Objective: Sleep disturbance is common in dementia, although it is unclear whether differences in sleep architecture precede dementia onset. We examined the associations between sleep architecture and the prospective risk of incident dementia in the community-based Framingham Heart Study (FHS). Methods: Our sample comprised a subset of 321 FHS Offspring participants who participated in the Sleep Heart Health Study between 1995 and 1998 and who were aged over 60 years at the time of sleep assessment (mean age 67 ± 5 years, 50% male). Stages of sleep were quantified using home-based polysomnography. Participants were followed for a maximum of 19 years for incident dementia (mean follow-up 12 ± 5 years). Results: We observed 32 cases of incident dementia; 24 were consistent with Alzheimer disease dementia. After adjustments for age and sex, lower REM sleep percentage and longer REM sleep latency were both associated with a higher risk of incident dementia. Each percentage reduction in REM sleep was associated with approximately a 9% increase in the risk of incident dementia (hazard ratio 0.91; 95% confidence interval 0.86, 0.97). The magnitude of association between REM sleep percentage and dementia was similar following adjustments for multiple covariates including vascular risk factors, depressive symptoms, and medication use, following exclusions for persons with mild cognitive impairment at baseline and following exclusions for early converters to dementia. Stages of non-REM sleep were not associated with dementia risk. Conclusions: Despite contemporary interest in slow-wave sleep and dementia pathology, our findings implicate REM sleep mechanisms as predictors of clinical dementia.

Objective: To evaluate the association between sleep duration and the risk of incident dementia and brain aging. Methods: Self-reported total hours of sleep were examined in the Framingham Heart Study (n = 2,457, mean age 72 ± 6 years, 57% women) as a 3-level variable: 9 hours (long), and was related to the risk of incident dementia over 10 years, and cross-sectionally to total cerebral brain volume (TCBV) and cognitive performance. Results: We observed 234 cases of all-cause dementia over 10 years of follow-up. In multivariable analyses, prolonged sleep duration was associated with an increased risk of incident dementia (hazard ratio [HR] 2.01; 95% confidence interval [CI] 1.24–3.26). These findings were driven by persons with baseline mild cognitive impairment (HR 2.83; 95% CI 1.06–7.55) and persons without a high school degree (HR 6.05; 95% CI 3.00–12.18). Transitioning to sleeping >9 hours over a mean period of 13 years before baseline was associated with an increased risk of all-cause dementia (HR 2.43; 95% CI 1.44–4.11) and clinical Alzheimer disease (HR 2.20; 95% CI 1.17–4.13). Relative to sleeping 6–9 hours, long sleep duration was also associated cross-sectionally with smaller TCBV (β ± SE, −1.08 ± 0.41 mean units of TCBV difference) and poorer executive function (β ± SE, −0.41 ± 0.13 SD units of Trail Making Test B minus A score difference). Conclusions: Prolonged sleep duration may be a marker of early neurodegeneration and hence a useful clinical tool to identify those at a higher risk of progressing to clinical dementia within 10 years.

The discovery of minimally invasive and cost-effective blood-based biomarkers for dementia has the potential to transform clinical research and practice by permitting widespread low-cost screening, risk stratification, and efficient identification of persons with the greatest dementia risk for inclusion in dementia prevention trials. Single-molecule array technology permits the detection of total tau (t-tau) from plasma with a greater than 1000-fold improvement in sensitivity over conventional enzyme-linked immunosorbent assay (ELISA).^1,2 Plasma t-tau level measured with this technology is greater in persons with Alzheimer disease (AD) dementia or mild cognitive impairment (MCI) compared with control participants.^3-5 However, the usefulness of plasma t-tau as a diagnostic biomarker is limited by the large overlap in values observed between diagnostic groups, which may signal a lack of specificity for AD. The latest National Institute on Aging–Alzheimer Association Research Framework (NIA-AA) describes t-tau as a biomarker of neuronal injury rather than of neurofibrillary tangle burden, noting that an elevated t-tau level reflects neuronal injury from various causes.⁶ Nevertheless, plasma t-tau shows early promise as a predictive biomarker for dementia with 2 longitudinal studies demonstrating that plasma t-tau is associated with endophenotypes of dementia, including cognitive decline.^7,8 However, evidence from representative community-based studies is limited, and studies to date have not been powered to examine the association with risk for dementia. Further studies are required to evaluate plasma t-tau as a predictive biomarker for incident dementia, permitting risk stratification in the setting where blood-based biomarkers would be most useful—in the general community and the age groups of relevance to early dementia prevention trials. Accordingly, we examined the association of plasma t-tau level as a predictive biomarker for dementia of any cause (all dementia) and incident dementia of the Alzheimer type (AD dementia) in the large community-based Framingham Heart Study (FHS), with replication performed in an independent multicenter cohort from France. We also examined endophenotypes associated with dementia, including cognitive function, hippocampal volume, and tau neurofibrillary tangle burden.

Background and Purpose—: Sugar- and artificially-sweetened beverage intake have been linked to cardiometabolic risk factors, which increase the risk of cerebrovascular disease and dementia. We examined whether sugar- or artificially sweetened beverage consumption was associated with the prospective risks of incident stroke or dementia in the community-based Framingham Heart Study Offspring cohort. Methods—: We studied 2888 participants aged >45 years for incident stroke (mean age 62 [SD, 9] years; 45% men) and 1484 participants aged >60 years for incident dementia (mean age 69 [SD, 6] years; 46% men). Beverage intake was quantified using a food-frequency questionnaire at cohort examinations 5 (1991–1995), 6 (1995–1998), and 7 (1998–2001). We quantified recent consumption at examination 7 and cumulative consumption by averaging across examinations. Surveillance for incident events commenced at examination 7 and continued for 10 years. We observed 97 cases of incident stroke (82 ischemic) and 81 cases of incident dementia (63 consistent with Alzheimer’s disease). Results—: After adjustments for age, sex, education (for analysis of dementia), caloric intake, diet quality, physical activity, and smoking, higher recent and higher cumulative intake of artificially sweetened soft drinks were associated with an increased risk of ischemic stroke, all-cause dementia, and Alzheimer’s disease dementia. When comparing daily cumulative intake to 0 per week (reference), the hazard ratios were 2.96 (95% confidence interval, 1.26–6.97) for ischemic stroke and 2.89 (95% confidence interval, 1.18–7.07) for Alzheimer’s disease. Sugar-sweetened beverages were not associated with stroke or dementia. Conclusions—: Artificially sweetened soft drink consumption was associated with a higher risk of stroke and dementia.

Background and Purpose—: Aortic stiffening increases the transfers of high pressure and flow pulsatility to small cerebral vessels potentially causing the accumulation of vascular brain injury. Our aim was to investigate the prospective association of aortic stiffness with the risks of incident mild cognitive impairment and dementia. Methods—: We studied 1101 dementia-free Framingham Offspring study participants (mean age, 69±6 years; 54% women). Aortic stiffness was measured as carotid–femoral pulse wave velocity using applanation tonometry and modeled as a linear variable and the top 2 quintiles (>11.4 m/s). Outcomes were the 10-year risk of incident mild cognitive impairment and dementia, including clinically characterized Alzheimer disease. We observed 106, 77, and 59 events of mild cognitive impairment, all-cause dementia, and clinical Alzheimer disease, respectively. Results—: After adjustment for age and sex, higher continuous aortic stiffness predicted an increased risk of mild cognitive impairment (hazard ratio, 1.40 [95% confidence interval, 1.13–1.73]), all-cause dementia (hazard ratio, 1.45 [95% confidence interval, 1.13–1.87]), and Alzheimer disease (hazard ratio, 1.41 [95% confidence interval, 1.06–1.87]). In risk factor–adjusted statistical models, aortic stiffness remained a significant predictor of mild cognitive impairment but not incident dementia. In nondiabetic patients, the top 2 quintiles of aortic stiffness were associated with a higher risk of incident all-cause dementia across all statistical models. Conclusions—: Aortic stiffness was an independent predictor of incident mild cognitive impairment in the whole sample and with incident dementia in nondiabetic patients. Our findings suggest aortic stiffness as a potentially modifiable risk factor for clinical cognitive impairment and dementia.