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Background: APOE-e4 is the strongest genetic risk factor for Alzheimer's disease. However, the influence of APOE-e4 on dietary fat intake and cognition has not been investigated., Objective: We aim to examine the association of types of dietary fat and their association to cognitive decline among those with and without the APOE-e4 allele., Methods: The study included 3,360 Chicago Health and Aging Project (CHAP) participants from four Southside Chicago communities. Global cognition was assessed using a composite score of episodic memory, perceptual speed, MMSE, and diet using a 144-item food frequency questionnaire. APOE genotype was assessed by the hME Sequenom mass-array platform. Longitudinal mixed-effect regression models were used to examine the association of dietary fat and the APOE-e4 allele with cognitive decline, adjusted for age, sex, education, smoking status, and calorie intake., Results: The present study involved 3,360 participants with a mean age of 74 at baseline, 62% African Americans, 63% females, and a mean follow-up of 7.8 years. Among participants with the APOE-e4 risk allele, higher intakes of total and saturated fat (SFA) were associated with a faster decline in global cognition. Among individuals with the APOE-e4 risk allele, a 5% increase in calories from SFA was associated with a 21% faster decline (β = -0.0197, P = 0.0038). In contrast, a higher intake of long-chain n-3 polyunsaturated fatty acids (LC-n3 PUFA) was associated with a slower rate of decline in global cognition among APOE-e4 carriers. Specifically, for every 1% energy increment from LC-n3 PUFA, the annual rate of global cognitive decline was slower by 0.024 standardized unit (SD 0.010, P = 0.023), about 30.4% slower annual cognitive decline. Higher SFA or other types of dietary fat were not associated with cognitive decline among APOE-e4 non-carriers., Conclusions: Our study found a significant association between SFA and faster cognitive decline, LC-n3 PUFA and slower cognitive decline among those with the APOE-e4 allele. Our findings suggested that higher intake of SFA might contribute faster cognitive decline in combination with APOE-e4 whereas LC-n3 PUFA might compensate the adverse effects of APOE-e4. The interaction between intakes of different types of dietary fat and APOE-e4 on cognitive function warrants further research., (Copyright © 2024. Published by Elsevier Masson SAS.)

Objective: To develop and externally validate a 10-year risk prediction model of natural onset of menopause using ready-to-use predictors., Design: Population-based prospective cohort study., Participants: Community-dwelling, premenopausal women aged 28 years and older enrolled in the Swiss (CoLaus) and Dutch (PREVEND) study., Main Outcome Measure: Incidence of self-reported natural menopause., Model Development: Based on existing literature, 11 predictors were tested in this study. The CoLaus cohort was used to develop the model by applying the backward-elimination approach and Bayesian Model Averaging. Internal validation was performed by bootstrapping. External validation was performed using data from the PREVEND cohort and recalibrating the baseline survival estimate. C-statistic, calibration slopes, and expected/observed probabilities were calculated as measures of model internal and/or external performances., Results: The final analysis included 750 and 1032 premenopausal women from the CoLaus and the PREVEND cohort, respectively. Among them, 445 (59%) from CoLaus and 387 (38%) from PREVEND experienced menopause over a median follow-up of 10.7 and 9 years, respectively. The final model included age, alcohol consumption, smoking status, education level, and systolic blood pressure. Upon external calibration in the PREVEND cohort, the model exhibited good discrimination, with a C-statistic of 0.888 and an expected/observed probability of 0.82., Conclusions: We present the first internally and externally validated prediction model of natural menopause onset using readily available predictors. Validation of our model to other populations is needed., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Importance: A healthy lifestyle is associated with better cognitive functioning in older adults, but whether this association is independent of the accumulation of dementia-related pathologies in the brain is uncertain., Objective: To determine the role of postmortem brain pathology, including β-amyloid load, phosphorylated tau tangles, cerebrovascular pathology, and other brain pathologies, in the association between lifestyle and cognition proximate to death., Design, Setting, and Participants: This cohort study used data from the Rush Memory and Aging Project, a longitudinal clinical-pathologic study with autopsy data from 1997 to 2022 and up to 24 years of follow-up. Participants included 754 deceased individuals with data on lifestyle factors, cognitive testing proximate to death, and a complete neuropathologic evaluation at the time of these analyses. Data were analyzed from January 2023 to June 2023., Exposures: A healthy lifestyle score was developed based on self-reported factors, including noncurrent smoking, at least 150 minutes of physical activity per week, limiting alcohol consumption, a Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet score higher than 7.5, and a late-life cognitive activity score higher than 3.2. The lifestyle score ranges from 0 to 5, with higher scores reflecting a healthier lifestyle., Main Outcomes and Measures: The global cognitive score was derived from a battery of nineteen standardized tests. Brain pathology measures included β-amyloid load, phosphorylated tau tangles, global Alzheimer disease pathology, vascular brain pathologies, Lewy body, hippocampal sclerosis, and TAR DNA-binding protein 43., Results: Of 586 included decedents, 415 (70.8%) were female, 171 (29.2%) were male, and the mean (SD) age at death was 90.9 (6.0) years. Higher lifestyle score was associated with better global cognitive functioning proximate to death. In the multivariable-adjusted model, a 1-point increase in lifestyle score was associated with 0.216 (SE = 0.036, P < .001) units higher in global cognitive scores. Neither the strength nor the significance of the association changed substantially when common dementia-related brain pathologies were included in the multivariable-adjusted models. The β estimate after controlling for the β-amyloid load was 0.191 (SE = 0.035; P < .001). A higher lifestyle score was associated with lower β-amyloid load in the brain (β = -0.120; SE = 0.041; P = .003), and 11.6% of the lifestyle-cognition association was estimated through β-amyloid load., Conclusions and Relevance: This study found that in older adults, a healthy lifestyle may provide a cognitive reserve to maintain cognitive abilities independently of common neuropathologies of dementia.

Background: Cardiovascular risk burden is associated with dementia risk and neurodegeneration-related brain structure, while the role of genetics and incident cardiovascular disease (CVD) remains unclear., Aims: To examine the association of overall cardiovascular risk burden with the risk of major dementia subtypes and volumes of related brain regions in a large sample, and to explore the role of genetics and CVD onset., Methods: A prospective study among 354 654 participants free of CVD and dementia (2006-2010, mean age 56.4 years) was conducted within the UK Biobank, with brain magnetic resonance imaging (MRI) measurement available for 15 104 participants since 2014. CVD risk burden was evaluated by the Framingham General Cardiovascular Risk Score (FGCRS). Dementia diagnosis was ascertained from inpatient and death register data., Results: Over a median 12.0-year follow-up, 3998 all-cause dementia cases were identified. Higher FGCRS was associated with increased all-cause dementia risk after adjusting for demographic, major lifestyle, clinical factors and the polygenic risk score (PRS) of Alzheimer's disease. Comparing the high versus low tertile of FGCRS, the odds ratios (ORs) and 95% confidence intervals (CIs) were 1.26 (1.12 to 1.41) for all-cause dementia, 1.67 (1.33 to 2.09) for Alzheimer's disease and 1.53 (1.07 to 2.16) for vascular dementia (all p trend <0.05). Incident stroke and coronary heart disease accounted for 14% (95% CI: 9% to 21%) of the association between FGCRS and all-cause dementia. Interactions were not detected for FGCRS and PRS on the risk of any dementia subtype. We observed an 83% (95% CI: 47% to 128%) higher all-cause dementia risk comparing the high-high versus low-low FGCRS-PRS category. For brain volumes, higher FGCRS was associated with greater log-transformed white matter hyperintensities, smaller cortical volume and smaller grey matter volume., Conclusions: Our findings suggest that the positive association of cardiovascular risk burden with dementia risk also applies to major dementia subtypes. The association of cardiovascular risk burden with all-cause dementia is largely independent of CVD onset and genetic predisposition to dementia., Competing Interests: Competing interests: As of June 2021, WG is a full-time employee of Novo Nordisk., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Total tau (t-tau), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) are neuronal cytoskeletal biomarkers that may indicate greater risk of poor outcomes in age-related conditions, including mortality. Health disparities experienced by some racial minority subgroups may influence biomarker expression and effects on longevity. We aimed to examine (a) associations of serum t-tau, NfL, and GFAP with overall and cardiovascular mortality and (b) differences in associations by racial background., Methods: Data came from 1327 older participants from the Chicago Health and Aging Project (CHAP), a longitudinal population-based study. Cox proportional hazards regression models were used to examine associations between concentrations of serum t-tau, NfL, and GFAP biomarker(s) and mortality (overall/cardiovascular mortality based on age at death). Interaction terms were used to examine differences between African-American and European-American participants. Models were adjusted for age, sex, education, the APOE-ε4 allele, body mass index, chronic health conditions, and cognitive and physical functioning., Results: Models showed that fivefold higher concentrations of t-tau (HR = 1.46, 95% CI: 1.27, 1.68), NfL (HR = 2.13, 95% CI: 1.76, 2.58), and GFAP (HR = 1.43, 95% CI: 1.08, 1.90) were separately associated with increased risk of overall mortality, with higher risk in African Americans in t-tau or NfL. In models with all biomarkers, NfL (HR = 2.17, 95% CI: 1.65, 2.85) was associated with risk of overall mortality, with racial differences in t-tau. Higher concentrations of t-tau (HR = 1.32, 95% CI: 1.02, 1.70), NfL (HR = 1.95, 95% CI: 1.40, 2.72), and GFAP (HR = 1.87, 95% CI: 1.18, 2.98) were separately associated with risk of cardiovascular mortality, with racial differences in t-tau, NfL, or GFAP. In combined models, NfL (HR = 1.73, 95% CI: 1.08, 2.78) was associated with cardiovascular mortality., Conclusions: Serum t-tau, NfL, and GFAP may be early indicators for mortality outcomes among older adults, with racial differences among associations., (© 2023 The Authors. Journal of the American Geriatrics Society published by Wiley Periodicals LLC on behalf of The American Geriatrics Society.)

Background and Objectives: To examine the association of whole grain consumption and longitudinal change in global cognition, perceptual speed, and episodic memory by different race/ethnicity., Methods: We included 3,326 participants from the Chicago Health and Aging Project who responded to a Food Frequency Questionnaire (FFQ), with 2 or more cognitive assessments. Global cognition was assessed using a composite score of episodic memory, perceptual speed, and the Mini Mental State Examination (MMSE). Diet was assessed by a 144-item FFQ. Linear mixed-effects models were used to estimate the association of intakes of whole grains and cognitive decline., Results: This study involved 3,326 participants (60.1% African American [AA], 63.7% female) with a mean age of 75 years at baseline and a mean follow-up of 6.1 years. Higher consumption of whole grains was associated with a slower rate of global cognitive decline. Among AA participants, those in the highest quintile of whole grain consumption had a slower rate of decline in global cognition (β = 0.024, 95% CI [0.008-0.039], p = 0.004), perceptual speed (β = 0.023, 95% CI [0.007-0.040], p = 0.005), and episodic memory (β = 0.028, 95% CI [0.005-0.050], p = 0.01) compared with those on the lowest quintile. Regarding the amount consumed, in AA participants, those who consumed >3 servings/d vs those who consumed <1 serving/d had a slower rate of decline in global cognition (β = 0.021, 95% CI [0.005-0.036], p = 0.0093). In White participants, with >3 servings/d, we found a suggestive association of whole grains with global cognitive decline when compared with those who consumed <1 serving/d (β = 0.025, 95% CI [-0.003 to 0.053], p = 0.08)., Discussion: Among AA participants, individuals with higher consumption of whole grains and more frequent consumption of whole grain had slower decline in global cognition, perceptual speed, and episodic memory. We did not see a similar trend in White adults., (© 2023 American Academy of Neurology.)

Introduction: The aim of this study was to evaluate the association of cardiovascular health (CVH) with cognitive outcomes, including incident Alzheimer's dementia, rate of cognitive decline, and measures of brain injury and structure., Methods: This study consisted of 1702 Black or African American and White participants living in the south side of Chicago, Illinois, and enrolled in the Chicago Health and Aging Project, a population-based cohort since 1993. CVH was based on seven risk factors, including diet, physical activity, body mass index, smoking, dyslipidemia, hypertension, and diabetes., Results: In a multivariable-adjusted model, CVH was associated with a lower risk of Alzheimer's dementia. The hazard ratio per 1 additional point in CVH score was 0.84 (95% CI 0.76, 0.94). CVH was also associated with a slower rate of cognitive decline and less volume (injury) in white matter hyperintensities., Discussion: Promoting CVH in communities with Black residents may lower the future risk of Alzheimer's dementia., (© 2023 the Alzheimer's Association.)

Introduction: This study estimates the prevalence and number of people living with Alzheimer's disease (AD) dementia in 50 US states and 3142 counties., Methods: We used cognitive data from the Chicago Health and Aging Project, a population-based study, and combined it with the National Center for Health Statistics 2020 bridged-race population estimates to determine the prevalence of AD in adults ≥65 years., Results: A higher prevalence of AD was estimated in the east and southeastern regions of the United States, with the highest in Maryland (12.9%), New York (12.7%), and Mississippi (12.5%). US states with the highest number of people with AD were California, Florida, and Texas. Among larger counties, those with the highest prevalence of AD were Miami-Dade County in Florida, Baltimore city in Maryland, and Bronx County in New York., Discussion: The state- and county-specific estimates could help public health officials develop region-specific strategies for caring for people with AD., (© 2023 the Alzheimer's Association.)

Background: Findings from observational studies suggest that dietary patterns may offer protective benefits against cognitive decline, but data from clinical trials are limited. The Mediterranean-DASH Intervention for Neurodegenerative Delay, known as the MIND diet, is a hybrid of the Mediterranean diet and the DASH (Dietary Approaches to Stop Hypertension) diet, with modifications to include foods that have been putatively associated with a decreased risk of dementia., Methods: We performed a two-site, randomized, controlled trial involving older adults without cognitive impairment but with a family history of dementia, a body-mass index (the weight in kilograms divided by the square of the height in meters) greater than 25, and a suboptimal diet, as determined by means of a 14-item questionnaire, to test the cognitive effects of the MIND diet with mild caloric restriction as compared with a control diet with mild caloric restriction. We assigned the participants in a 1:1 ratio to follow the intervention or the control diet for 3 years. All the participants received counseling regarding adherence to their assigned diet plus support to promote weight loss. The primary end point was the change from baseline in a global cognition score and four cognitive domain scores, all of which were derived from a 12-test battery. The raw scores from each test were converted to z scores, which were averaged across all tests to create the global cognition score and across component tests to create the four domain scores; higher scores indicate better cognitive performance. The secondary outcome was the change from baseline in magnetic resonance imaging (MRI)-derived measures of brain characteristics in a nonrandom sample of participants., Results: A total of 1929 persons underwent screening, and 604 were enrolled; 301 were assigned to the MIND-diet group and 303 to the control-diet group. The trial was completed by 93.4% of the participants. From baseline to year 3, improvements in global cognition scores were observed in both groups, with increases of 0.205 standardized units in the MIND-diet group and 0.170 standardized units in the control-diet group (mean difference, 0.035 standardized units; 95% confidence interval, -0.022 to 0.092; P = 0.23). Changes in white-matter hyperintensities, hippocampal volumes, and total gray- and white-matter volumes on MRI were similar in the two groups., Conclusions: Among cognitively unimpaired participants with a family history of dementia, changes in cognition and brain MRI outcomes from baseline to year 3 did not differ significantly between those who followed the MIND diet and those who followed the control diet with mild caloric restriction. (Funded by the National Institute on Aging; ClinicalTrials.gov number, NCT02817074.)., (Copyright © 2023 Massachusetts Medical Society.)

Importance: Dementia threatens the well-being of older adults, making efforts toward prevention of great importance., Objective: To evaluate the association of the Mediterranean-Dietary Approaches to Stop Hypertension (DASH) Intervention for Neurodegenerative Delay (MIND) diet with the risk of dementia in 3 prospective studies and a meta-analysis., Design, Setting, and Participants: Cohort analyses included the Whitehall II study (WII), the Health and Retirement Study (HRS), and the Framingham Heart Study Offspring cohort (FOS), and the meta-analysis included 11 cohort studies. Participants were middle-aged and older women and men from WII in 2002 to 2004, HRS in 2013, and FOS in 1998 to 2001 without dementia at the study baseline. Data were analyzed from May 25 to September 1, 2022., Exposures: MIND diet score was measured using food frequency questionnaires, and scores ranged from 0 to 15, with a higher score indicating higher adherence to the MIND diet., Main Outcome and Measures: Incident all-cause dementia, with cohort-specific definitions., Results: Included in this study were 8358 participants (mean [SD] age, 62.2 [6.0] years; 5777 male [69.1%]) from WII, 6758 participants (mean [SD] age, 66.5 [10.4] years; 3965 female [58.7%]) from HRS, and 3020 participants (mean [SD] age, 64.2 [9.1] years; 1648 female [54.6%]) from FOS. The mean (SD) baseline MIND diet score was 8.3 (1.4) in WII, 7.1 (1.9) in HRS, and 8.1 (1.6) in FOS. Over 166 516 person-years, a total of 775 participants (220 in WII, 338 in HRS, and 217 in FOS) developed incident dementia. In the multivariable-adjusted Cox proportional hazard model, higher MIND diet score was associated with lower risk of dementia (pooled hazard ratio [HR] for every 3-point increment, 0.83; 95% CI, 0.72-0.95; P for trend = .01; I2 = 0%). The associations were consistently observed in subgroups defined by sex, age, smoking status, and body mass index. In the meta-analysis of 11 cohort studies with 224 049 participants (5279 incident dementia cases), the highest tertile of MIND diet score was associated with lower risk of dementia compared with the lowest tertile (pooled HR, 0.83; 95% CI, 0.76-0.90; I2 = 35%)., Conclusions and Relevance: Results suggest that adherence to the MIND diet was associated with lower risk of incident dementia in middle-aged and older adults. Further studies are warranted to develop and refine the specific MIND diet for different populations.

Background and Objectives: Diet may reduce Alzheimer dementia risk and slow cognitive decline, but the understanding of the relevant neuropathologic mechanisms remains limited. The association of dietary patterns with Alzheimer disease (AD) pathology has been suggested using neuroimaging biomarkers. This study examined the association of Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) and Mediterranean dietary patterns with β-amyloid load, phosphorylated tau tangles, and global AD pathology in postmortem brain tissue of older adults., Methods: Autopsied participants of the Rush Memory and Aging Project with complete dietary information (collected through a validated food frequency questionnaire) and AD pathology data (β-amyloid load, phosphorylated tau tangles, and global AD pathology [summarized neurofibrillary tangles and neuritic and diffuse plaques]) were included in this study. Linear regression models controlled for age at death, sex, education, APOE-ε4 status, and total calories were used to investigate the dietary patterns (MIND and Mediterranean diets) and dietary components associated with AD pathology. Further effect modification was tested for APOE-ε4 status and sex., Results: Among our study participants (N = 581, age at death: 91.0 ± 6.3 years; mean age at first dietary assessment: 84.2 ± 5.8 years; 73% female; 6.8 ± 3.9 years of follow-up), dietary patterns were associated with lower global AD pathology (MIND: β = -0.022, p = 0.034, standardized β = -2.0; Mediterranean: β = -0.007, p = 0.039, standardized β = -2.3) and specifically less β-amyloid load (MIND: β = -0.068, p = 0.050, standardized β = -2.0; Mediterranean: β = -0.040, p = 0.004, standardized β = -2.9). The findings persisted when further adjusted for physical activity, smoking, and vascular disease burden. The associations were also retained when participants with mild cognitive impairment or dementia at the baseline dietary assessment were excluded. Those in the highest tertile of green leafy vegetables intake had less global AD pathology when compared with those in the lowest tertile (tertile 3 vs tertile 1: β = -0.115, p = 0.0038)., Discussion: The MIND and Mediterranean diets are associated with less postmortem AD pathology, primarily β-amyloid load. Among dietary components, higher green leafy vegetable intake was associated with less AD pathology., (© 2023 American Academy of Neurology.)

Introduction: To determine the role of vitamin D intake on cognitive decline among Blacks and Whites., Methods: Using data from the population-based Chicago Health and Aging Project, we studied 2061 Blacks and 1329 Whites with dietary vitamin D data and cognitive testing over 12 years of follow-up. Multivariable linear mixed-effects models were used to determine the association of vitamin D intake with cognitive decline., Results: Vitamin D intake, particularly dietary vitamin D, was associated with a slower rate of decline in cognitive function among Blacks. In Blacks, comparing individuals in the lowest tertile of dietary intake, those in the highest tertile had a slower cognitive decline of 0.017 units/year (95% confidence interval 0.006, 0.027), independently of supplementation use. In Whites, vitamin D intake was not associated with cognitive decline., Discussion: Dietary vitamin D may help to slow the decline in cognitive abilities among Blacks as they age., (© 2022 the Alzheimer's Association.)

Neurofilament light chain (NfL), a neuron-specific protein, has been related to several neurodegenerative diseases. In addition, elevated levels of NfL have also been observed in patients admitted to the hospital for stroke, suggesting that NfL as a biomarker may extend well beyond neurodegenerative diseases. Therefore, using data from the Chicago Health and Aging Project (CHAP), a population-based cohort study, we prospectively investigated the association of serum NfL levels with incident stroke and brain infarcts. During a follow-up of 3603 person-years, 133 (16.3%) individuals developed incident stroke, including ischemic and hemorrhagic. The HR (95%CI) of incident stroke was 1.28 (95%CI 1.10-1.50) per 1 standard deviation (SD) increase of log10 NfL serum levels. Compared to participants in the first tertile of NfL (i.e., lower levels), the risk of stroke was 1.68 times higher (95%CI 1.07-2.65) in those in the second tertile and 2.35 times higher (95%CI 1.45-3.81) in those in the third tertile of NfL. NfL levels were also positively associated with brain infarcts; 1-SD in log10 NfL levels was associated with 1.32 (95%CI 1.06-1.66) higher odds of one or more brain infarcts. These results suggest that NfL may serve as a biomarker of stroke in older adults., (© 2023. Springer Nature B.V.)

Objective: We aimed to determine whether combining white matter hyperintensity (WMH) with neurofilament light chain (NfL) could provide additional information for cognition in older adults., Methods: Utilizing data from the population-based Chicago Health and Aging Project, we studied 701 individuals with both biomarkers and cognitive data during the follow-up period. NfL was measured using an ultrasensitive immunoassay, single-molecule array technology. MRI scans of the brain were acquired using 1.5-T systems. Global cognitive function was created as a composite measure of four neuropsychological tests, standardized and averaged to z-scores. Multivariable linear mixed-effects models were used to evaluate the association of WMH and NfL with the rate of cognitive decline., Results: Higher WMH and NfL were associated with a faster rate of cognitive decline during the follow-up; β -coefficients (95%CIs) were -0.011 (-0.02, -0.001) and -0.010 (-0.017, -0.003), respectively. In individuals with lower concentration of NfL (i.e., bottom tertile), a higher WMH volume was associated with a faster cognitive decline ( β : -0.030; 95%CI -0.046, -0.014). Similarly, in individuals with lower volumes of WMH (i.e., bottom tertile), a higher concentrations of NfL was associated with a faster cognitive decline ( β : -0.023; 95%CI -0.042, -0.005). When we combined WMH with NfL, we noted a graded association with increasing volumes of WMH, particularly in people with lower NfL values., Interpretation: While both biomarkers, WMH and NfL, were similarly associated with the annual rate of cognitive decline, our study suggests that they provide different underlying mechanisms affecting cognition., (© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background and Objectives: Previous research has examined the association between cognition and flavonoids: bioactives found in foods, known to possess anti-inflammatory and antioxidant properties. We extend this research by investigating associations of dietary intakes of total flavonols and constituents (kaempferol, quercetin, myricetin, and isorhamnetin) on the change in cognitive performance in global cognition, episodic memory, semantic memory, visuospatial ability, perceptual speed, and working memory., Methods: The study was conducted using 961 participants (aged 60-100 years) of the Rush Memory and Aging Project, a prospective cohort of community-dwelling Chicagoans who were followed for an average of 6.9 years. Diet was assessed using a validated semiquantitative food frequency questionnaire. Cognitive performance was assessed annually with a battery of 19 standardized tests. Flavonol intake was analyzed as a continuous variable using linear mixed-effects models. Cognitive domain scores were regressed on baseline calorie-adjusted flavonol variables., Results: Higher dietary intakes of total flavonols and flavonol constituents were associated with a slower rate of decline in global cognition and multiple cognitive domains. In continuous models adjusted for age, sex, education, APOE ɛ4 , late-life cognitive activity, physical activity, and smoking, total flavonol intake was associated with slower decline in global cognition β estimate = 0.004 (95% CI 0.001-0.006), episodic memory β = 0.004 (95% CI 0.002-0.006), semantic memory β = 0.003 (95% CI 0.001-0.007), perceptual speed β = 0.003 (95% CI 0.001-0.004), and working memory β = 0.003 (95% CI 0.001-0.005) and marginally associated with visuospatial ability β = 0.001 (95% CI -0.001 to 0.003). Analyses of individual flavonol constituents demonstrated that intakes of kaempferol and quercetin were associated with slower global cognitive decline (β = 0.01 [95% CI 0.006-0.02] and β = 0.004 [95% CI 0.0005-0.007]), respectively. Myricetin and isorhamnetin were not associated with global cognition., Discussion: Results suggest that dietary intakes of total flavonols and several flavonol constituents may be associated with slower decline in global cognition and multiple cognitive abilities with older age., (© 2022 American Academy of Neurology.)

Background: The association of different types of tocopherols (vitamin E) with cognition might vary by the APOEɛ4 allele status., Objective: We examined the association of dietary tocopherols with cognitive decline among participants with and without the APOEɛ4 allele over a median of 12 years., Methods: 2,193 participants from the Chicago Health and Aging Project were included in the analyses. Global cognition was assessed in three-year cycles. We used a 144-item FFQ to assess dietary intakes of tocopherols and hME Sequenom mass-array platform to assess APOE genotype. We used linear mixed effects models to examine the relationship between tocopherol from food sources and global cognitive decline., Results: The mean baseline age was 74.1 (SD = 5.9) years. Among APOEɛ4 carriers, participants in the highest quintile of intakes of dietary vitamin E had a slower cognitive decline of 0.022 SDU (95% CI: 0.000, 0.043) compared to those in the lowest quintile. A higher intake of dietary α-tocopherol from food sources only was associated with slower cognitive decline in APOEɛ4 carriers (p for trend 0.002) but not among the non-carriers (p for trend 0.937). Among APOEɛ4 carriers, those in the highest quintile of intake of α-tocopherol had a 16.4% slower rate of decline of global cognition compared to those in the lowest quintile (β= 0.034, 95% CI: 0.013, 0.054)., Conclusions: Individuals consuming high α-tocopherol from food sources had slower cognitive decline among APOEɛ4 carriers. In older adults, different forms of vitamin E might moderate the relationship of APOEɛ4 with global cognition.

Background: We have limited evidence for the relationship of high sugar intake with dementia risk., Objective: To determine whether high sugar intake is associated with an increased risk of dementia in community-dwelling older adultsMethods:This study included 789 participants of the Rush Memory and Aging Project (community-based longitudinal cohort study of older adults free of known dementia at enrollment), with annual clinical assessments and complete nutrient data (obtained by validated food frequency questionnaire). Clinical diagnosis of dementia is based on the criteria of the joint working group of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association. We used Cox proportional hazard models., Results: 118 participants developed dementia during 7.3±3.8 years of follow-up. Those in the highest quintile of total sugar intake were twice as likely to develop dementia than those in the lowest quintile (Q5 versus Q1:HR=2.10 (95% CI: 1.05, 4.19) when adjusted for age, sex, education, APOEɛ4 allele, calories from sources other than sugar, physical activity, and diet score. Higher percent calories from sugar were positively associated with dementia risk (β=0.042, p = 0.0009). In exploratory analyses, the highest versus lowest quintile of fructose and sucrose in the diet had higher dementia risk by 2.8 (95% CI: 1.38, 5.67) and 1.93 (95% CI: 1.05, 3.54) times, respectively., Conclusions: A higher intake of total sugar or total calories from sugar is associated with increased dementia risk in older adults. Among simple sugars, fructose (e.g., sweetened beverages, snacks, packaged desserts) and sucrose (table sugar in juices, desserts, candies, and commercial cereals) are associated with higher dementia risk.

Background: African American (AA) adults have about twice the risk of developing dementia compared with white adults. However, evidence on dietary modification in preventing cognitive decline from diverse populations focusing on AA adults is minimal., Objectives: We aimed to evaluate the association between a plant-based diet and the rate of cognitive decline in a population-based sample of AA and white adults., Methods: This study consisted of 3337 participants from the Chicago Health and Aging Project (60% AA participants, 64% female). Plant-based diet quality was evaluated by the overall plant-based diet index (PDI), the healthful PDI (hPDI), and the unhealthful PDI (uPDI). Global cognition was assessed using a composite score of 4 individual tests of cognition. We used mixed models to examine the associations of PDI, hPDI, and uPDI with the rates of decline in global cognition, perceptual speed, and episodic memory. Models were adjusted for age, sex, presence of apoE e4 allele, lifestyle factors including education, cognitive activities, smoking status, calorie intake, risk factors for cardiovascular disease, time, and the interaction terms of time × each covariate., Results: AA and white participants had various dietary patterns. Higher hPDI was associated with a slower rate of decline in global cognition, perceptual speed, and episodic memory in AA participants but not white participants. AA study participants in the highest quintile of hPDI had significantly slower rates of global cognitive decline (β: 0.0183 ± 0.0086; P = 0.032), perceptual speed (β: 0.0179 ± 0.0088; P = 0.04), and episodic memory (β: 0.0163 ± 0.0118; P = 0.04) than individuals in the lowest quintile of hPDI. There were no associations of either PDI or uPDI with the rate of cognitive decline in either racial group., Conclusions: A healthy plant-based diet was associated with a slower rate of decline in global cognition, perceptual speed, and episodic memory in AA adults., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Copper is an essential micronutrient for brain health and dyshomeostasis of copper could have a pathophysiological role in Alzheimer's disease (AD), however, there are limited data from community-based samples. In this study, we investigate the association of brain copper (assessed using ICP-MS in four regions -inferior temporal, mid-frontal, anterior cingulate, and cerebellum) and dietary copper with cognitive decline and AD pathology burden (a quantitative summary of neurofibrillary tangles, diffuse and neuritic plaques in multiple brain regions) at autopsy examination among deceased participants (N = 657; age of death: 90.2(±6.2)years, 70% women, 25% APOE-ɛ4 carriers) in the Rush Memory and Aging Project. During annual visits, these participants completed cognitive assessments using a 19-test battery and dietary assessments (using a food frequency questionnaire). Regression, linear mixed-effects, and logistic models adjusted for age at death, sex, education, and APOE-ε4 status were used. Higher composite brain copper levels were associated with slower cognitive decline (β(SE) = 0.028(0.01), p = 0.001) and less global AD pathology (β(SE) = -0.069(0.02), p = 0.0004). Participants in the middle and highest tertile of dietary copper had slower cognitive decline (T2vs.T1: β = 0.038, p = 0.0008; T3vs.T1: β = 0.028, p = 0.01) than those in the lowest tertile. Dietary copper intake was not associated with brain copper levels or AD pathology. Associations of higher brain copper levels with slower cognitive decline and with less AD pathology support a role for copper dyshomeostasis in AD pathogenesis and suggest that lower brain copper may exacerbate or indicate disease severity. Dietary and brain copper are unrelated but dietary copper is associated with slower cognitive decline via an unknown mechanism., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Context: Predicting the onset of menopause is important for family planning and to ensure prompt intervention in women at risk of developing menopause-related diseases., Objective: We aimed to summarize risk prediction models of natural menopause onset and their performance., Methods: Five bibliographic databases were searched up to March 2022. We included prospective studies on perimenopausal women or women in menopausal transition that reported either a univariable or multivariable model for risk prediction of natural menopause onset. Two authors independently extracted data according to the CHARMS (critical appraisal and data extraction for systematic reviews of prediction modelling studies) checklist. Risk of bias was assessed using a prediction model risk of bias assessment tool (PROBAST)., Results: Of 8132 references identified, we included 14 articles based on 8 unique studies comprising 9588 women (mainly Caucasian) and 3289 natural menopause events. All included studies used onset of natural menopause (ONM) as outcome, while 4 studies also predicted early ONM. Overall, there were 180 risk prediction models investigated, with age, anti-Müllerian hormone, and follicle-stimulating hormone being the most investigated predictors. Estimated C-statistic for the prediction models ranged from 0.62 to 0.95. Although all studies were rated at high risk of bias mainly due to the methodological concerns related to the statistical analysis, their applicability was satisfactory., Conclusion: Predictive performance and generalizability of current prediction models on ONM is limited given that these models were generated from studies at high risk of bias and from specific populations/ethnicities. Although in certain settings such models may be useful, efforts to improve their performance are needed as use becomes more widespread., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To evaluate the properties of the cognitive battery used in the MIND Diet Intervention to Prevent Alzheimer's Disease. The MIND Diet Intervention is a randomized control trial to determine the relative effectiveness of the MIND diet in slowing cognitive decline and reducing brain atrophy in older adults at risk for Alzheimer's dementia., Methods: The MIND cognitive function battery was administered at baseline to 604 participants of an average age of 70 years, who agreed to participate in the diet intervention study, and was designed to measure change over time. The battery included 12 cognitive tests, measuring the 4 cognitive domains of executive function, perceptual speed, episodic memory, and semantic memory. We conducted a principal component analysis to examine the consistency between our theoretical domains and the statistical performance of participants in each domain. To further establish the validity of each domain, we regressed the domain scores against a late-life cognitive activity score, controlling for age, race, sex, and years of education., Results: Four factors emerged in the principal component analyses that were similar to the theoretical domains. In regression equations, we found the expected associations with age, education, and late-life cognitive activity with each of the four cognitive domains., Conclusions: These results indicate that the MIND cognitive battery is a comprehensive and valid battery of four separate domains of cognitive function that can be used in diet intervention trials for older adults.

Aims: To determine associations of three dietary patterns (Mediterranean (MEDI) diet, the Dietary Approaches to Stop Hypertension (DASH) diet and the Mediterranean- DASH Intervention for Neurodegenerative Delay (MIND) diet) with cognitive decline in older adults with type 2 diabetes mellitus (T2D)., Methods: This is a longitudinal observational study. Participants (N = 960) from the Israel Diabetes and Cognitive Decline (IDCD) study were included in this study. A multivariable-adjusted model including all three dietary patterns concurrently was developed to investigate their independent effect on cognitive decline., Results: The mean follow up was 4.1 ± 2.1 years. While high adherence to both the MIND and the MEDI diet was associated with a slower decline, in the multivariable model only the associations of higher MEDI diet intake with greater decline in global cognition and in executive functions remained significant (β = 0.013, SE = 0.006; P = 0.042; β = 0.001, SE = 0.008, Pv = 0.023 respectively)., Conclusions: In older adults with T2D, adherence to the MEDI is related to better cognitive trajectory. Diet is a meaningful factor in the path linking T2D and cognition., 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 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To determine the impact of lifestyle factors on life expectancy lived with and without Alzheimer's dementia., Design: Prospective cohort study., Setting: The Chicago Health and Aging Project, a population based cohort study in the United States., Participants: 2449 men and women aged 65 years and older., Main Exposure: A healthy lifestyle score was developed based on five modifiable lifestyle factors: a diet for brain health (Mediterranean-DASH Diet Intervention for Neurodegenerative Delay-MIND diet score in upper 40% of cohort distribution), late life cognitive activities (composite score in upper 40%), moderate or vigorous physical activity (≥150 min/week), no smoking, and light to moderate alcohol consumption (women 1-15 g/day; men 1-30 g/day)., Main Outcome: Life expectancy with and without Alzheimer's dementia in women and men., Results: Women aged 65 with four or five healthy factors had a life expectancy of 24.2 years (95% confidence interval 22.8 to 25.5) and lived 3.1 years longer than women aged 65 with zero or one healthy factor (life expectancy 21.1 years, 19.5 to 22.4). Of the total life expectancy at age 65, women with four or five healthy factors spent 10.8% (2.6 years, 2.0 to 3.3) of their remaining years with Alzheimer's dementia, whereas women with zero or one healthy factor spent 19.3% (4.1 years, 3.2 to 5.1) with the disease. Life expectancy for women aged 65 without Alzheimer's dementia and four or five healthy factors was 21.5 years (20.0 to 22.7), and for those with zero or one healthy factor it was 17.0 years (15.5 to 18.3). Men aged 65 with four or five healthy factors had a total life expectancy of 23.1 years (21.4 to 25.6), which is 5.7 years longer than men aged 65 with zero or one healthy factor (life expectancy 17.4 years, 15.8 to 20.1). Of the total life expectancy at age 65, men with four or five healthy factors spent 6.1% (1.4 years, 0.3 to 2.0) of their remaining years with Alzheimer's dementia, and those with zero or one healthy factor spent 12.0% (2.1 years, 0.2 to 3.0) with the disease. Life expectancy for men aged 65 without Alzheimer's dementia and four or five healthy factors was 21.7 years (19.7 to 24.9), and for those with zero or one healthy factor life expectancy was 15.3 years (13.4 to 19.1)., Conclusion: A healthy lifestyle was associated with a longer life expectancy among men and women, and they lived a larger proportion of their remaining years without Alzheimer's dementia. The life expectancy estimates might help health professionals, policy makers, and stakeholders to plan future healthcare services, costs, and needs., Competing Interests: Competing interests: Authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from the National Institutes On Aging of the National Institute of Health for the submitted work; support from National Institutes On Aging of the National Institute of Health outside the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: We investigated the role of genetic risk and adherence to lifestyle factors on cognitive decline in African Americans and European Americans., Methods: Using data from the Chicago Health and Aging Project (1993-2012; n = 3874), we defined the genetic risk based on presence of apolipoprotein E (APOE) ε 4 $\varepsilon 4$ allele and determined a healthy lifestyle using a scoring of five factors: non-smoking, exercising, being cognitively active, having a high-quality diet, and limiting alcohol use. We used linear mixed-effects models to estimate cognitive decline by genetic risk and lifestyle score., Results: APOE  ε 4 $\varepsilon 4$ allele was associated with faster cognitive decline in both races. However, within APOE  ε 4 $\varepsilon 4$ carriers, adherence to a healthy lifestyle (eg., 4 to 5 healthy factors) was associated with a slower cognitive decline by 0.023 (95% confidence interval [CI] 0.004, 0.042) units/year in African Americans and 0.044 (95% CI 0.008, 0.080) units/year in European Americans., Discussion: A healthy lifestyle was associated with a slower cognitive decline in African and European Americans., (© 2021 the Alzheimer's Association.)

Importance: Subjective memory complaints (SMCs) are associated with a faster cognitive decline; whether this association is also associated with structural brain alterations, such as white matter hyperintensity (WMH) volumes, requires investigation., Objective: To evaluate the association of SMCs with WMH volumes and cognitive decline and investigate the role of WMH volumes in the association between SMCs and cognitive decline., Design, Setting, and Participants: The Chicago Health and Aging Project, a population-based cohort study, enrolled adults aged 65 years or older. Data collection occurred in 3-year cycles from 1993 until 2012. Our study comprised 975 participants with magnetic resonance imaging assessments, of which 900 participants had data on SMCs and covariates, and 713 participants provided 2 or more cognitive assessments during the follow-up. Statistical analyses were conducted from May to October 2021., Exposures: SMCs were obtained from self-reported questionnaire data during clinical evaluations, and the cycle, when reported, constituted the baseline of our study. Based on the frequency and severity of concerns, we categorized participants into 3 groups, (1) no concerns, (2) moderate concerns, and (3) very worried., Main Outcomes and Measures: Volumetric magnetic resonance imaging measures of WMH volume and neuropsychological testing assessments of global cognition. Linear regression analysis was used to investigate the association between SMCs and WMH volumes in a multivariable model adjusted for age, sex, race and ethnicity, education, APOE4 status, and total intracranial volume. The association of SMCs with cognitive decline was investigated using linear mixed-effects models for age, sex, race and ethnicity, education, APOE4 status, follow-up time, and each variable in interaction with time to estimate the annual longitudinal change in cognitive function., Results: Of the 900 participants with data on SMCs, covariates, and WMH volumes, 553 (61.4%) were women, 539 (59.9%) were African American, and the mean (SD) age was 79.5 (6.2) years. SMCs were associated with a larger WMH volume and faster cognitive decline. Compared with participants with no concerns, participants who were very worried had higher WMH volumes (β = 0.833; 95% CI, 0.203-1.463) and 174% faster cognitive decline (β = -0.049; 95% CI, -0.076 to -0.022). The association between SMCs and cognitive decline remained statistically significant among individuals with large WMH volumes (ie, within the fourth quartile). Within the fourth quartile of WMH volumes, participants who were very worried had 428% faster cognitive decline (β = -0.077; 95% CI, -0.144 to -0.011) compared with participants with no concerns., Conclusions and Relevance: This cohort study suggests that SMCs, frequently reported by older individuals, are an important sign of cognitive impairment, especially among people with abnormalities in brain structure, such as larger WMH volumes.

This study examined the relationship between walking and cognitive function among Chicago Health and Aging Project participants. Data collection occurred during six 3-year cycles, of which Cycles 4-6 were used for this specific analysis. Information was obtained regarding walking frequency and duration, demographics, chronic conditions, cognitive activities, apolipoprotein E4, physical function, and cognitive function (global and domains). A composite walking measure was developed and categorized as follows: no walking, ≤105 min/week, and >105 min/week. Mixed-effects regression analyses tested associations between walking and global cognitive function, episodic memory, and perceptual speed. The sample consisted of 4,320 participants (African American/Black: 65%; female: 65%; mean education: 13 years; mean age: 75 years). Composite or total walking had a statistically significant association with global cognitive function and perceptual speed, after adjustments were made.

Carotid intima media thickness (cIMT) is a biomarker of subclinical atherosclerosis and a predictor of future cardiovascular events. Identifying associations between gene expression levels and cIMT may provide insight to atherosclerosis etiology. Here, we use two approaches to identify associations between mRNA levels and cIMT: differential gene expression analysis in whole blood and S-PrediXcan. We used microarrays to measure genome-wide whole blood mRNA levels of 5647 European individuals from four studies. We examined the association of mRNA levels with cIMT adjusted for various potential confounders. Significant associations were tested for replication in three studies totaling 3943 participants. Next, we applied S-PrediXcan to summary statistics from a cIMT genome-wide association study (GWAS) of 71 128 individuals to estimate the association between genetically determined mRNA levels and cIMT and replicated these analyses using S-PrediXcan on an independent GWAS on cIMT that included 22 179 individuals from the UK Biobank. mRNA levels of TNFAIP3, CEBPD and METRNL were inversely associated with cIMT, but these associations were not significant in the replication analysis. S-PrediXcan identified associations between cIMT and genetically determined mRNA levels for 36 genes, of which six were significant in the replication analysis, including TLN2, which had not been previously reported for cIMT. There was weak correlation between our results using differential gene expression analysis and S-PrediXcan. Differential expression analysis and S-PrediXcan represent complementary approaches for the discovery of associations between phenotypes and gene expression. Using these approaches, we prioritize TNFAIP3, CEBPD, METRNL and TLN2 as new candidate genes whose differential expression might modulate cIMT., (Published by Oxford University Press 2021.)

Importance: Little is known about the association of serum neurofilament light chain (NfL) concentrations and physical activity with the rate of cognitive decline in older adults., Objective: To examine the association of physical activity and NfL concentrations with cognitive decline in older adults over time., Design, Setting, and Participants: This cohort study used data from the Chicago Health and Aging Project (CHAP), a population-based cohort study that recruited participants through door-to-door census in 4 Chicago-area communities and collected data between 1993 and 2012 in cycles of 3 years. Participants in CHAP who had 2 or more cognitive function assessments and at least 1 blood sample collected for NfL measurement were selected for inclusion in the current study. Data were analyzed from January to December 2021., Exposures: Self-reported physical activity (minutes per week) and serum NfL concentration (pg/mL)., Main Outcomes and Measures: Associations of baseline physical activity and NfL concentrations with changes in global cognitive function over time as evaluated using the East Boston Memory Test for episodic memory, the Symbol Digit Modalities Test for perceptual speed, and the Mini-Mental State Examination. Mixed-effects regression analyses were conducted to examine associations at baseline and longitudinally., Results: The study sample included 1158 participants (695 [60%] African American; 728 [63%] female), with a mean (SD) age of 77.4 (6.0) years and a mean educational level of 12.6 (3.5) years. Among participants with high NfL concentrations (>25 pg/mL), those who engaged in medium physical activity (<150 minutes per week) had a 12% slower rate of global cognitive decline (SD units, or β, -0.065; 95% CI, -0.099 to -0.032) and participants who engaged in high physical activity (≥150 minutes per week) had a 36% slower rate of decline (β, -0.048; 95% CI, -0.080 to -0.016) than did participants with low physical activity (no reported participation) (β, -0.075; 95% CI, -0.108 to -0.041). For participants with low NfL concentrations (≤25 pg/mL), those who took part in medium physical activity had 43% slower global cognitive decline (β, -0.025; 95% CI, -0.043 to -0.007) and individuals who participated in high physical activity had 30% slower decline (β, -0.031; 95% CI, -0.048 to -0.014) than did those who participated in low physical activity (β, -0.046; 95% CI, -0.066 to -0.025)., Conclusions and Relevance: The findings suggest that physical activity is associated with diminished cognitive decline among older adults with increased serum NfL concentrations. The results support the potential use of blood biomarkers in measuring the benefits of health behaviors, such as physical activity, and early intervention for older adults at risk for cognitive decline.

Objective: To evaluate the association of a healthy lifestyle, involving seven low-risk factors mentioned in diabetes management guidelines (no current smoking, moderate alcohol consumption, regular physical activity, healthy diet, less sedentary behavior, adequate sleep duration, and appropriate social connection), with all-cause and cause-specific mortality among individuals with type 2 diabetes., Research Design and Methods: This study included 13,366 participants with baseline type 2 diabetes from the UK Biobank free of cardiovascular disease (CVD) and cancer. Lifestyle information was collected through a baseline questionnaire., Results: During a median follow-up of 11.7 years, 1,561 deaths were documented, with 625 from cancer, 370 from CVD, 115 from respiratory disease, 81 from digestive disease, and 74 from neurodegenerative disease. In multivariate-adjusted model, each lifestyle factor was significantly associated with all-cause mortality, and hazard ratios associated with the lifestyle score (scoring 6-7 vs. 0-2 unless specified) were 0.42 (95% CI 0.34, 0.52) for all-cause mortality, 0.57 (0.41, 0.80) for cancer mortality, 0.35 (0.22, 0.56) for CVD mortality, 0.26 (0.10, 0.63) for respiratory mortality, and 0.28 (0.14, 0.53) for digestive mortality (scoring 5-7 vs. 0-2). In the population-attributable risk analysis, 29.4% (95% CI 17.9%, 40.9%) of deaths were attributable to a poor lifestyle (scoring 0-5). The association between a healthy lifestyle and all-cause mortality was consistent, irrespective of factors reflecting diabetes severity (diabetes duration, glycemic control, diabetes-related microvascular disease, and diabetes medication)., Conclusions: A healthy lifestyle was associated with a lower risk of all-cause mortality and mortality due to CVD, cancer, respiratory disease, and digestive disease among individuals with type 2 diabetes., (© 2022 by the American Diabetes Association.)

Coronavirus disease 2019 (COVID-19) has taken hundreds of thousands of lives globally. Besides the respiratory tract, the virus can affect the gastrointestinal (GI) tract. Data regarding the significance of GI symptoms in the COVID-19 course are limited. In this largest US study to date, the authors reviewed electronic encounters of 1003 consecutive patients who were tested positive for the virus between March 12 and April 3, 2020. Initial GI symptoms were present in up to 22.4% of patients and were associated with worse outcomes after adjustment for demographics, comorbidities, and other clinical symptoms. COVID-19 with GI involvement may define a more severe phenotype., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Patients with stroke are at a higher risk of cognitive impairment and Alzheimer's disease dementia., Objective: To quantify the role of lifestyle pre-stroke, post-stroke, and changes in lifestyle before and after stroke with cognitive decline in community-dwelling stroke survivors., Methods: Utilizing data from the Chicago Health and Aging Project, a population-based cohort study, we studied 1,078 individuals with stroke (662 incident and 416 prevalent) who underwent cognitive testing during the study period. A healthy lifestyle score was defined by scoring four behaviors: non-smoking, exercising, being cognitively active, and having a high-quality diet. The global cognitive score was derived from a comprehensive battery of 4 standardized tests., Results: The mean age at incident stroke was 78.2 years, and 60.1% were women. A healthy lifestyle pre-incident stroke was associated with a slower rate of cognitive decline after stroke. Participants with 3-4 healthy lifestyle factors pre-incident stroke had a slower cognitive decline after stroke by 0.046 units/year (95% CI 0.010, 0.083), or 47.7% slower, than participants with 0-1 healthy lifestyle factor. Lifestyle score post-prevalent stroke was not associated with cognitive decline. Changes in lifestyle behaviors from pre- to post-incident stroke were related to cognitive decline after stroke. Individuals who deteriorated their lifestyle quality after stroke had a faster cognitive decline by 0.051 units/year (β -0.051, 95% CI -0.090, -0.012) than participants with no change in lifestyle score., Conclusion: A healthy lifestyle pre-stroke was associated with a slower rate of cognitive decline in stroke survivors, highlighting the importance of primary prevention. After the stroke, changes in lifestyle behaviors may influence the cognitive abilities of older adults as they age.

Background: Few older adults are able to achieve recommended levels of moderate-vigorous physical activity despite known cognitive benefits. Alternatively, less intense activities such as standing can be easily integrated into daily life. No existing study has examined the impact of free-living standing activity during daily life as measured by a device on cognition in older adults. Our purpose was to examine the association between free-living standing activity and cognitive function in cognitively healthy older adults., Method: Participants were 98 adults aged 65 years or older from the ongoing MIND trial (NCT02817074) without diagnoses or symptoms of mild cognitive impairment or dementia. Linear regression analyses tested cross-sectional associations between standing activity (duration and intensity from the MoveMonitor+ accelerometer/gyroscope) and cognition (4 cognitive domains constructed from 12 cognitive performance tests)., Results: Participants were on average 69.7 years old (SD = 3.7), 69.4% women, and 73.5% had a college degree or higher. Higher mean intensity of standing activity was significantly associated with higher levels of perceptual speed when adjusting for age, gender, and education level. Each log unit increase in standing activity intensity was associated with 0.72 units higher of perceptual speed (p = .023). When we additionally adjusted for cognitive activities and moderate-vigorous physical activity, and then also for body mass index, depressive symptoms, prescription medication use, and device wear time, the positive association remained., Conclusions: These findings should be further explored in longitudinal analyses and interventions for cognition that incorporate small changes to free-living activity in addition to promoting moderate-vigorous physical activity., (© The Author(s) 2021. 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: Vitamin D is critical to brain health and a promising candidate to prevent cognitive decline and onset of Alzheimer disease (AD), although the underlying brain mechanisms are unclear., Objectives: This study aimed to determine the association between vitamin D intake and brain cortical thickness in older adults., Methods: This was a cross-sectional investigation of 263 cognitively unimpaired participants, aged 65 y and older, participating in the MIND (Mediterranean-DASH Intervention for Neurodegenerative Delay) trial (an ongoing study testing the effects of a 3-y diet intervention on cognitive decline). Vitamin D intake, from diet and supplements, was ascertained from an FFQ. Linear regression analysis, adjusted for age, sex, race, education, income, cognitive and physical activities, and cardiovascular disease risk factors, was used to determine the association between vitamin D intake and cortical thickness of the whole brain, lobes, and AD signature., Results: Total vitamin D intake was associated with cortical thickness of the temporal lobe and AD signature. Compared with individuals in the lowest quartile of total vitamin D intake [median: 140 international units (IU)/d], those in the highest quartile (median: 1439 IU/d) had a 0.038-mm (95% CI: 0.006, 0.069 mm) thicker temporal lobe and 0.041-mm (95% CI: 0.012, 0.070 mm) thicker AD signature. Most vitamin D intake was from supplements, and supplemental intake was also associated with cortical thickness. Compared with those who used no supplement, individuals taking 800-1000 IU/d and >1000 IU/d of supplemental vitamin D had a 0.039-mm (95% CI: 0.013, 0.066 mm) and 0.047-mm (95% CI: 0.013, 0.081 mm) thicker temporal lobe and a 0.037-mm (95% CI: 0.013, 0.061 mm) and 0.046-mm (95% CI: 0.015, 0.077 mm) thicker AD signature, respectively. Dietary vitamin D was not related to brain cortical thickness in our sample., Conclusions: In cognitively unimpaired older adults, total and supplemental vitamin D intakes were associated with cortical thickness in regions vulnerable to AD.This trial was registered at clinicaltrials.gov as NCT02817074., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

There is emerging evidence linking fruit and vegetable consumption and cognitive function. However, studies focusing on the nutrients underlying this relationship are lacking. We aim to examine the association between plasma nutrients and cognition in a population at risk for cognitive decline with a suboptimal diet. The Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) trial is a randomized controlled intervention that examines the effects of the MIND diet to prevent cognitive decline. The primary outcome is global cognition. A multivariate linear model was used to investigate the association between blood nutrients and global and/or domain-specific cognition. The model was adjusted for age, sex, education, study site, smoking status, cognitive activities and physical activities. High plasma α-carotene was associated with better global cognition. Participants in the highest tertile of plasma α-carotene had a higher global cognition z score of 0⋅17 when compared with individuals in the lowest tertile ( P 0⋅002). Circulating α-carotene levels were also associated with higher semantic memory scores ( P for trend 0⋅007). Lutein and zeaxanthin (combined) was positively associated with higher semantic memory scores ( P for trend 0⋅009). Our study demonstrated that higher α-carotene levels in blood were associated with higher global cognition scores in a US population at risk for cognitive decline. The higher α-carotene levels in blood reflected greater intakes of fruits, other types of vegetables and lesser intakes of butter and margarine and meat. The higher circulating levels of lutein plus zeaxanthin reflected a dietary pattern with high intakes of fruits, green leafy, other vegetables and cheese, and low consumption of fried foods. Objective nutrient markers in the blood can better characterize dietary intake, which may facilitate the implementation of a tailored dietary intervention for the prevention of cognitive decline., (© The Author(s) 2021.)

Importance: Tau is a brain protein located in neurons and develops abnormally in individuals with Alzheimer disease. New technology is convenient for measuring blood total tau concentrations and provides a unique and increased opportunity for early intervention to slow cognitive decline., Objective: To evaluate the association of physical activity and total tau concentrations with cognitive decline at baseline and over time., Design, Setting, and Participants: The Chicago Health and Aging Project is a population-based cohort study conducted in 4 Chicago communities. Data collection occurred in 3-year cycles between 1993 and 2012. Participants completed in-home interviews. Clinical evaluations, which included blood samples, were performed with a stratified random sample of 1159 participants. Statistical analyses were conducted from October 30, 2020, to May 25, 2021., Exposures: Physical activity and total serum tau concentrations. Data on physical activity were obtained through self-report items, and a sum of minutes per week was calculated. Little physical activity was defined as no participation in a minimum of 4 of the items on the physical activity measure. Medium activity was defined as participating in less than 150 minutes of physical activity per week, and high activity was defined as participating in 150 minutes or more of physical activity per week., Main Outcomes and Measures: The main outcome for this study is global cognitive function, measured through a battery of cognitive tests. The study hypothesis was developed after data were collected., Results: Of the 1159 participants in the study, 728 were women (63%), and 696 were African American (60%); the mean (SD) age was 77.4 (6.0) years, and the mean (SD) educational level was 12.6 (3.5) years. Participants with high total tau concentrations with medium physical activity had a 58% slower rate of cognitive decline (estimate, -0.028 standard deviation unit [SDU] per year [95% CI, -0.057 to 0.002 SDU per year]; difference, 0.038 SDU per year [95% CI, 0.011-0.065 SDU per year]), and those with high physical activity had a 41% slower rate of cognitive decline (estimate, -0.038 SDU per year [95% CI, -0.068 to -0.009 SDU per year]; difference, 0.027 SDU per year [95% CI, -0.002 to 0.056 SDU per year]), compared with those with little physical activity. Among participants with low total tau concentrations, medium physical activity was associated with a 2% slower rate of cognitive decline (estimate, -0.050 SDU per year [95% CI, -0.069 to -0.031 SDU per year]; difference, 0.001 SDU per year [95% CI, -0.019 to 0.021 SDU per year]), and high physical activity was associated with a 27% slower rate of cognitive decline (estimate, -0.037 SDU per year [95% CI, -0.055 to -0.019 SDU per year]; difference, 0.014 SDU per year [95% CI, -0.007 to 0.034 SDU per year]), compared with little physical activity. Individual tests of cognitive function showed similar results., Conclusions and Relevance: This study suggests that, among participants with both high and low total tau concentrations, physical activity was associated with slower cognitive decline. Results support the potential utility of blood biomarkers in measuring the benefits associated with health behaviors and may contribute to specifying target populations or informing interventions for trials that focus on improving physical activity behavior. Future work should examine the association of total tau concentrations with other health behaviors and physical activity types.

Adherence to a healthy lifestyle-characterized by abstaining from smoking, being physically and cognitively active, having a high-quality diet, and limiting alcohol use-is associated with slower cognitive decline in older adults, but whether this relationship extends to persons with a genetic predisposition (e.g., carriers of the ε4 allele of the apolipoprotein E gene (APOE*E4)) remains uncertain. Using data from a population-based study, the Chicago Health and Aging Project (Chicago, Illinois), we followed 3,886 individuals who underwent regular clinical and cognitive assessments from 1993 to 2012. Of 3,886 older adults, 1,269 (32.7%) were APOE*E4 carriers. Compared with noncarriers, APOE*E4 carriers had faster cognitive decline (β = -0.027 units/year, 95% confidence interval (CI): -0.032, -0.023). In contrast, persons with 2-3 and 4-5 healthy lifestyle factors had slower cognitive decline (β = 0.008 units/year (95% CI: 0.002, 0.014) and β = 0.019 units/year (95% CI: 0.011, 0.026), respectively) compared with those with 0-1 factor. In analyses stratified by APOE*E4 status, adherence to a healthy lifestyle (e.g., 4-5 factors vs. 0-1 factors) was associated with a slower rate of cognitive decline in both APOE*E4 carriers (β = 0.029, 95% CI: 0.013, 0.045) and noncarriers (β = 0.013, 95% CI: 0.005, 0.022). These results underscore the impact of a healthy lifestyle on cognition, particularly among persons with a genetic predisposition, who are more vulnerable to cognitive decline as they age., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: It is unclear whether eating Western diet food components offsets the Mediterranean diet's (MedDiet) potential benefits on cognitive decline., Methods: The study includes 5001 Chicago Health and Aging Project participants (63% African American, 36% males, 74 ± 6.0 years old), with food frequency questionnaires and ≥ two cognitive assessments over 6.3 ± 2.8 years of follow-up. Mixed-effects models were adjusted for age, sex, education, race, cognitive activities, physical activity, and total calories., Results: Stratified analysis showed a significant effect of higher MedDiet on cognitive decline only with a low Western diet score (highest vs lowest MedDiet tertile: β = 0.020, P = .002; p trend = 0.002) and not with a high Western diet score (highest vs lowest MedDiet tertile: β = 0.010, P = .11; p trend = 0.09)., Conclusion: This prospective study found that high consumption of Western diet components attenuates benefits of the MedDiet on cognition., (© 2021 the Alzheimer's Association.)

Here we examine the association between DNA methylation in circulating leukocytes and blood lipids in a multi-ethnic sample of 16,265 subjects. We identify 148, 35, and 4 novel associations among Europeans, African Americans, and Hispanics, respectively, and an additional 186 novel associations through a trans-ethnic meta-analysis. We observe a high concordance in the direction of effects across racial/ethnic groups, a high correlation of effect sizes between high-density lipoprotein and triglycerides, a modest overlap of associations with epigenome-wide association studies of other cardio-metabolic traits, and a largely non-overlap with lipid loci identified to date through genome-wide association studies. Thirty CpGs reached significance in at least 2 racial/ethnic groups including 7 that showed association with the expression of an annotated gene. CpGs annotated to CPT1A showed evidence of being influenced by triglycerides levels. DNA methylation levels of circulating leukocytes show robust and consistent association with blood lipid levels across multiple racial/ethnic groups.

Alzheimer's dementia (AD) is the sixth leading cause of death in the U.S., with an estimated $305 billion cost of care in 2020. Currently there are no cures or therapies to ameliorate the disease progression and symptoms. Growing evidence links a diet characterized by high antioxidant components with benefits to cognitive function, which is indicative of the preventative potential of dietary inteventions. The Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) study is a 3-year, multicenter, randomized controlled trial to test the effects of the MIND diet on cognitive function in 604 individuals at risk for AD. Men and women ages 65 to 84 years were recruited. Eligible participants were randomized to either the MIND diet with mild caloric restriction or their usual diet with mild caloric restriction. Cognitive assessments, medical history, blood pressure, anthropometric measurements, and blood and urine sample collections will be taken at baseline and follow-up visits. MRI scans will be completed on approximately half of the enrolled participants at the start and end of the study. Unique features of the MIND study include: 1) a dietary pattern, rather than single nutrient or food, tested in an at-risk population; 2) foods featured as key components of the MIND diet (i.e. extra-virgin olive oil, blueberries, and nuts) provided for participants; and 3) MRI scans of brain structure and volume that may provide potential mechanistic evidence on the effects of the diet. Results from the study will be crucial to the development of dietary guidelines for the prevention of AD., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: Non-pharmacological treatments (NPTs) have the potential to improve meaningful outcomes for older people at risk of, or living with dementia, but research often lacks methodological rigor and continues to produce mixed results., Methods: In the current position paper, experts in NPT research have specified treatment targets, aims, and ingredients using an umbrella framework, the Rehabilitation Treatment Specification System., Results: Experts provided a snapshot and an authoritative summary of the evidence for different NPTs based on the best synthesis efforts, identified main gaps in knowledge and relevant barriers, and provided directions for future research. Experts in trial methodology provide best practice principles and recommendations for those working in this area, underscoring the importance of prespecified protocols., Discussion: We conclude that the evidence strongly supports various NPTs in relation to their primary targets, and discuss opportunities and challenges associated with a unifying theoretical framework to guide future efforts in this area., (© 2020 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: MIND diet, a hybrid of the Mediterranean diet and the Dietary Approaches to Stop Hypertension diet, is associated with a slower cognitive decline and lower risk of Alzheimer's disease (AD) dementia in older adults., Objective: We aim to examine whether the association of the MIND diet with cognition is independent of common brain pathologies., Methods: Utilizing data from the Rush Memory and Aging Project (MAP), a longitudinal clinical-pathologic study, we studied 569 decedents with valid dietary data, cognitive testing proximate to death, and complete autopsy data at the time of these analyses. A series of regression analyses were used to examine associations of the MIND diet, dementia-related brain pathologies, and global cognition proximate to death adjusting for age, sex, education, APOEɛ4, late-life cognitive activities, and total energy intake., Results: A higher MIND diet score was associated with better global cognitive functioning proximate to death (β= 0.119, SE = 0.040, p = 0.003), and neither the strength nor the significance of association changed substantially when AD pathology and other brain pathologies were included in the model. The β-estimate after controlling for global AD pathology was 0.111 (SE = 0.037, p = 0.003). The MIND diet-cognition relationship remained significant when we restricted our analysis to individuals without mild cognitive impairment at the baseline (β= 0.121, SE = 0.042, p = 0.005) or in people diagnosed with postmortem diagnosis of AD based on NIA-Reagan consensus recommendations (β= 0.114, SE = 0.050, p = 0.023)., Conclusion: MIND diet is associated with better cognitive functioning independently of common brain pathology, suggesting that the MIND diet may contribute to cognitive resilience in the elderly.

Objective: To quantify the impact of a healthy lifestyle on the risk of Alzheimer dementia., Methods: Using data from the Chicago Health and Aging Project (CHAP; n = 1,845) and the Rush Memory and Aging Project (MAP; n = 920), we defined a healthy lifestyle score on the basis of nonsmoking, ≥150 min/wk moderate/vigorous-intensity physical activity, light to moderate alcohol consumption, high-quality Mediterranean-DASH Diet Intervention for Neurodegenerative Delay diet (upper 40%), and engagement in late-life cognitive activities (upper 40%), giving an overall score ranging from 0 to 5. Cox proportional hazard models were used for each cohort to estimate the hazard ratio (HR) and 95% confidence interval (CI) of the lifestyle score with Alzheimer dementia, and a random-effect meta-analysis was used to pool the results., Results: During a median follow-up of 5.8 years in CHAP and 6.0 years in MAP, 379 and 229 participants, respectively, had incident Alzheimer dementia. In multivariable-adjusted models, the pooled HR (95% CI) of Alzheimer dementia across 2 cohorts was 0.73 (95% CI 0.66-0.80) per each additional healthy lifestyle factor. Compared to participants with 0 to 1 healthy lifestyle factor, the risk of Alzheimer dementia was 37% lower (pooled HR 0.63, 95% CI 0.47-0.84) in those with 2 to 3 healthy lifestyle factors and 60% lower (pooled HR 0.40, 95% CI 0.28-0.56) in those with 4 to 5 healthy lifestyle factors., Conclusion: A healthy lifestyle as a composite score is associated with a substantially lower risk of Alzheimer's dementia., (© 2020 American Academy of Neurology.)

Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing the pandemic of coronavirus disease 2019 (COVID-19) is a global health crisis. Possible pancreatic involvement has recently been observed in these patients; however, its significance is unclear. The aim of this study was to evaluate the association of significantly elevated lipase with disease outcomes., Methods: Data about demographics, symptoms, laboratory values, and clinical outcomes were collected for 1,003 consecutive patients testing positive for COVID-19. Elevated lipase was defined as greater than 3 times the upper limit of normal (>3 × ULN). Baseline characteristics among patients with or without elevated lipase were compared using Fisher exact test or Student t-test for categorical or numerical variables, respectively. Logistic regression was used to evaluate the association of lipase levels with primary clinical outcomes (intensive care unit admission and intubation) adjusted for age, sex, body mass index, history of diabetes, and hypertension., Results: Of 1,003 patients with COVID-19, 83 had available lipase levels and were all admitted to the hospital. Of 83, 14 (16.8%) had elevated lipase (>3 × ULN), which was associated with higher rates of leukocytosis (P < 0.001) and abnormal liver enzymes (P < 0.01). Compared with lower lipase levels (<3 × ULN), patients with elevated lipase had higher rates of ICU admission (92.9% vs 32.8%; P < 0.001) and intubation (78.6% vs 23.5%; P 0.002). In a multivariable-adjusted model, higher lipase levels were significantly associated with admission to the ICU and rate of intubation., Discussion: Lipase elevation is seen in COVID-19 and is associated with worse disease outcomes.

Objective: People with diabetes show great variability in weight gain and duration of obesity at the time of diagnosis. BMI trajectories and other cardiometabolic risk factors prior to type 2 diabetes were investigated., Methods: A total of 6,223 participants from the Rotterdam Study cohort were included. BMI patterns before diagnosis of diabetes were identified through latent class trajectories., Results: During a mean follow-up of 13.7 years, 565 participants developed type 2 diabetes. Three distinct trajectories of BMI were identified, including the "progressive overweight" group (n = 481, 85.1%), "progressive weight loss" group (n = 59, 10.4%), and "persistently high BMI" group (n = 25, 4.4%). The majority, the progressive overweight group, was characterized by a steady increase of BMI in the overweight range 10 years before diabetes diagnosis. The progressive weight loss group had fluctuations of glucose and marked beta cell function loss. The persistently high BMI group was characterized by a slight increase in insulin levels and sharp increase of insulin resistance accompanied by a rapid decrease of beta cell function., Conclusions: Heterogeneity of BMI changes prior to type 2 diabetes was found in a middle-aged and elderly white population. Prevention strategies should be tailored rather than focusing only on high-risk individuals., (© 2020 The Authors. Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society (TOS).)

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F ROH ) for >1.4 million individuals, we show that F ROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F ROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F ROH are confirmed within full-sibling pairs, where the variation in F ROH is independent of all environmental confounding.

Objective: To evaluate changes in left ventricular diastolic function (LVDF) parameters and their associated risk factors over a period of 11 years among community-dwelling women and men., Methods: Echocardiography was performed three times among 870 women and 630 men (age 67±3 years) from the prospective population-based Rotterdam Study during a period of 11-year follow-up. Changes in six continuous LVDF parameters were correlated with cardiovascular risk factors using a linear-mixed effect model (LMM)., Results: In women, smoking was associated with deleterious longitudinal changes in deceleration time (DT) (Beta (β): 7.73; 95% CI 2.56 to 12.9) and high-density lipoprotein cholesterol was associated with improvement of septal e' (β: 0.37; 95% CI 0.13 to 0.62) and E/e' ratio (β: -0.46; 95% CI -0.84 to -0.08) trajectories. Among men, diabetes was associated with deleterious longitudinal changes in A wave (β: 3.83; 95% CI 0.06 to 7.60), septal e' (β: -0.40; 95% CI -0.70 to -0.09) and E/e' ratio (β: 0.60; 95% CI 0.14 to 1.06) and body mass index was associated with deleterious longitudinal changes in A wave (β: 1.25; 95% CI 0.84 to 1.66), E/A ratio (β: -0.007; 95% CI -0.01 to -0.003), DT (β: 0.86; 95% CI 0.017 to 1.71) and E/e' ratio (β: 0.12; 95% CI 0.06 to 0.19)., Conclusions: Smoking among women and metabolic factors (diabetes mellitus and body mass index) among men showed larger deleterious associations with longitudinal changes in LVDF parameters. The favourable association of HDL was mainly observed among women. This study, for the first time, evaluates risk factors associated with changes over time in continuous LVDF parameters among women and men and generates new hypothesis for further medical research., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

Reliable population estimates of life expectancy with dementia are required for shaping health-care policy. From the Dutch, population-based Rotterdam Study, 10,348 persons were followed during 1990-2015 for dementia and death. We created multistate lifetables, and assessed the effect of postponing disease onset. During 120,673 person-years, 1,666 persons developed dementia, and 6,150 died. Overall life expectancy of women ranged from 18.0 years (95% confidence interval (CI): 17.8, 18.2) at age 65 to 2.3 years (95% CI: 2.2, 2.3) at age 95. Of total life expectancy at age 65, 5.7% (1.0 year (95% CI: 1.0, 1.1)) was lived with dementia, increasing with age to 42.1% (1.0 year, 95% CI: 0.9, 1.0) at age 95. For men, life expectancy ranged from 15.6 years (95% CI: 15.4, 15.9) at age 65 to 1.8 years (95% CI: 1.7, 1.8) at age 95, of which 3.7% (95% CI: 0.6 year, 0.5, 0.6) and 35.3% (95% CI: 0.6 year, 0.5, 0.7), respectively, was lived with dementia. Postponing dementia onset by 1-3 years resulted in 25%-57% reductions in years lived with dementia. Survival after diagnosis ranged from 6.7 years (95% CI: 5.3, 8.1) before age 70, to 2.6 years (95% CI: 2.3, 2.9) after age 90. The burden of dementia on individuals and society in terms of healthy life-years lost is large but could potentially be mitigated by preventive interventions at the population level.

Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.