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Introduction: We investigated whether depression modified the associations between sleep duration and cognitive performance., Methods: Multivariable linear regression models examined the associations between sleep duration and cognition in 1,853 dementia- and stroke-free participants from the Framingham Heart Study. Participants were categorized in four groups: no depressive symptoms, no antidepressants; depressive symptoms without antidepressants use; antidepressant use without depressive symptoms; both depressive symptoms and antidepressant use., Results: Long sleep was associated with reduced overall cognitive function. Strong associations between sleep duration and cognitive performance were found in individuals with depressive symptoms, regardless of antidepressant use. Weaker but significant effects were observed in those without depressive symptoms. No significant associations were observed in participants using antidepressants without depressive symptoms., Discussion: These findings provide new evidence that sleep duration may be a modifiable risk factor for cognitive decline, particularly in individuals with depressive symptoms. Future research should elucidate underlying mechanisms and temporal relationships., Competing Interests: Conflict of Interests: Dr. Seshadri reports consulting for Eisai and Biogen. Dr. Baril reports speaking fees from Eisai. Dr. Salardini reports speaking fees from Lilly.

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.

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 macro-architecture and dementia incidence across five US-based cohort studies from the Sleep and Dementia Consortium (SDC)., Methods: Percent of time spent in stages of sleep (N1, N2, N3, REM sleep), wake after sleep onset and sleep maintenance efficiency 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, anti-depressant use, sedative use, and APOE e4 status. Results were then pooled in random effects meta-analyses., Results: The pooled sample comprised 4,657 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 meta-analyses were restricted to the three cohorts which had dementia case ascertainment based on DSM-IV/V criteria (n=2,374), higher N3% was marginally associated with an increased risk of dementia (HR: 1.06; 95%CI: 1.00-1.12, per percent increase N3, p=0.050)., Conclusions: There were no consistent associations between sleep macro-architecture measured and the risk of incident dementia. Implementing more nuanced sleep metrics remains an important next step for uncovering more about sleep-dementia associations.

Importance: Human brain development and maintenance is under both genetic and environmental influences that likely affect later-life dementia risk., Objective: To examine environmental influences by testing whether time-dependent secular differences occurred in cranial and brain volumes and cortical thickness over birth decades spanning 1930 to 1970., Design, Setting, and Participants: This cross-sectional study used data from the community-based Framingham Heart Study cohort for participants born in the decades 1930 to 1970. Participants did not have dementia or history of stroke and had magnetic resonance imaging (MRI) obtained from March 18, 1999, to November 15, 2019. The final analysis dataset was created in October 2023., Exposure: Years of birth ranging from 1925 to 1968., Main Measures: Cross-sectional analysis of intracranial, cortical gray matter, white matter, and hippocampal volumes as well as cortical surface area and cortical thickness. The secular measure was the decade in which the participant was born. Covariates included age at MRI and sex., Results: The main study cohort consisted of 3226 participants with a mean (SD) age of 57.7 (7.8) years at the time of their MRI. A total of 1706 participants were female (53%) and 1520 (47%) were male. The birth decades ranged from the 1930s to 1970s. Significant trends for larger intracranial, hippocampal, and white matter volumes and cortical surface area were associated with progressive birth decades. Comparing the 1930s birth decade to the 1970s accounted for a 6.6% greater volume (1234 mL; 95% CI, 1220-1248, vs 1321 mL; 95% CI, 1301-1341) for ICV, 7.7% greater volume (441.9 mL; 95% CI, 435.2-448.5, vs 476.3 mL; 95% CI, 467.0-485.7) for white matter, 5.7% greater value (6.51 mL; 95% CI, 6.42-6.60, vs 6.89 mL; 95% CI, 6.77-7.02) for hippocampal volume, and a 14.9% greater value (1933 cm2; 95% CI, 1908-1959, vs 2222 cm2; 95% CI, 2186-2259) for cortical surface area. Repeat analysis applied to a subgroup of 1145 individuals of similar age range born in the 1940s (mean [SD] age, 60.0 [2.8] years) and 1950s (mean [SD] age, 59.0 [2.8] years) resulted in similar findings., Conclusion and Relevance: In this study, secular trends for larger brain volumes suggested improved brain development among individuals born between 1930 and 1970. Early life environmental influences may explain these results and contribute to the declining dementia incidence previously reported in the Framingham Heart Study cohort.

Dementia disproportionately affects individuals from disadvantaged backgrounds, including those living in areas of lower neighborhood-level socioeconomic status. It is important to understand whether there are specific neighborhood characteristics associated with dementia risk factors and cognition which may inform dementia risk reduction interventions. We sought to examine whether greenspace, walkability, and crime associated with the cumulative burden of modifiable dementia risk factors and cognition. This was a cross-sectional analysis of 2016-2020 data from the Healthy Brain Project, a population-based cohort of community-dwelling individuals across Australia. Participants were aged 40-70 and free of dementia. Measures included greenspace (greenspace % in the local area, and distance to greenspace, n = 2,181); and intersection density (n = 1,159), and crime (rate of recorded offences; n = 1,159). Outcomes included a modified Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) dementia risk score to index the burden of modifiable vascular dementia risk factors; and composite scores of both memory and attention, derived from the Cogstate Brief Battery. Linear regressions adjusted for age, sex, education, and personal socio-economic status, demonstrated distance to greenspace ( b  ±  SE per 2-fold increase = 0.09 ± 0.03, p  =.005) and crime rate ( b  ±  SE per 2-fold increase = 0.07 ± 0.03, p  =.018) were associated with higher modified CAIDE. Higher crime was associated with lower memory performance ( b  ±  SE  = -0.03 ± 0.01, p  =.018). The association between distance to greenspace and modified CAIDE was only present in low-moderate socioeconomic status neighborhoods (p interaction = 0.004). Dementia prevention programs that address modifiable risk factors in midlife should consider the possible role of neighborhood characteristics., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr Cavuoto and Dr Pase are supported by a Dementia Australia Research Foundation award (Lucas' Papaw Remedies Project Grant). Dr Pase reported receiving grants from the Alzheimer’s Association, the Bethlehem Griffiths Research Foundation, the National Health and Medical Research Council (NHMRC), and the National Heart Foundation of Australia during the conduct of the study and grants from the Alzheimer's Disease Drug Discovery Foundation, the Brain Foundation, the National Institutes of Health, the NHMRC, and the Stroke Foundation outside the submitted work. Dr Lim reported receiving grants from the NHMRC outside the submitted work. Dr Maruff is a full-time employee of Cogstate Ltd, the company that provided the Cogstate Brief Battery. No other disclosures were reported., (© 2024 The Authors.)

Accumulating evidence supports a link between sleep disorders, disturbed sleep, and adverse brain health, ranging from stroke to subclinical cerebrovascular disease to cognitive outcomes, including the development of Alzheimer disease and Alzheimer disease-related dementias. Sleep disorders such as sleep-disordered breathing (eg, obstructive sleep apnea), and other sleep disturbances, as well, some of which are also considered sleep disorders (eg, insomnia, sleep fragmentation, circadian rhythm disorders, and extreme sleep duration), have been associated with adverse brain health. Understanding the causal role of sleep disorders and disturbances in the development of adverse brain health is complicated by the common development of sleep disorders among individuals with neurodegenerative disease. In addition to the role of sleep disorders in stroke and cerebrovascular injury, mechanistic hypotheses linking sleep with brain health and biomarker data (blood-based, cerebrospinal fluid-based, and imaging) suggest direct links to Alzheimer disease-specific pathology. These potential mechanisms and the increasing understanding of the "glymphatic system," and the recognition of the importance of sleep in poststroke recovery, as well, support a biological basis for the indirect (through the worsening of vascular disease) and direct (through specific effects on neuropathology) connections between sleep disorders and brain health. Given promising evidence for the benefits of treatment and prevention, sleep disorders and disturbances represent potential targets for early treatment that may improve brain health more broadly. In this scientific statement, we discuss the evidence supporting an association between sleep disorders and disturbances and poor brain health ranging from stroke to dementia and opportunities for prevention and early treatment.

Background and Objectives: Higher YKL-40 levels in the CSF are a known biomarker of brain inflammation. We explored the utility of plasma YKL-40 as a biomarker for accelerated brain aging and dementia risk., Methods: We performed cross-sectional and prospective analyses of 4 community-based cohorts in the United States or Europe: the Age, Gene/Environment Susceptibility-Reykjavik Study, Atherosclerosis Risk in the Communities study, Coronary Artery Risk Development in Young Adults study, and Framingham Heart Study (FHS). YKL-40 was measured from stored plasma by a single laboratory using Mesoscale Discovery with levels log transformed and standardized within each cohort. Outcomes included MRI total brain volume, hippocampal volume, and white matter hyperintensity volume (WMHV) as a percentage of intracranial volume, a general cognitive composite derived from neuropsychological testing (SD units [SDU]), and the risk of incident dementia. We sought to replicate associations with dementia in the clinic-based ACE csf cohort, which also had YKL-40 measured from the CSF., Results: Meta-analyses of MRI outcomes included 6,558 dementia-free participants, and for analysis of cognition, 6,670. The blood draw preceded MRI/cognitive assessment by up to 10.6 years across cohorts. The mean ages ranged from 50 to 76 years, with 39%-48% male individuals. In random-effects meta-analysis of study estimates, each SDU increase in log-transformed YKL-40 levels was associated with smaller total brain volume (β = -0.33; 95% CI -0.45 to -0.22; p < 0.0001) and poorer cognition (β = -0.04; 95% CI -0.07 to -0.02; p < 0.01), following adjustments for demographic variables. YKL-40 levels did not associate with hippocampal volume or WMHV. In the FHS, each SDU increase in log YKL-40 levels was associated with a 64% increase in incident dementia risk over a median of 5.8 years of follow-up, following adjustments for demographic variables (hazard ratio 1.64; 95% CI 1.25-2.16; p < 0.001). In the ACE csf cohort, plasma and CSF YKL-40 were correlated ( r = 0.31), and both were associated with conversion from mild cognitive impairment to dementia, independent of amyloid, tau, and neurodegeneration status., Discussion: Higher plasma YKL-40 levels were associated with lower brain volume, poorer cognition, and incident dementia. Plasma YKL-40 may be useful for studying the association of inflammation and its treatment on dementia risk.

Background and Objectives: Irregular sleep may increase the risk of cardiometabolic conditions, but its association with incident dementia is unclear. The aim of this study was to assess the association between sleep regularity, that is, the day-to-day consistency in sleep-wake patterns and the risk of incident dementia and related brain MRI endophenotypes., Methods: We used Cox proportional hazard models to investigate the relationships between sleep regularity and incident dementia in 88,094 UK Biobank participants. The sleep regularity index (SRI) was calculated as the probability of being in the same state (asleep/awake) at any 2 time points 24 hours apart, averaged over 7 days of accelerometry., Results: The mean age of the sample was 62 years (SD = 8), 56% were women, and the median SRI was 60 (SD = 10). There were 480 cases of incident dementia over a median 7.2 years of follow-up. Following adjustments for demographic, clinical, and genetic confounders ( APOE ε4), there was a nonlinear association between the SRI and dementia hazard ( p [global test of spline term] < 0.001) with hazard ratios (HRs) following a U-shape pattern. HRs, relative to the median SRI, were 1.53 (95% CI 1.24-1.89) for participants with SRI at the 5th percentile (SRI = 41) and 1.16 (95% CI 0.89-1.50) for those with SRI at the 95th percentile (SRI = 71). In a subset with brain MRI (n = 15,263), gray matter and hippocampal volume tended to be lowest at the extremes of the SRI., Discussion: Sleep regularity displayed a U-shaped association with risk of incident dementia. Irregular sleep may represent a novel dementia risk factor.

Background and Objectives: Both short and long sleep duration were previously associated with incident dementia, but underlying mechanisms remain unclear. We evaluated how self-reported sleep duration and its change over time associate with (A)myloid, (T)au, (N)eurodegeneration, and (V)ascular neuroimaging markers of Alzheimer disease., Methods: Two Framingham Heart Study overlapping samples were studied: participants who underwent 11 C-Pittsburg Compound B amyloid and 18 F-flortaucipir tau PET imaging and participants who underwent an MRI. MRI metrics estimated neurodegeneration (total brain volume) and cerebrovascular injuries (white matter hyperintensities [WMHs] volume, covert brain infarcts, free-water [FW] fraction). Self-reported sleep duration was assessed and split into categories both at the time of neuroimaging testing and approximately 13 years before: short ≤6 hours. average 7-8 hours, and long ≥9 hours. Logistic and linear regression models were used to examine sleep duration and neuroimaging metrics., Results: The tested cohort was composed of 271 participants (age 53.6 ± 8.0 years; 51% male) in the PET imaging sample and 2,165 participants (age 61.3 ± 11.1 years; 45% male) in the MRI sample. No fully adjusted association was observed between cross-sectional sleep duration and neuroimaging metrics. In fully adjusted models compared with consistently sleeping 7-8 hours, groups transitioning to a longer sleep duration category over time had higher FW fraction (short to average β [SE] 0.0062 [0.0024], p = 0.009; short to long β [SE] 0.0164 [0.0076], p = 0.031; average to long β [SE] 0.0083 [0.0022], p = 0.002), and those specifically going from average to long sleep duration also had higher WMH burden (β [SE] 0.29 [0.11], p = 0.007). The opposite associations (lower WMH and FW) were observed in participants consistently sleeping ≥9 hours as compared with people consistently sleeping 7-8 hours in fully adjusted models (β [SE] -0.43 [0.20], p = 0.028; β [SE] -0.019 [0.004], p = 0.020). Each hour of increasing sleep (continuous, β [SE] 0.12 [0.04], p = 0.003; β [SE] 0.002 [0.001], p = 0.021) and extensive increase in sleep duration (≥2 hours vs 0 ± 1 hour change; β [SE] 0.24 [0.10], p = 0.019; β [SE] 0.0081 [0.0025], p = 0.001) over time was associated with higher WMH burden and FW fraction in fully adjusted models. Sleep duration change was not associated with PET amyloid or tau outcomes., Discussion: Longer self-reported sleep duration over time was associated with neuroimaging biomarkers of cerebrovascular pathology as evidenced by higher WMH burden and FW fraction. A longer sleep duration extending over time may be an early change in the neurodegenerative trajectory.

Background: Associations of plasma total tau levels with future risk of AD have been described., Objective: To examine the extent to which plasma tau reflects underlying AD brain pathology in cognitively healthy individuals., Methods: We examined cross-sectional associations of plasma total tau with 11C-Pittsburgh Compound-B (PiB)-PET and 18F-Flortaucipir (FTP)-PET in middle-aged participants at the community-based Framingham Heart Study., Results: Our final sample included 425 participants (mean age 57.6± 9.9, 50% F). Plasma total tau levels were positively associated with amyloid-β deposition in the precuneus region (β±SE, 0.11±0.05; p = 0.025). A positive association between plasma total tau and tau PET in the rhinal cortex was suggested in participants with higher amyloid-PET burden and in APOEɛ4 carriers., Conclusions: Our study highlights that plasma total tau is a marker of amyloid deposition as early as in middle-age.

The neurovascular unit (NVU) is a complex structure that facilitates nutrient delivery and metabolic waste clearance, forms the blood-brain barrier (BBB), and supports fluid homeostasis in the brain. The integrity of NVU subcomponents can be measured in vivo using magnetic resonance imaging (MRI), including quantification of enlarged perivascular spaces (ePVS), BBB permeability, cerebral perfusion and extracellular free water. The breakdown of NVU subparts is individually associated with aging, pathology, and cognition. However, how these subcomponents interact as a system, and how interdependencies are impacted by pathology remains unclear. This systematic scoping review identified 26 studies that investigated the inter-relationships between multiple subcomponents of the NVU in nonclinical and neurodegenerative populations using MRI. A further 112 studies investigated associations between the NVU and white matter hyperintensities (WMH). We identify two putative clusters of NVU interdependencies: a 'vascular' cluster comprising BBB permeability, perfusion and basal ganglia ePVS; and a 'fluid' cluster comprising ePVS, free water and WMH. Emerging evidence suggests that subcomponent coupling within these clusters may be differentially related to aging, neurovascular injury or neurodegenerative pathology., (© 2023. The Author(s).)

Objectives: Psychological stress has been proposed as a risk factor for cognitive impairment and dementia. However, it remains unclear how an individual's stress-coping ability (i.e., psychological resilience) is related to cognition. This cross-sectional study investigated whether perceived stress and psychological resilience were associated with cognition and a modifiable dementia risk score in a large community-based sample of cognitively normal adults. The moderating effect of psychological resilience was also examined., Methods: Participants (mean age = 57 ± 7 years) enrolled in the web-based Healthy Brain Project completed the Perceived Stress Scale and the Connor-Davidson Resilience Scale. Domains of attention and working memory were assessed using the Cogstate Brief Battery (n = 1,709), and associative memory was assessed using the Cambridge Neuropsychological Test Automated Battery (n = 1,522). Dementia risk was estimated for 1,913 participants using a modified version of the Cardiovascular Risk Factors, Aging, and Incidence of Dementia dementia risk score, calculated using only readily modifiable dementia risk factors., Results: In separate linear regression analyses adjusted for age, sex, education, and race, greater levels of perceived stress and lower levels of psychological resilience were associated with poorer performance across all cognitive domains, as well as a higher modifiable dementia risk score. Psychological resilience did not moderate the effect of perceived stress on cognition or the dementia risk score., Discussion: Higher perceived stress and lower resilience were associated with poorer cognition and a greater burden of modifiable dementia risk factors. Intervention studies are required to determine if lowering stress and building resilience can mitigate cognitive deficits and reduce dementia risk., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America.)

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 ε4 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 ε4 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.

Psychological stress is a potential modifiable risk factor for cognitive decline. However, the extent to which self-reported psychological stress is differentially associated with decline in specific cognitive domains remains unclear. Differences may be due to heterogeneity in the aspects of psychological stress investigated, for example, neuroticism (which is linked to vulnerability to stress), perceived stress, or exposure to stressful life events. This review aims to establish the associations between these aspects of self-reported psychological stress and cognitive decline. PsychINFO, Embase and MEDLINE were searched from database inception to September 2021. Studies were included if they were observational, prospective, and if they investigated the association between self-reported psychological stress and cognitive decline in adults with a minimum mean age of 40 years at baseline. Thirty studies satisfied the inclusion criteria, with most examining neuroticism (n = 17) as a predictor of cognitive decline. Fewer examined perceived stress (n = 7) or stressful life events (n = 6). There was evidence of an association between neuroticism and cognitive decline, particularly in the domain of memory. Similarly, across studies, perceived stress was also associated with memory decline. Research investigating the relationship between stressful life events and cognitive decline had fewer outcomes to interpret. Overall, the findings highlight that memory may be particularly susceptible to high levels of neuroticism and perceived stress. We identified a lack of research into some cognitive domains, such as executive function, which should be addressed by future studies., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Irregular sleep-wake timing may cause circadian disruption leading to several chronic age-related diseases. We examined the relationship between sleep regularity and risk of all-cause, cardiovascular disease (CVD), and cancer mortality in 88,975 participants from the prospective UK Biobank cohort., Methods: The sleep regularity index (SRI) was calculated as the probability of an individual being in the same state (asleep or awake) at any two time points 24 hr apart, averaged over 7 days of accelerometry (range 0-100, with 100 being perfectly regular). The SRI was related to the risk of mortality in time-to-event models., Results: The mean sample age was 62 years (standard deviation [SD], 8), 56% were women, and the median SRI was 60 (SD, 10). There were 3010 deaths during a mean follow-up of 7.1 years. Following adjustments for demographic and clinical variables, we identified a non-linear relationship between the SRI and all-cause mortality hazard ( p [global test of spline term]<0.001). Hazard ratios, relative to the median SRI, were 1.53 (95% confidence interval [CI]: 1.41, 1.66) for participants with SRI at the 5th percentile (SRI = 41) and 0.90 (95% CI: 0.81, 1.00) for those with SRI at the 95th percentile (SRI = 75), respectively. Findings for CVD mortality and cancer mortality followed a similar pattern., Conclusions: Irregular sleep-wake patterns are associated with higher mortality risk., Funding: National Health and Medical Research Council of Australia (GTN2009264; GTN1158384), National Institute on Aging (AG062531), Alzheimer's Association (2018-AARG-591358), and the Banting Fellowship Program (#454104)., Competing Interests: LC, RS, SY, NG, MC, AB, MP No competing interests declared, (© 2023, Cribb et al.)

Psychological stress is associated with dementia risk. However, the underlying mechanisms are unclear. This cross-sectional study examined the association between self-reported psychological stress and cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease and neurodegeneration in 73 cognitively unimpaired middle-aged adults from the Healthy Brain Project (mean age = 58±7 years). Linear regression analyses did not reveal any significant associations of psychological stress with CSF amyloid-β 42 , phosphorylated tau-181, total tau, or neurofilament light chain. Cohen's f 2 effect sizes were small in magnitude (f 2 ≤0.08). Further research is needed to replicate our findings, particularly given that the sample reported on average low levels of stress., Competing Interests: TC reports personal fees/honoraria for lectures from Roche. KF, LC, LB, RB, NY, YYL, and MP have no known conflicts of interest to disclose., (© 2023 – The authors. Published by IOS Press.)

Importance: Good sleep is essential for health, yet associations between sleep and dementia risk remain incompletely understood. The Sleep and Dementia Consortium was established to study associations between polysomnography (PSG)-derived sleep and the risk of dementia and related cognitive and brain magnetic resonance imaging endophenotypes., Objective: To investigate association of sleep architecture and obstructive sleep apnea (OSA) with cognitive function in the Sleep and Dementia Consortium., Design, Setting, and Participants: The Sleep and Dementia Consortium curated data from 5 population-based cohorts across the US with methodologically consistent, overnight, home-based type II PSG and neuropsychological assessments over 5 years of follow-up: the Atherosclerosis Risk in Communities study, Cardiovascular Health Study, Framingham Heart Study (FHS), Osteoporotic Fractures in Men Study, and Study of Osteoporotic Fractures. Sleep metrics were harmonized centrally and then distributed to participating cohorts for cohort-specific analysis using linear regression; study-level estimates were pooled in random effects meta-analyses. Results were adjusted for demographic variables, the time between PSG and neuropsychological assessment (0-5 years), body mass index, antidepressant use, and sedative use. There were 5946 participants included in the pooled analyses without stroke or dementia. Data were analyzed from March 2020 to June 2023., Exposures: Measures of sleep architecture and OSA derived from in-home PSG., Main Outcomes and Measures: The main outcomes were global cognitive composite z scores derived from principal component analysis, with cognitive domains investigated as secondary outcomes. Higher scores indicated better performance., Results: Across cohorts, 5946 adults (1875 females [31.5%]; mean age range, 58-89 years) were included. The median (IQR) wake after sleep onset time ranged from 44 (27-73) to 101 (66-147) minutes, and the prevalence of moderate to severe OSA ranged from 16.9% to 28.9%. Across cohorts, higher sleep maintenance efficiency (pooled β per 1% increase, 0.08; 95% CI, 0.03 to 0.14; P < .01) and lower wake after sleep onset (pooled β per 1-min increase, -0.07; 95% CI, -0.13 to -0.01 per 1-min increase; P = .02) were associated with better global cognition. Mild to severe OSA (apnea-hypopnea index [AHI] ≥5) was associated with poorer global cognition (pooled β, -0.06; 95% CI, -0.11 to -0.01; P = .01) vs AHI less than 5; comparable results were found for moderate to severe OSA (pooled β, -0.06; 95% CI, -0.11 to -0.01; P = .02) vs AHI less than 5. Differences in sleep stages were not associated with cognition., Conclusions and Relevance: This study found that better sleep consolidation and the absence of OSA were associated with better global cognition over 5 years of follow-up. These findings suggest that the role of interventions to improve sleep for maintaining cognitive function requires investigation.

Objective: Studies of modifiable dementia risk factors (MDRFs) generally consider MDRFs individually, despite strong evidence that they co-occur in adult populations. In a large sample of middle-aged adults, this study aimed to determine the frequency and co-occurrence of MDRFs, spanning five domains (mood symptomatology, risky lifestyle behaviors, cardiovascular conditions, cognitive/social engagement, sleep disorders/symptomatology). The relationship between number of domains in which MDRFs were reported with cognitive performance and subjective cognitive concerns was then determined., Method: Middle-aged adults ( n = 1,610) enrolled in the Healthy Brain Project and completed self-report surveys about their health and lifestyle. Participants also completed the Cogstate Brief Battery and the Cognitive Function Instrument, a measure of subjective ratings of cognition. Participants were classified according to number of domains (mood symptomatology, risky lifestyle behaviors, cardiovascular conditions, cognitive/social engagement, sleep disorders/symptomatology) in which they reported at least one MDRF (0-5). Age, sex, education, and ethnicity were adjusted for in analyses., Results: Most individuals (66.5%) reported MDRFs in two or more domains. Compared with individuals displaying no MDRFs, individuals with MDRFs in 3-5 domains showed worse learning/working memory performance and greater subjective cognitive concerns, with the magnitude of these differences moderate-to-large ( d = 0.30-0.93). Individuals displaying MDRFs in five domains also showed worse attention/psychomotor function ( d = 0.58) compared to those displaying no MDRFs., Conclusions: These findings may suggest that multidomain MDRFs are highly frequent in middle-aged adults and are related to poorer cognition. This supports that modifiable dementia risk is multidimensional and raises the possibility that multidomain behavioral intervention trials in middle-aged adults may be useful to delay or prevent cognitive impairment or decline. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Objective: To calibrate cognitive assessment data across multiple waves of the Framingham Heart Study (FHS), addressing study design considerations, ceiling effects, and measurement precision., Method: FHS participants completed several cognitive assessments including screening instruments and more comprehensive batteries at different study visits. We used expert opinion to assign each cognitive test item to a single domain-memory, executive function, language, visuospatial abilities, or none of the above. As part of a larger cross-study harmonization effort, we calibrated each domain separately using bifactor confirmatory factor analysis (CFA) models, incorporating item parameters for anchor items previously calibrated from other studies and freely estimating item parameters for FHS-specific items. We obtained scores and standard errors (SEs) for each participant at each study visit. We addressed psychometric considerations of ceiling effects and measurement precision., Results: Overall, memory domain scores were the most precisely estimated. Scores for all domains from visits where the Mini-Mental State Examination (MMSE) was the only test administered were imprecisely estimated and suffered from ceiling effects. Scores from visits with a more extensive battery were estimated more precisely and better differentiated between ability levels., Conclusions: The harmonized and calibrated cognitive data from the FHS should prove useful for future analyses examining cognition and cognitive decline. They will be of particular interest when combining FHS with other studies that have been similarly calibrated. Researchers should be aware of varying levels of measurement precision and the possibility of ceiling effects in their planned analyses of data from the FHS and similar studies. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Background: Sleep medications may contribute to dementia development or indicate sleep disturbances that are markers of or contributors to neurologic disease. The objective of this study was to examine the use of sleep medications and incident dementia in a community-based cohort of older adults. We hypothesize late-life sleep medication use is associated with a greater risk of dementia., Methods: The Atherosclerosis Risk in Communities (ARIC) study is an ongoing community-based cohort study. ARIC participants taking barbiturates, benzodiazepines, antidepressants, non-benzodiazepine receptor agonists (Z-drugs), or other hypnotics in 2011-2013 were categorized as sleep medication users. Participants were followed through 2019 for incident dementia. Logistic regression propensity scores were used to match sleep medication users with nonusers (1:2). Cox proportional hazards regression models were used to estimate hazard ratios (HR) for time to dementia diagnosis with adjustment for demographics, lifestyle characteristics, and cardiovascular risk factors., Results: One-quarter of the eligible ARIC participants used sleep medications. In the matched sample (N = 4 197; 69% female; mean age 75.3 + 5.0 years), 632 dementia cases were ascertained over a median follow-up of 6.5 years. In the fully adjusted model, sleep medication use compared to nonuse was associated with a 48% greater risk of dementia (HR: 1.48; 95% confidence interval (CI): 1.26-1.74)., Conclusion: To expand on these findings, studies with longer follow-up and earlier assessment of sleep medication use are needed. Furthermore investigation of the potential dose-response association of multiple sleep medications and the potential causal role of sleep medications in the development of dementia may be clinically meaningful., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Magnetic resonance imaging (MRI) visible perivascular spaces (PVS) are associated with the risk of incident dementia but their association with the early stages of cognitive impairment remains equivocal., Objective: We examined the association between MRI visible PVS and the risk of incident mild cognitive impairment (MCI) in the community-based Framingham Heart Study (FHS)., Methods: FHS participants aged at least 50 years free of stroke, cognitive impairment, and dementia at the time of MRI were included. PVS were rated according to severity in the basal ganglia and centrum semiovale (CSO) using established criteria. Cox regression analyses were used to relate PVS to incident MCI adjusted for demographic and cardiovascular variables., Results: The mean age of the sample (1,314 participants) at MRI was 68 years (SD, 9; 54% women). There were 263 cases of incident MCI over a median 7.4 years follow-up (max, 19.8 years). MCI risk increased with higher PVS severity in the CSO. Relative to persons with the lowest severity rating, persons with the highest severity rating in the CSO had a higher risk of incident MCI (hazard ratio [HR] = 2.55; 95% confidence interval [CI], 1.48-4.37; p = 0.0007). In secondary analysis, this association seemed stronger in women. Risk of incident MCI was nominally higher for participants with the highest severity grade of PVS in the basal ganglia, though not statistically significant relative to the lowest grade (HR = 2.19; 95% CI, 0.78-6.14; p = 0.14)., Conclusions: PVS burden in the CSO may be a risk marker for early cognitive impairment.

Midlife hypertension increases risk for dementia. Around one third of adults have diagnosed hypertension; however, many adults are undiagnosed, or remain hypertensive despite diagnosis or treatment. Since blood pressure (BP) follows a circadian rhythm, ambulatory BP monitoring allows for the assessment of BP over a 24-hour period and provides an important tool for improving the diagnosis and management of hypertension. The measurement of 24-hour BP profiles, especially nocturnal BP, demonstrate better predictive ability for cardiovascular disease and mortality than office measurement. However, few studies have examined 24-hour BP profiles with respect to dementia risk. This is an important topic since improvements in BP management could facilitate the primary prevention of vascular cognitive impairment and dementia. Therefore, this review discusses the evidence linking BP to dementia, with a focus on whether the implementation of 24-hour BP measurements can improve risk prediction and prevention strategies. Pathways linking nocturnal BP to dementia are also discussed as are risk reduction strategies. Overall, limited research suggests an association between 24-hour BP elevation and poorer cognition, cerebral small vessel disease, and dementia. However, most studies were cross-sectional. Further evidence is needed to substantiate 24-hour BP profiles, over and above office BP, as predictors of vascular cognitive impairment and incident dementia.

Objective: This meta-analysis of randomized controlled trials (RCTs) evaluates if treating sleep disturbances improves cognitive function over at least 12 weeks., Methods: Multiple data sources were searched until November 1, 2021. RCTs were included if they examined the effect of an intervention (behavioral or medical) on sleep and cognition in an adult sample with sleep disturbances and had an intervention duration and follow-up of at least 12 weeks. Two independent reviewers located 3784 studies; 16 satisfied the inclusion criteria. Primary outcomes included the broad cognitive domains of visual processing, short-term memory, long-term storage and retrieval, processing speed, and reaction time., Results: Most trials were conducted in participants with obstructive sleep apnea (OSA; N = 13); the most studied intervention was continuous positive airway pressure (CPAP; N = 10). All RCTs were 12 months in duration or less. The estimates of mean pooled effects were not indicative of significant treatment effect for any primary outcome. Although the interventions reduced daytime sleepiness (Hedge's g, 0.51; 95% confidence interval, 0.29-0.74; p < 0.01), this did not lead to cognitive enhancement., Conclusions: Overall, there was insufficient evidence to suggest that treating sleep dysfunction can improve cognition. Further studies with longer follow-up duration and supporting biomarkers are needed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Insomnia is one of the most common sleep disorders yet its relationship to the biology of Alzheimer's disease remains equivocal., Objective: We investigated the cross-sectional relationship between insomnia symptom severity and cerebrospinal fluid (CSF) concentrations of Alzheimer's disease biomarkers in a cognitively unimpaired middle-aged community sample., Methods: A total of 63 participants from the Healthy Brain Project (age = 59±7 years; 67% women) completed a lumbar puncture and two weeks of actigraphy to measure two of insomnia's core features: difficulty initiating sleep (prolonged sleep onset latency) and difficulty maintaining sleep (wake after sleep onset [WASO] and number of awakenings). Additionally, the Insomnia Severity Index (ISI) was completed by 58 participants. Linear and Tobit regression were used to estimate the associations between each insomnia variable and CSF Aβ42, phosphorylated tau 181 (p-tau181), total-tau, and neurofilament light chain protein (NfL), adjusting for age, sex, and APOEɛ4 genotype., Results: Higher ISI score was associated with greater average levels of CSF Aβ42 (per point: 30.7 pg/mL, 95% CI: 4.17-57.3, p = 0.023), as was higher WASO (per 10 min: 136 pg/mL, 95% CI: 48-223, p = 0.002) and more awakenings (per 5:123 pg/mL, 95% CI = 55-192, p < 0.001). Difficulty initiating sleep was not associated with CSF Aβ42, nor were insomnia features associated with p-tau181, total-tau, or NfL levels., Conclusion: Insomnia symptoms were associated with higher CSF Aβ42 levels in this relatively young, cognitively unimpaired sample. These findings may reflect increased amyloid production due to acute sleep disruption.

Background: While healthy sleep is suggested to promote glymphatic clearance in the brain, poorer sleep may be associated with higher enlarged perivascular spaces (ePVS) burden, potentially representing impaired perivascular drainage. This study aims to evaluate the association between ePVS burden and polysomnographic sleep characteristics in a large community-based sample., Methods: 552 dementia and stroke-free Framingham Heart Study participants (age: 58.6 ± 8.9 years; 50.4% men) underwent a full-night in-home polysomnography. Three years later on average, participants underwent a brain MRI. ePVS were rated in the basal ganglia and centrum semiovale, and dichotomized as low burden (<20 counts, grades 1 and 2) or high burden (>20 counts, grades 3 and 4). Logistic regression analyses relating sleep variables to subsequent ePVS burden were used, adjusted for age, sex, time interval between polysomnography and MRI, ApoE ε4 allele carrier status, hypertension, and smoking., Results: Longer N1 sleep and shorter N3 sleep duration were associated with higher ePVS burden in the centrum semiovale. When stratifying these associations by subpopulations, longer N1 sleep duration with ePVS burden was observed especially in older individuals and hypertensive participants. Associations between ePVS burden and other sleep characteristics such as total sleep time and REM sleep duration varied according to ApoE ε4 allele carrier status., Conclusions: Lighter sleep, as characterized by longer N1 sleep and shorter slow-wave sleep, is associated with higher ePVS burden. These findings suggest that sleep architecture may be involved in glymphatic clearance and cerebral small vessel disease, which could be an important biological link between sleep and dementia risk., (Copyright © 2022 Elsevier B.V. All rights reserved.)