Short sleep duration, low physical activity and high sedentary time are associated with higher dementia risk. To date, previous studies have considered these behaviors in isolation, and not as inter-related behaviors part of the 24-h day. Compositional data analysis (CoDA) treats these behaviors as inter-related within a constrained 24hrs. This allows for estimating the association of reallocating time from one behavior to another on health outcomes whilst adjusting for the remaining behaviors. Using CoDA, we estimated the association of substituting sleep duration for daytime behaviors (sedentary, light and moderate-to-vigorous physical activity [MVPA]) on dementia risk in those with short (<6h) and normal sleep (≥6h). 88,654 dementia-free participants (63 years (Q1, Q3: 56, 68); 56% female) from the UK Biobank completed 7-day/night accelerometry (Axivity AX3). Incident all-cause dementia was ascertained based on hospital records, death records, and primary care. CoDA isometric log-ratios were used to examine the association between 24-h use of time and dementia risk. Risk ratios for the associations between reallocating up to 1h sleep time to time in other activities and all-cause dementia were estimated. There were 484 incident all-cause dementia cases over a median follow-up of 7.2 years. Figure 1 presents the associations between discrete time-use substitutions and dementia risk. In persons with normal sleep duration, replacing light activity with sleep time was associated with a lowering of dementia risk (Fig. 1c). Conversely, replacing MVPA with sleep time was associated with the largest increase in dementia risk (Fig. 1e). In persons with short sleep duration, replacing inactivity and light activity with sleep time was associated with a lowering of dementia risk (Fig. 1b-d). In contrast to those with normal sleep duration, replacing sleep with MVPA did not lower risk of dementia in short sleepers (Fig. 1f). The way in which 24-h time use, comprised of sedentary behavior, light activity, MVPA, and sleep, is balanced may have implications for dementia risk. In short sleepers, prioritising 1h of sleep over sedentary or light activity could be a beneficial for dementia prevention. These findings have the potential to inform more targeted and precise dementia risk prevention guidelines.

Increasing evidence suggests a link between sleep and Alzheimer disease’s (AD) pathology and cognitive decline. We investigated whether sleep disturbances might be accompanied by faster AD pathology accumulation and/or cognitive decline before the onset of cognitive symptoms. We investigated cross-sectional and longitudinal associations between sleep quality, AD pathology and cognition in 220 participants from the PREVENT-AD cohort. A subsample of 99 participants had longitudinal amyloid and tau PET data (mean follow-up:4.33±0.53y, range: 1.59 – 6.11y) and a subsample of 218 had longitudinal cognitive evaluations (mean follow-up:0.80±0.50y, range 1-9). We used the PSQI global score and the actigraphy day-to-day sleep efficiency and fragmentation index variability, amyloid and tau-PET to measure amyloid and tau respectively and the Repeated Battery for the Assessment of Neuropsychological Status (RBANS) to assess cognition. All participants were cognitively unimpaired at their first sleep measurement and 32 individuals developed mild cognitive impairment (MCI) during the study. In supplementary analyses individuals were classified as having high or low to moderated levels of amyloid based on a centiloid of 40. We used robust linear models (RLM) and ANOVAs to assess the association between sleep, and AD pathology and cognition. We found that higher levels of amyloid pathology were associated with greater day-to-day sleep efficiency and fragmentation index variability (Fig. 1). Higher levels of tau pathology were associated with greater day-to-day sleep efficiency and fragmentation variability (Fig. 1). We further found longitudinal associations between annual amyloid change and greater day-to-day sleep efficiency variability (Fig. 1). These associations were only present in individuals who had centiloid values lower than or equal to 40 (Fig. 2). While no association was found between sleep quality and cognition, individuals who developed MCI (n = 32) had higher baseline PSQI scores (Fig. 3) and greater day-to-day sleep efficiency (Fig. 3) years before they were classified as MCI. Higher variability in sleep quality and worst self-reported sleep relates to AD pathology. Subjective and objective sleep impairments were also present years prior the development of MCI. Sleep variability and subjective sleep assessment changes might precede sleep disruptions observed later in the disease, which could promote further pathological processes in the brain.

Recent research has highlighted the importance of sleep on cognitive processes. However, conflicting evidence exists regarding optimal sleep duration and the impact of other co-occurring conditions, such as depression. A diagnosis of depression in mid-life may increase the risk of developing dementia. We examined the association between self-reported sleep duration and cognition and whether depression status modified this relationship. Dementia-and-stroke-free participants 45 years and older from the Framingham Heart Study Third-Generation, Omni 2, and New Off-spring Cohorts were included (n = 1,853; age 49.8[SD 9.2] years; 42.69% male; Table 1 ). Neuropsychological testing assessed verbal learning and memory abilities, abstract reasoning skills, processing speed and visuospatial memory. Depression was defined as having CES-D ≥16 or being under pharmacological treatment (n = 448; 32%). Multivariable linear regression models examined the association between sleep duration categories (≤6h; >6-<9h [reference]; ≥9h), individual cognitive tasks and global cognition, adjusting for age, sex, education and time between sleep and cognitive assessments. A second model included further adjustment for vascular risk factors and APOE4 status. Long sleep duration (≥9h) was associated with worse global cognition (β±SE: -0.24±0.07; p <0.001) compared to average sleep duration. In cognitive domain-specific tasks, long sleep was associated with worse verbal learning and memory abilities (-1.50±0.60, p = 0.013), visuospatial memory (-1.74±0.42, p <0.001), and processing speed (-0.08±0.03, p = 0.014), but not with abstract reasoning skills (-0.06±0.28, p = 0.838). Depression status significantly modified the association (global cognition int. p = 0.015; visual int. p = 0.006; and processing speed int. p = 0.038), where long sleep duration was associated with global cognition (-0.34±0.11; p = 0.003), visuospatial memory (-2.16±0.68; p = 0.002), and processing speed (-0.14±0.05; p = 0.011) in those with depression. Long sleep duration was also associated with visuospatial memory in those without depression (-1.27±0.55, p = 0.022) ( Table 3 ). Short sleep duration (≤6h) was not associated with cognition ( Table 2 ) and did not interact with depression status ( Table 3 ). Long sleep duration was associated with worse cognition particularly among adults with depression, underscoring the complex sleep-mood-cognition interplay. Further research should explore the longitudinal impacts and causal mechanisms of suboptimal sleep. These findings may inform public health promotion of optimal sleep to maintain cognitive health among persons with depression.

Disrupted sleep patterns have been shown to exacerbate Alzheimer's disease (AD) risk, potentially because of sleep's role in memory consolidation and synaptic plasticity. Recent evidence highlights that high brain-derived neurotrophic factor (BDNF) levels, a protein enabling neuroplasticity and memory functions, could play a protective role in age related cognitive impairment. We examined the association between total sleep time and cognition, and BDNF levels as a potential modifier. Third Generation, Omni 2, and New Offspring cohorts from the Framingham Heart Study Exam 2 (2008-2011) were included (n=2,344; age 48(9.1) y; 48%F; Table 1). Self-reported total sleep duration was categorized as: short sleep duration (≤6h), average sleep (7-8h, reference), and long sleep duration (≥9h). A composite measure of global cognition was calculated from neuropsychological tests, including Trails B, visual reproduction (VR), logical memory (LM), and similarities. A multivariable linear regression estimated the association between sleep duration and global cognition, and individual cognitive tasks. We further tested effect modification by BDNF level (median split). Long sleep duration was associated with worse global cognition (β±SE: -2.19 ±0.06; p<.001), compared to average sleep (Table 2). The association between sleep duration and individual cognitive tests are shown in Table 2. BDNF levels significantly modified the association of sleep duration with global cognition (p=0.03). Long sleep duration was associated with poorer global cognition (-0.17±0.08; p=0.04) in persons with lower BDNF, but not in those with higher BDNF levels (Table 3). Finally, short sleep duration was associated with poorer global cognition (-0.1±0.05; p=0.04) only among those with higher BDNF (Table 3). Long sleep duration was associated with poorer global cognition, an effect most notable in those with lower BDNF levels. Short sleep duration was also associated with worse global cognition, but in those with higher BDNF. An appropriate sleep duration may promote neuronal integrity and prevent age-related cognitive disorders. Further studies shall elucidate the role of BDNF in the interplay between sleep duration and cognition.

STUDY OBJECTIVES:Poor sleep may play a role in the risk of dementia. However, few studies have investigated the association between polysomnography (PSG)-derived sleep architecture and dementia incidence. We examined the relationship between sleep architecture and dementia incidence across five US-based cohort studies from the Sleep and Dementia Consortium. METHODS:Percent of time spent in stages of sleep (N1, N2, N3, rapid eye movement sleep), wake after sleep onset, sleep maintenance efficiency, apnea-hypopnea index, and relative delta power were derived from a single night home-based PSG. Dementia was ascertained in each cohort using its cohort-specific criteria. Each cohort performed Cox proportional hazard regressions for each sleep exposure and incident dementia, adjusting for age, sex, body mass index, antidepressant use, sedative use, and APOE e4 status. Results were then pooled in a random effects model. RESULTS:The pooled sample comprised 4657 participants (30% women) aged ≥ 60 years (mean age was 74 years at sleep assessment). There were 998 (21.4%) dementia cases (median follow-up time of 5 to 19 years). Pooled effects of the five cohorts showed no association between sleep architecture and incident dementia. When pooled analysis was restricted to the three cohorts which had dementia case ascertainment based on DSM-IV/V criteria (n = 2374), higher N3% was marginally associated with an increased risk of dementia (hazard ratio (HR): 1.06; 95%CI: 1.00-1.12, per percent increase N3, p = .050). CONCLUSIONS:There were no consistent associations between sleep architecture measured and the risk of incident dementia. Implementing more nuanced sleep metrics and examination of associations with dementia subtypes remains an important next step for uncovering more about sleep-dementia associations.

INTRODUCTION:We investigated whether depression modified the associations between sleep duration and cognitive performance. METHODS:We examined the associations between sleep duration and cognition in 1853 dementia-and-stroke-free participants (mean age 49.8 years, [range 27-85]; 42.7% male). Participants were categorized into four groups: no depressive symptoms, no antidepressants; depressive symptoms without antidepressant use; antidepressant use without depressive symptoms; and depressive symptoms and antidepressant use. RESULTS:Long sleep was associated with reduced overall cognitive function (β ± standard error = -0.25 ± 0.07, p < 0.001), with strongest effects in those with depressive symptoms using (-0.74 ± 0.30, p = 0.017) and not using antidepressants (-0.60 ± 0.26, p = 0.024). Weaker but significant effects were observed in those without depressive symptoms (-0.18 ± 0.09, p = 0.044). No significant associations were observed in participants using antidepressants without depressive symptoms. DISCUSSION:Associations between sleep duration and cognitive performance are strongest in individuals with depressive symptoms, regardless of antidepressant use. Future research should elucidate underlying mechanisms and temporal relationships. HIGHLIGHTS:Sleeping ≥ 9 hours/night was associated with worse cognitive performance. This association was stronger among those with depression. Long sleepers were more likely to report symptoms of depression. Sleep may be a modifiable risk for cognitive decline in people with depression.

Study Objectives Although short sleep could promote neurodegeneration, long sleep may be a marker of ongoing neurodegeneration, potentially as a result of neuroinflammation. The objective was to evaluate sleep patterns with age of expected Alzheimer's disease (AD) onset and neuroinflammation.Methods We tested 203 dementia-free participants (68.5 +/- 5.4 years old, 78M). The PREVENT-AD cohort includes older persons with a parental history of AD whose age was nearing their expected AD onset. We estimated expected years to AD onset by subtracting the participants' age from their parent's at AD dementia onset. We extracted actigraphy sleep variables of interest (times of sleep onset and morning awakening, time in bed, sleep efficiency, and sleep duration) and general profiles (sleep fragmentation, phase delay, and hypersomnia). Cerebrospinal fluid (CSF) inflammatory biomarkers were assessed with OLINK multiplex technology.Results Proximity to, or exceeding, expected age of onset was associated with a sleep profile suggestive of hypersomnia (longer sleep and later morning awakening time). This hypersomnia sleep profile was associated with higher CSF neuroinflammatory biomarkers (IL-6, MCP-1, and global score). Interaction analyses revealed that some of these sleep-neuroinflammation associations were present mostly in those closer/exceeding the age of expected AD onset, APOE4 carriers, and those with better memory performance.Conclusions Proximity to, or exceeding, parental AD dementia onset was associated with a longer sleep pattern, which was related to elevated proinflammatory CSF biomarkers. We speculate that longer sleep may serve a compensatory purpose potentially triggered by neuroinflammation as individuals are approaching AD onset. Further studies should investigate whether neuroinflammatory-triggered long sleep duration could mitigate cognitive deficits. Graphical Abstract

Background Short sleep duration has been associated with an increased risk of cognitive impairment and dementia. Short sleep is associated with elevated blood pressure, yet the combined insult of short sleep and hypertension on brain health remains unclear. We assessed whether the association of sleep duration with cognition and vascular brain injury was moderated by hypertensive status. Methods and Results A total of 682 dementia‐free participants (mean age, 62±9 years; 53% women) from the Framingham Heart Study completed assessments of cognition, office blood pressure, and self‐reported habitual and polysomnography‐derived sleep duration; 637 underwent brain magnetic resonance imaging. Linear regressions were performed to assess effect modification by hypertensive status on total sleep time (coded in hours) and cognitive and magnetic resonance imaging outcomes. There was a significant interaction between sleep duration and hypertensive status when predicting executive function/processing speed (Trail Making B‐A) and white matter hyperintensities. When results were stratified by hypertensive status, longer sleep duration was associated with better executive functioning/processing speed scores in the hypertensive group (meaning that shorter sleep duration was associated with poorer executive function/processing speed scores) (self‐report sleep: β=0.041 [95% CI, 0.012–0.069], P =0.005; polysomnography sleep: β=0.045 [95% CI, 0.002–0.087], P =0.038), but no association was observed for the normotensive group. Similarly, shorter subjective sleep duration was associated with higher white matter hyperintensity burden in the hypertensive group (β=−0.115 [95% CI, −0.227 to −0.004], P =0.042), but not in the normotensive group. Conclusions In individuals with hypertension, shorter sleep duration was associated with worse cognitive performance and greater brain injury.

Background and ObjectivesIdiopathic/isolated REM sleep behavior disorder (iRBD) is associated with dementia with Lewy bodies and Parkinson disease. Despite evidence of abnormal cerebral perfusion in iRBD, there is currently no pattern that can predict whether an individual will develop dementia with Lewy bodies or Parkinson disease. The objective was to identify a perfusion signature associated with conversion to dementia with Lewy bodies in iRBD.MethodsPatients with iRBD underwent video-polysomnography, neurologic and neuropsychological assessments, and baseline 99mTc-HMPAO SPECT to assess relative cerebral blood flow. Partial least squares correlation was used to identify latent variables that maximized covariance between 27 clinical features and relative gray matter perfusion. Patient-specific scores on the latent variables were used to test the association with conversion to dementia with Lewy bodies compared with that with Parkinson disease. The signature's expression was also assessed in 24 patients with iRBD who underwent a second perfusion scan, 22 healthy controls, and 19 individuals with Parkinson disease.ResultsOf the 137 participants, 93 underwent SPECT processing, namely 52 patients with iRBD (67.9 years, 73% men), 19 patients with Parkinson disease (67.3 years, 37% men), and 22 controls (67.0 years, 73% men). Of the 47 patients with iRBD followed up longitudinally (4.5 years), 12 (26%) developed a manifest synucleinopathy (4 dementia with Lewy bodies and 8 Parkinson disease). Analysis revealed 2 latent variables between relative blood flow and clinical features: the first was associated with a broad set of features that included motor, cognitive, and perceptual variables, age, and sex; the second was mostly associated with cognitive features and RBD duration. When brought back into the patient's space, the expression of the first variable was associated with conversion to a manifest synucleinopathy, whereas the second was associated with conversion to dementia with Lewy bodies. The expression of the patterns changed over time and was associated with worse motor features.DiscussionThis study identified a brain perfusion signature associated with cognitive impairment in iRBD and transition to dementia with Lewy bodies. This signature, which can be derived from individual scans, has the potential to be developed into a biomarker that predicts dementia with Lewy bodies in at-risk individuals.

Study Objectives Apolipoprotein E ɛ4 (APOE4) is the strongest genetic risk factor for Alzheimer’s disease (AD). In addition, APOE4 carriers may exhibit sleep disturbances, but conflicting results have been reported, such that there is no clear consensus regarding which aspects of sleep are impacted. Our objective was to compare objective sleep architecture between APOE4 carriers and non-carriers, and to investigate the modulating impact of age, sex, cognitive status, and obstructive sleep apnea (OSA). Methods A total of 198 dementia-free participants aged >55 years old (mean age: 68.7 ± 8.08 years old, 40.91% women, 41 APOE4 carriers) were recruited in this cross-sectional study. They underwent polysomnography, APOE4 genotyping, and a neuropsychological evaluation. ANCOVAs assessed the effect of APOE4 status on sleep architecture, controlling for age, sex, cognitive status, and the apnea–hypopnea index. Interaction terms were added between APOE4 status and covariates. Results Rapid eye movement (REM) sleep percentage (F = 9.95, p = .002, ηp2 = 0.049) and duration (F = 9.23, p = .003, ηp2 = 0.047) were lower in APOE4 carriers. The results were replicated in a subsample of 112 participants without moderate-to-severe OSA. There were no significant interactions between APOE4 status and age, sex, cognitive status, and OSA in the whole sample. Conclusions Our results show that APOE4 carriers exhibit lower REM sleep duration, including in cognitively unimpaired individuals, possibly resulting from early neurodegenerative processes in regions involved in REM sleep generation and maintenance.

INTRODUCTION:The limbic system is critical for memory function and degenerates early in the Alzheimer's disease continuum. Whether obstructive sleep apnea (OSA) is associated with alterations in the limbic white matter tracts remains understudied. METHODS:Polysomnography, neurocognitive assessment, and brain magnetic resonance imaging (MRI) were performed in 126 individuals aged 55-86 years, including 70 cognitively unimpaired participants and 56 participants with mild cognitive impairment (MCI). OSA measures of interest were the apnea-hypopnea index and composite variables of sleep fragmentation and hypoxemia. Microstructural properties of the cingulum, fornix, and uncinate fasciculus were estimated using free water-corrected diffusion tensor imaging. RESULTS:Higher levels of OSA-related hypoxemia were associated with higher left fornix diffusivities only in participants with MCI. Microstructure of the other white matter tracts was not associated with OSA measures. Higher left fornix diffusivities correlated with poorer episodic verbal memory. DISCUSSION:OSA may contribute to fornix damage and memory dysfunction in MCI. HIGHLIGHTS:Sleep apnea-related hypoxemia was associated with altered fornix integrity in MCI. Altered fornix integrity correlated with poorer memory function. Sleep apnea may contribute to fornix damage and memory dysfunction in MCI.

INTRODUCTION Measuring day-to-day sleep variability might reveal unstable sleep-wake cycles reflecting neurodegenerative processes. We evaluated the association between Alzheimer's disease (AD) fluid biomarkers with day-to-day sleep variability. METHODS In the PREVENT-AD cohort, 203 dementia-free participants (age: 68.3 +/- 5.4; 78 males) with a parental history of sporadic AD were tested with actigraphy and fluid biomarkers. Day-to-day variability (standard deviations over a week) was assessed for sleep midpoint, duration, efficiency, and nighttime activity count. RESULTS Lower cerebrospinal fluid (CSF) ApoE, higher CSF p-tau181/amyloid-beta (A beta)(42), and higher plasma p-tau231/A beta(42) were associated with higher variability of sleep midpoint, sleep duration, and/or activity count. The associations between fluid biomarkers with greater sleep duration variability were especially observed in those that carried the APOE4 allele, mild cognitive impairment converters, or those with gray matter atrophy. DISCUSSION Day-to-day sleep variability were associated with biomarkers of AD in at-risk individuals, suggesting that unstable sleep promotes neurodegeneration or, conversely, that AD neuropathology disrupts sleep-wake cycles.

Study Objectives: Apolipoprotein E epsilon 4 (APOE4) is the strongest genetic risk factor for Alzheimer's disease (AD). In addition, APOE4 carriers may exhibit sleep disturbances, but conflicting results have been reported, such that there is no clear consensus regarding which aspects of sleep are impacted. Our objective was to compare objective sleep architecture between APOE4 carriers and non-carriers, and to investigate the modulating impact of age, sex, cognitive status, and obstructive sleep apnea (OSA). Methods: A total of 198 dementia-free participants aged >55 years old (mean age: 68.7 +/- 8.08 years old, 40.91% women, 41 APOE4 carriers) were recruited in this cross-sectional study. They underwent polysomnography, APOE4 genotyping, and a neuropsychological evaluation. ANCOVAs assessed the effect of APOE4 status on sleep architecture, controlling for age, sex, cognitive status, and the apnea-hypopnea index. Interaction terms were added between APOE4 status and covariates. Results: Rapid eye movement (REM) sleep percentage (F = 9.95, p = .002, eta p2 = 0.049) and duration (F = 9.23, p = .003, eta p2 = 0.047) were lower in APOE4 carriers. The results were replicated in a subsample of 112 participants without moderate-to-severe OSA. There were no significant interactions between APOE4 status and age, sex, cognitive status, and OSA in the whole sample. Conclusions: Our results show that APOE4 carriers exhibit lower REM sleep duration, including in cognitively unimpaired individuals, possibly resulting from early neurodegenerative processes in regions involved in REM sleep generation and maintenance.

Engaging in regular physical activity and obtaining recommended amounts of sleep are touted as strategies to promote healthy brain aging. However, as each day is only 24 hours long, changing time spent in one activity must come at the expense or gain of another, making it necessary to understand how the whole 24-hour activity composition impacts dementia risk. We applied compositional data analysis to investigate the effect of substituting sleep duration for different levels of physical activity (i.e., inactivity, light activity, and moderate to vigorous physical activity; MVPA) on dementia risk relative to two reference compositions; a “typical” short sleeper (< 6hrs) and normal sleeper (≥ 6hrs). The study sample comprised participants from the community-based UK Biobank with 24-hour behaviors estimated using 7 days of accelerometry. The mean age of the sample was 63 years (Q1, Q3: 56, 68); 56% were women. Of the 88,654 participants, there were 718 incident all-cause dementia cases over a median follow-up of 8.2 years. For short sleepers, increasing sleep duration at the expense of inactivity or light activity was associated with a lowering of dementia risk, but not when at the expense of MVPA. For persons with normal sleep duration, the effect of increasing or decreasing sleep duration on dementia risk differed for all three substituted behaviors (i.e., inactivity, light, or MVPA). Most notably, dementia risk was higher when increasing sleep at the expense of MVPA and lower when increasing MVPA at the expense of sleep. The interpretation of the results was broadly consistent when using MRI-based outcomes (e.g., hippocampal volume) in a subset with brain imaging (n = 15,263). Our findings underscore the complexity of optimizing dementia risk reduction strategies, emphasizing the need for personalized approaches that balance trade-offs between sleep duration and differing physical activity levels based on individual circumstances, such as habitual sleep duration.

Background: Whether obstructive sleep apnea (OSA) increases the risk of cognitive decline and how sex and age influence this association is not clear. Here, we characterized the sex- and age-specific associations between OSA risk and 3-year cognitive change in middle-aged and older adults.Methods: We included 24,819 participants aged 45-85 (52% women) from the Canadian Longitudinal Study on Aging. OSA risk was measured at baseline using the STOP combined to body mass index (STOP-B). Neuropsychological tests assessed memory, executive functioning, and psychomotor speed at baseline and at 3-year follow-up. We conducted age- and sex-specific linear mixed models to estimate the predictive role of baseline STOP-B score on 3-year cognitive change.Results: Men at high-risk for OSA aged 45-59 years showed a steeper decline in psychomotor speed (+13.2 [95% CI: -1.6, 27.9]) compared to men at low-risk. Men at high-risk for OSA aged 60-69 showed a steeper decline in mental flexibility (-1.2 [-1.9, -0.5]) and processing speed (+0.6 [0.3, 0.9]) than those at low-risk. Women at high-risk for OSA aged 45-59 showed a steeper decline in processing speed (+0.1 [-0.2, 0.4]) than women at low-risk, while women at high-risk >70 years had a steeper decline in memory (-0.2 [-0.6, 0.1]) and processing speed (+1.0 [0.4, 1.5]).Conclusions: Associations between OSA risk and cognitive decline over 3 years depend on age and sex. Being at high-risk for OSA is associated with a generalized cognitive decline in attention and processing speed, while a memory decline is specific to older women (>70 years).

We previously showed that day-to-day sleep variability was associated with biomarkers of Alzheimer’s disease (AD) pathology. Given that brain-derived neurotrophic factor (BDNF) activity has been involved in both AD and cognitive impacts of lifestyle risk factors, we sought to evaluate day-to-day sleep variability in those carrying the Met allele of the Val66Met BDNF polymorphism, which affects BDNF release. Additionally, we explored whether BDNF polymorphism modified the association between CSF AD pathology and day-to-day sleep variability. The PREVENT-AD cohort enrolls dementia-free persons with a parental history of sporadic AD. We characterized 203 dementia-free participants from this cohort at the polymorphic BDNF locus, identifying 136 persons with genotype Val/Val (age 68.2±5.3y, 75%women), 67 Met heterozygotes/homozygotes (68.4±5.6y, 73% women, including six Met/Met homozygotes). After a week of actigraphy, we calculated these participants’ standard deviation of day-to-day sleep characteristics. We used t-tests to compare day-to-day sleep variability in sleep characteristics between Val homozygotes and Met carriers. In a subsample of 101 participants, we assayed CSF Aβ 42 , t-tau and p-tau181, and used age- and sex-adjusted linear regressions with an interaction term to test for moderation by BDNF genotype (36 Met carriers vs. 65 Val homozygotes) between sleep variability and CSF biomarker results. As compared to Val homozygotes, sleep was disturbed and unstable in BDNF Met carriers (heterozygotes/homozygotes). They had higher day-to-day variability in sleep fragmentation (activity counts, wake after sleep onset, fragmentation index), sleep onset latency, and sleep duration, resulting in weekly sleep patterns that were more fragmented and less efficient. Further, BDNF genotype moderated the association between CSF t-tau and p-tau181 with day-to-day sleep duration variability, such that only Met carriers showed an association between elevated tau concentration and sleep duration variability. BDNF Met carriers had disturbed and unstable daily sleep patterns. Because the Met allele is known to decrease plasticity of neural mechanisms, the ability to achieve healthy and stable sleep may depend on such mechanisms. Thus, poorer sleep in Met carriers might be a biological mechanism by which altered BDNF activity affects tau pathology or, alternatively, accumulated AD pathology in Met carriers may disrupt sleep-wake patterns.

IMPORTANCE Slow-wave sleep (SWS) supports the aging brain in many ways, including facilitating the glymphatic clearance of proteins that aggregate in Alzheimer disease. However, the role of SWS in the development of dementia remains equivocal. OBJECTIVE To determine whether SWS loss with aging is associated with the risk of incident dementia and examine whether Alzheimer disease genetic risk or hippocampal volumes suggestive of early neurodegeneration were associated with SWS loss. DESIGN, SETTING, AND PARTICIPANTS This prospective cohort study included participants in the Framingham Heart Study who completed 2 overnight polysomnography (PSG) studies in the time periods 1995 to 1998 and 2001 to 2003. Additional criteria for individuals in this study sample were an age of 60 years or older and no dementia at the time of the second overnight PSG. Data analysis was performed from January 2020 to August 2023. EXPOSURE Changes in SWS percentage measured across repeated overnight sleep studies over a mean of 5.2 years apart (range, 4.8-7.1 years). MAIN OUTCOME Risk of incident all-cause dementia adjudicated over 17 years of follow-up from the second PSG. RESULTS From the 868 Framingham Heart Study participants who returned for a second PSG, this cohort included 346 participants with a mean age of 69 years (range, 60-87 years); 179 (52%) were female. Aging was associated with SWS loss across repeated overnight sleep studies (mean [SD] change, -0.6 [1.5%] per year; P <.001). Over the next 17 years of follow-up, there were 52 cases of incident dementia. In Cox regression models adjusted for age, sex, cohort, positivity for at least 1 APOE e4 allele, smoking status, sleeping medication use, antidepressant use, and anxiolytic use, each percentage decrease in SWS per year was associated with a 27% increase in the risk of dementia (hazard ratio, 1.27; 95% CI, 1.06-1.54; P =.01). SWS loss with aging was accelerated in the presence of Alzheimer disease genetic risk (ie, APOE e4 allele) but not hippocampal volumes measured proximal to the first PSG. CONCLUSIONS AND RELEVANCE This cohort study found that slow-wave sleep percentage declined with aging and Alzheimer disease genetic risk, with greater reductions associated with the risk of incident dementia. These findings suggest that SWS loss may be a modifiable dementia risk factor.

INTRODUCTION:We investigated whether novel plasma biomarkers are associated with cognition, cognitive decline, and functional independence in activities of daily living across and within neurodegenerative diseases. METHODS:Glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), phosphorylated tau (p-tau)181 and amyloid beta (Aβ)42/40 were measured using ultra-sensitive Simoa immunoassays in 44 healthy controls and 480 participants diagnosed with Alzheimer's disease/mild cognitive impairment (AD/MCI), Parkinson's disease (PD), frontotemporal dementia (FTD) spectrum disorders, or cerebrovascular disease (CVD). RESULTS:GFAP, NfL, and/or p-tau181 were elevated among all diseases compared to controls, and were broadly associated with worse baseline cognitive performance, greater cognitive decline, and/or lower functional independence. While GFAP, NfL, and p-tau181 were highly predictive across diseases, p-tau181 was more specific to the AD/MCI cohort. Sparse associations were found in the FTD and CVD cohorts and for Aβ42/40 . DISCUSSION:GFAP, NfL, and p-tau181 are valuable predictors of cognition and function across common neurodegenerative diseases, and may be useful in specialized clinics and clinical trials.

Increasing evidence suggests a link between sleep and late-life Alzheimer disease’s (AD) pathology. We investigated whether sleep degradation might be accompanied by faster AD pathology accumulation and/or whether early AD pathologic changes might be accompanied by sleep changes before the onset of cognitive symptoms. We investigated 228 PREVENT-AD participants with available sleep data who underwent Aβ, [18F] NAV-4694, and tau,[18F] Flortaucipir, positron emission tomography (PET). Longitudinal subjective sleep quality data were available for 191 participants (follow-up:1.03±0.19y), longitudinal objective sleep data measured with actigraphy was available for 152 participants (follow-up:2.5±1.24y), and longitudinal PET scans were available for 104 participants (follow-up:4.3±0.24y). We assessed sleep quality using the Pittsburgh sleep quality index (PSQI) global score along with 7-day actigraphy to indicate sleep duration, efficiency, and fragmentation index. Daily variation in sleep was measured using cross-sectional and longitudinal standard deviations across the 7 days of actigraphy. Linear mixed effect models tested for longitudinal association of baseline sleep measures with PET outcomes over time. We also examined whether an increase in PET AD tracer uptake predicted changes in sleep quality and day-to-day variability. Every model controlled for age and sex. We found no association between sleep measures and Aβ PET. Higher baseline PSQI scores were associated with higher levels of tau over time (p = 0.004, R2 = 0.034, 𝛽 = 0.007, Fig.1, A). Higher baseline variability of sleep duration and fragmentation index were also associated with higher levels of tau longitudinally (p = 0.001, R2 = 0.05, 𝛽 = 0.001, Fig.1, B; p = 0.029, R2 = 0.022, 𝛽 = 0.01; Fig.1, C). Furthermore, increased tau at baseline was associated with lower sleep quality (p = 0.006, R2 = 0.026, 𝛽 = 4.12, Fig.2, A), and with higher sleep duration variability over time (p = 0.004, R2 = 0.06, 𝛽 = 61.56, Fig.1, B.) Poor sleep quality and higher day-to-day sleep variability in older age could contribute to faster rate of tau pathology accumulation, which could in turn disrupt sleep further. Targeting sleep disturbances may therefore serve in delaying tau burden and slowing down disease progression.

Due to low success rates in clinical trials for Alzheimer’s disease (AD), there is a need to apply precision medicine approaches, such as stratifying based on APOE genotype, in order to assess its effects on outcome measures. Herein, we aim to better understand how plasma biomarkers of AD and neurodegenerative pathology are associated with cognition and neurodegeneration in APOE E4 carriers compared to non-carriers. Patients from the Ontario Neurodegenerative Disease Research Initiative (ONDRI) diagnosed with AD were included (n = 126, age = 71.0±8.2, 55%M). Plasma concentrations of Aβ 40 and Aβ 42 (Aβ 42/40 ratio), glial fibrillary acidic protein (GFAP), neurofilament light (NfL) and phosphorylated-tau181 (p-tau181) were measured using Simoa assays. Composite cognitive domain scores (attention & working memory, executive function, language, memory, and visuospatial function) were computed from a comprehensive neuropsychological assessment. Volumes of regional grey matter, ventricular cerebrospinal fluid, white matter hyperintensities, perivascular spaces, lacunes and strokes were extracted from 3T structural MRI sequences using the SABRE pipeline. Linear regression models with an interaction term, controlling for age, sex and education were used to test the moderating effect of the APOE E4 allele on the association of plasma biomarkers with cognitive and MRI variables. When interaction effects were significant, post-hoc models stratified by APOE E4 carrier status and controlling for age, sex and education were assessed. The APOE E4 allele moderated the association of GFAP, NfL and p-tau181 with memory. Further stratification revealed that higher levels of GFAP, NfL and p-tau181 were all associated with worse memory only in APOE E4 carriers. APOE E4 was also found to moderate the association of GFAP and p-tau181 with many imaging markers. Further stratification revealed that higher levels of GFAP were associated with increased white matter hyperintensities, ventricular expansion and grey matter atrophy (temporal lobe, occipital lobe, hippocampus, basal ganglia and thalamus) only in APOE E4 carriers. Higher levels of p-tau181 were also associated with increased temporal, parietal, and hippocampal atrophy only in APOE E4 carriers. Plasma biomarkers, especially GFAP and p-tau181, appear to be significantly more predictive of memory deficits and brain neurodegeneration in APOE E4 carriers compared to non-carriers in AD.