PSG), actigraphy, and self-report will also be collected at all visits except visit 2. All human subjects research and procedures, including advertising and recruitment methods, will be carried out following the rules and regulations of the Johns Hopkins Medicine IRB and in accordance with HIPAA regulations.

Figure 1:

REST study design and visit timeline. The total study period is approximately 13–15 weeks and involves a series of five in-person visits for eligible participants.

Abbreviations: Hopkins Verbal Learning Test-Revised (HVLT-R), Clinical Dementia Rating (CDR), Mini-Mental State Exam (MMSE), Neuropsychiatric Inventory-Clinician Rating Scale (NPI-C), Pittsburgh Sleep Quality Index (PSQI), Activities of Daily living (ADLs), Epworth Sleepiness Scale (ESS), Short-Form 12 Health Survey (SF-12), Home Sleep Study (HST)

Recruitment

Individuals with self-identified memory and sleep complaints will be recruited primarily through automated electronic health record (EHR) messages sent to potential participants based on age, zip code, and excluded sleep medications. Additional recruitment strategies will include patient referrals from the Alzheimer’s Disease Research Center and the Memory and Alzheimer’s Treatment Center at Johns Hopkins, advertisements placed in local newspapers, radio stations, community events, social media, and postings in primary care offices in the local catchment area.

Eligibility Criteria

Individuals who express interest in the study will undergo a screening telephone assessment to determine study eligibility. Those who meet the study criteria during the phone screening will be invited to a baseline visit which will include medical, cognitive, neuropsychiatric, and assessments of daily function. Participants must meet diagnostic criteria for aMCI at baseline to be included in the study, as supported by a Clinical Dementia Rating Scale equal to 0.5. The study physician will obtain a history, including information from a knowledgeable informant on each participant’s cognitive status, and review participant assessment data in order to make a clinical diagnosis.

Specific inclusion criteria for the study are as follows: (1) clinical diagnosis of aMCI as defined by Albert et al. [33] which includes subjective memory complaint and objective evidence of memory problems; (2) Clinical Dementia Rating of 0.5 with a Memory Box score of >0.5; (3) Evidence of sleep complaints with Pittsburgh Sleep Quality Index score of >5 (a cutoff observed in >40% of older persons) [34]; (4) Memory performance >1.0 SD below age-education norms on HVLT-R; (5) Adequate visual and auditory acuity for neuropsychological testing; (6) Good general health with no disease expected to interfere with participation in the study; (7) Ability to have an MRI scan; and (8) Availability of knowledgeable informant.

The following criteria will be used as exclusion: (1) Less than 55 years of age; (2) Too frail or medically unstable to undergo study procedures; (3) Prior diagnosis of obstructive sleep apnea or evidence of moderate to severe obstructive sleep apnea on baseline PSG as evidenced by an apnea/hypopnea index of ≥15; (4) moderate or severe dementia with CDR 2 or greater (5) Cognitive complaints and deficits better explained by other medical/neurologic conditions; (6) Delirium; (7) Allergic to TRZ; (8) Taking sleep medications including TRZ and unwilling to undergo four-week pre-study washout period; (9) Current substance abuse; (10) Current major depressive, manic, or acute psychotic episode; (11) Prior diagnosis of significant systemic illness or unstable medical condition which could lead to difficulty complying with the study protocol or represent alternate primary cause of memory problems beyond AD pathology; (12) Lack of available knowledge informant; (13) Prior diagnosis of QT (corrected for heart rate) prolongation (> 470 msec in females or > 450 msec in males); and (14) Inability to provide informed consent.

Study Measures

Medical History, Clinical Data and Demographics:

During the screening telephone assessment, we will collect participant medical history and current medications. Participants taking medications prescribed for sleep including TRZ are asked to pause treatment to participate in the study and will undergo a minimum of a four-week pre-study washout period prior to enrollment. At visit 1, we will collect participant demographic information including age, sex, race, ethnicity, and education. Clinical measures will be recorded at each visit, including vital signs, physical exams. Electrocardiogram will be performed only at Visit 1.

Cognitive Battery:

To characterize cognition in aMCI patients, a comprehensive battery will be administered that spans all major cognitive domains. The Mini-Mental State Examination and the Clinical Dementia Rating will be administered during Visit 1 to assess baseline cognition. [35,36] Visits 1, 3, 4 and 5 will include tasks such as Digit Span, Trail Making Test, Letter (Phonemic) Fluency, and several tasks from the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), including Coding, List Learning and Recall, and Story Memory and Recall. [37–40] These tests collectively assess domains of attention, processing speed, declarative memory, and executive functioning. Practice effects are minimized with the use of alternate forms of each test.

Neuropsychiatric Measures:

Sleep and cognition can affect and be affected by neuropsychiatric symptoms other than sleep/wake problems, particularly depression and anxiety [41]. The Neuropsychiatric Inventory-Clinician rating scale (NPI-C) is administered at visits 1, 3, 4 and 5 to evaluate 14 neuropsychiatric symptoms common throughout the dementia spectrum. These domains include delusions, hallucinations, agitation/aggression, depression/dysphoria, anxiety, elation/euphoria, apathy/indifference, disinhibition, irritability, aberrant motor behavior, sleep, and appetite/eating disorders. [41] The frequency of symptoms will be rated based on participant interview and responses from participants’ caregivers, and the study clinician will make an expert judgment as to the overall symptom severity coded from 0 (‘none’) to 3 (‘severe’). In addition to participant psychopathology, caregiver distress caused by each of the neuropsychiatric symptoms will be captured by the NPI-C.

Functional Ability and Quality of Life:

To determine participant functional ability and quality of life, participants and their caregivers complete the Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL), a 27-item instrument assessing the ability to perform activities of daily living. [42] A study clinician will also rate participant physical and mental well-being through the 12-Item Short Form Health Survey (SF-12). [43]

Sleep Assessments:

Participants are given Actiwatch Spectrum Plus devices (Philips Respironics, Murrysville, PA, U.S.A) to wear throughout the 13- to 15-week study period beginning at Visit 1. The devices measure omnidirectional movement via an accelerometer with a piezoelectric bimorph element that generates a voltage when moved. The device determines activity by capturing voltage differences and will be set to record voltages in 1-minute epochs. Participants or study partners also fill out sleep diaries daily to record several events, including when they (1) got into bed each night, (2) intended to begin sleeping, (3) got out of bed, and (4) removed the Actiwatch. Participants are instructed to wear the Actiwatch 24/7 and leave it on during showering, bathing, and swimming. The Actiwatch will be replaced at 4-week intervals in the clinic; participants will not charge it themselves; if the battery runs out in less than 4 weeks, the data remains intact and retrievable.

Participants undergo four separate overnight home sleep studies following visits 1, 3, 4 and 5 with the Sleep Profiler PSG2 (Advanced Brain Monitoring, Carlsbad, CA, U.S.A). During visit 1, participants and their study partners are trained on the administration of the PSG2 device at home. The PSG2 records electrooculography (EOG), electromyography (EMG), and electrocardiography (EKG) signals via leads that can be placed by the participant, or their care partner based on provided instructions. [44] The device allows for full polysomnography and measures nasal airflow, respiratory effort (chest and abdomen), pulse oximetry, body position, and snoring. This system enables high-quality measurements of sleep staging and amount, including SWS and rapid eye movement (REM) sleep, as well as other signals of interest including wake after sleep onset, sleep onset latency, and sleep efficiency. Signs of obstructive sleep apnea, such as snoring, will also be monitored during the first home sleep study. Any incidental findings will be reported to the participant and assessed as a potential exclusion criterion.

Participant sleep habits are also evaluated through self-report questionnaires, including the Pittsburgh Sleep Quality Index and the Epworth Sleepiness Scale. [34,45] These questionnaires are administered on visits when an ambulatory PSG is provided (visits 1, 3, 4 and 5). [34, 45]

Functional Magnetic Resonance Imaging Encoding Task:

Participants complete three MRI sessions during visits 2,3 and 5. Each MRI session includes task-based functional MRI scans as well as structural imaging (6 min). The task-based fMRI scan acquires high-resolution functional images with an isotropic resolution of 1.5 mm × 1.5 mm × 1.5 mm with no gap. Seventy triple-oblique slices are acquired parallel to the principal longitudinal axis of the hippocampus to cover almost the entire brain. In addition, a whole-brain MP-RAGE structural scan with 0.65 mm isotropic resolution is acquired. Techniques that maximize power and signal-to-noise ratio in the hippocampus will be utilized including manual segmentation of the hippocampal subfields following previously described methods (Bakker et. al, 2008;2012;2015) and the use of Advanced Normalization Tools (ANTs), which implements a diffeomorphic algorithm, symmetric normalization (SyN) to register the entire brain. [46,47]

During the task-based fMRI scans, participants complete the behavioral pattern separation task (BPS-O). [26–28, 48] This memory task aims to examine hippocampal subregion specific activity. Participants are presented with a series of pictures of everyday objects, and asked to determine whether each item is new, old (in the context of the task), or similar to a previously seen item. Objects that are merely similar but not identical to an item they’ve seen before are termed “lures,” and the correct identification of these merely “similar” or ‘lure” items have been shown to depend critically on DG/CA3 mediated pattern separation. Several cohort studies have reported that aMCI participants show a deficit in their ability to encode inputs with some degree of overlapping information (pattern separation), which is associated with increased activity in the DG/CA3 subregion on the fMRI scan. [48]

Exploratory Analyses – Plasma Measures of Aβ, Tau and GFAP:

Blood are collected during visits 1, 3, and 5 (baseline and after each treatment phase) in ethylenediaminetetraacetic acid (EDTA) tubes by venipuncture and centrifuged twice at 2500 xg for 15 minutes sequentially. 500 μl aliquots will be stored at −80°C with glycerol freezing component until ready for analysis. Genomic DNA will be extracted from a buffy coat culture using the QIAamp DNA Mini QIAcube Kit (Qiagen, Germantown MD). ApoE genotyping will be performed via pre-made TaqMan single nucleotide polymorphism assays including C-905013–10 (rs405509), C-3084793–20 (rs429358) and C-904973–10 (rs7412) using an Applied Biosystems 7900HT Real Time PCR System. Plasma samples will be analyzed for biomarkers such as Aβ40, Aβ42, phosphorylated tau181, neurofilament light, and glial fibrillary acidic protein using single molecule array (SIMOA) on the Quanterix HDX platform, run at 1:4 onboard automated dilution in duplicate with the appropriate kit calibrators and kit controls. In addition, two control human plasma samples will be run on each plate with normal and low A42/A40 to assess inter-plate variability.

Safety Monitoring

An independent Data and Safety Monitoring Board (DSMB) will act in an advisory capacity to the REST investigators. Three experienced and knowledgeable investigators with expertise in dementia research, sleep research, and statistical support for trials will comprise the DSMB. A representative from the National Institute of Aging (NIA) will also be present. The DSMB will have access to unblinded results stratified by the treatment arm. Quality and Assurance Monitoring reports of the accumulating study data provided by the Data Coordinating Center will be presented to the DSMB and will include comparisons of baseline characteristics, measures of disturbance, functional and cognitive outcomes variables, and occurrence of adverse events between treatment groups. The board may recommend for changes in study procedures or even pausing or stopping the trial if they observe convincing evidence of adverse treatment-associated safety issues.

Data Analytic Strategy

Power Analysis:

Sample size estimates were based on the pre-post change in the BPS-O score observed in a relevant drug trial for aMCI patients. [27] A one-sample t-test was used to estimate the power needed to see a treatment effect. To protect against a potential loss in power due to the influence of baseline covariates on outcomes, as well as data loss due to participants lost to follow-up, our estimated sample size is inflated by 24–45 patients above that needed to achieve 80% power, giving a total sample size of 100.

Aim 1 - Sleep:

In assessing the impact of TRZ on sleep, we will first compare sleep duration, percent time spent in SWS, SWA (0.5–4 Hz), sleep onset latency, and fragmentation indices (wake after sleep onset and sleep efficiency) between treatment arms. These outcome variables will be treated as continuous, assuming the normal approximation for binomial data. We will also conduct a repeated measures ANCOVA by performing a mixed-effects regression, whereby patients will act as their own controls. This analysis will allow for assessment of a period effect in which treatment order modifies the effect of treatment arms on outcome. Adjustments will be made for baseline covariates such as age, sex, ApoE genotype, and medical/mental health comorbidities if they are imbalanced by treatment arm.

Aim 2 - Memory:

In assessing the impact of TRZ on memory performance, we will compare hippocampal activation as measured by fMRI and BPS-O scores between treatment arms. We also determine whether improvements in these measures are impacted by time spent in SWS and SWA. Hippocampal activation is a continuous outcome and analysis of this outcome will mirror the procedure outlined in Aim 1. BPS-O scores will be measured as the difference in correct responses between the TRZ and placebo arms, and thus, positive values indicate memory improvements while taking TRZ. Treatment effect will be evaluated by the proportion of participants who improve on TRZ, and scores will be analyzed using a mixed-effects regression model to account for patient-specific differences in baseline Behavioral Task Performance scores and hippocampal activation. Finally, a mediation analysis will be performed to parse out the effect of TRZ on sleep measures listed above, the effect of sleep measures on hippocampal-dependent memory and other cognitive outcomes, and the direct effect of TRZ on hippocampal-dependent memory. The mediation analyses will help to determine whether the impacts of TRZ on memory may be mediated through its impact on sleep.

Exploratory Analyses:

We will also analyze whether the presence of the ApoE4 allele or baseline plasma levels of Aβ42/Aβ40 ratios, phosphorylated tau181, neurofilament light and glial fibrillary acidic protein predict responses in the sleep and memory outcomes outlined above. ANCOVA regression models controlling for clinical and demographic covariates will be used to determine whether changes in plasma levels (Aβ42/Aβ40 ratios, phosphorylated tau181, neurofilament light and glial fibrillary acidic protein) occur after exposure to TRZ in groups stratified by ApoE4 genotype. Secondly, unblinded post-hoc analyses of samples collected after each treatment phase will determine whether pre- and post-measures of Aβ42/Aβ40 ratios, phosphorylated tau181, neurofilament light and glial fibrillary acidic protein are modified by exposure to TRZ in the presence or absence of ApoE4 using a TRZ by ApoE interaction term in the ANCOVA regression models.

Discussion

We describe a study on the use of TRZ for improving sleep and cognition in aMCI and assess its potential use as a disease modifying treatment. In particular, the glymphatic system, or human equivalent of this mechanism, may be particularly active during slow wave sleep (SWS), which has been found to be reduced in many patients across the AD spectrum. [6] Thus, reduced SWS in the prodromal stages of AD may reduce or prevent the clearance of abnormal protein aggregates, disrupting cognition and memory. Evidence has shown that TRZ may increase SWS and is a widely used and safe drug that has shown potential in inducing SWS in older adults and even in slowing memory decline [17]. Therefore, this trial examines whether TRZ is effective as a pharmacological intervention to induce SWS and potentially disrupt the buildup of amyloid and tau protein aggregates in older adults with prodromal AD/aMCI and sleep complaints.

We have two major biological/mechanistic outcomes: 1) The potential benefit of TRZ on sleep and sleep architecture. To this end, we will measure sleep variables with actigraphy and home sleep testing. 2) The potential benefit of TRZ on hippocampal function and encoding mechanisms. To this end, we will assess TRZ’s effect on hippocampal activation during a pattern separation task as measured by fMRI, hypothesizing that TRZ will reduce hippocampal activation during the task and improve memory outcomes. Additionally, our exploratory aim is to analyze the presence of plasma biomarkers relevant to AD-related pathology, including Aβ42/Aβ40 ratio, phosphorylated tau181, glial fibrillary acidic protein and neurofilament light, to understand whether levels of these AD biomarkers are modified in response to impacts of TRZ on sleep.

Findings that TRZ does not negatively impact memory and/or cognitive function would encourage several areas of future research. First, future trials with longer treatment phases of TRZ would be warranted to observe changes in cognitive functioning. Additionally, a null primary outcome would motivate efforts to identify covariates that predict response, such as the moderating effects of severity of cognitive impairment, age, or medical history.

There has been increasing interest in targeting sleep to improve cognitive and functional outcomes throughout the AD spectrum. Thus, our clinical trial of a promising and safe drug (TRZ) to address these issues in very early AD, with a thorough set of mechanistically oriented biological markers may increase potential treatment response. We regard this as a promising first step in targeting sleep to improve AD outcomes.

Data Availability

The data from this trial will be made available to the field as a whole following NIH guidelines, with the current plan being to make them publicly available one year after the last data are collected.