Possession of the APOE-ε4 allele is the best established genetic risk factor for sporadic Alzheimer's disease (AD), while the ε2 allele may confer protection against the disease. Previous functional magnetic resonance imaging (fMRI) studies have shown an effect of APOE genotype on brain function, typically by comparing only ε4 carriers with noncarriers. Here we included a wide range of genotype groups to determine how closely the effects of APOE on brain function are related to differences in relative risk for AD. We used functional magnetic resonance imaging (fMRI) to compare the pattern of activation during an episodic encoding task and during a counting Stroop task in 76 adults, aged 32 to 55, with different APOE genotypes (23 ε2/ε3, 20 ε3/ε3, 26 ε3/ε4, and 7 ε4/ε4). Strikingly, participants with an increased risk (ε4 carriers) and with a decreased risk (ε2 carriers) for AD both showed increased activation, relative to ε3 homozygotes, during both tasks. The increased activation was due to decreased deactivation or paradoxical activation of nontask-related regions of the brain, which suggests an intrinsic effect of APOE on the differentiation of functional cortical networks. These results question the often assumed link between APOE, the blood oxygenation level dependent (BOLD) response, and AD risk.

Evidence on the association between social support and leisure time physical activity (LTPA) is scarce and mostly based on cross-sectional data with different types of social support collapsed into a single index. The aim of this study was to investigate whether social support from the closest person was associated with LTPA.

The status of psychosocial stress at work as a risk factor for type 2 diabetes is unclear because existing evidence is based on small studies and is subject to confounding by lifestyle factors, such as obesity and physical inactivity. This collaborative study examined whether stress at work, defined as "job strain," is associated with incident type 2 diabetes independent of lifestyle factors.

The Whitehall II (WHII) study of British civil servants provides a unique source of longitudinal data to investigate key factors hypothesized to affect brain health and cognitive ageing. This paper introduces the multi-modal magnetic resonance imaging (MRI) protocol and cognitive assessment designed to investigate brain health in a random sample of 800 members of the WHII study.

Unfavorable work characteristics, such as low job control and too high or too low job demands, have been suggested to increase the likelihood of physical inactivity during leisure time, but this has not been verified in large-scale studies. The authors combined individual-level data from 14 European cohort studies (baseline years from 1985-1988 to 2006-2008) to examine the association between unfavorable work characteristics and leisure-time physical inactivity in a total of 170,162 employees (50% women; mean age, 43.5 years). Of these employees, 56,735 were reexamined after 2-9 years. In cross-sectional analyses, the odds for physical inactivity were 26% higher (odds ratio = 1.26, 95% confidence interval: 1.15, 1.38) for employees with high-strain jobs (low control/high demands) and 21% higher (odds ratio = 1.21, 95% confidence interval: 1.11, 1.31) for those with passive jobs (low control/low demands) compared with employees in low-strain jobs (high control/low demands). In prospective analyses restricted to physically active participants, the odds of becoming physically inactive during follow-up were 21% and 20% higher for those with high-strain (odds ratio = 1.21, 95% confidence interval: 1.11, 1.32) and passive (odds ratio = 1.20, 95% confidence interval: 1.11, 1.30) jobs at baseline. These data suggest that unfavorable work characteristics may have a spillover effect on leisure-time physical activity.

Many clinicians, patients and patient advocacy groups believe stress to have a causal role in inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis. However, this is not corroborated by clear epidemiological research evidence. We investigated the association between work-related stress and incident Crohn's disease and ulcerative colitis using individual-level data from 95,000 European adults.

To assess the association of a "metabolically healthy obese" phenotype with mortality using five definitions of metabolic health.

To investigate whether work related stress, measured and defined as job strain, is associated with the overall risk of cancer and the risk of colorectal, lung, breast, or prostate cancers.

Reports of the association between cardiovascular risk factors and depression in later life are inconsistent; to establish the nature of their association seems important for prevention and treatment of late-life depression. We searched MEDLINE, EMBASE, and PsycINFO for relevant cohort or case control studies over the last 22 years; 1097 were retrieved; 26 met inclusion criteria. Separate meta-analyses were performed for Risk Factor Composite Scores (RFCS) combining different subsets of risk factors, Framingham Stroke Risk Score, and single factors. We found a positive association (odds ratio [OR]: 1.49; 95% confidence interval [CI]: 1.27-1.75) between RFCS and late-life depression. There was no association between Framingham Stroke Risk Score (OR: 1.25; 95% CI: .99-1.57), hypertension (OR: 1.14; 95% CI: .94-1.40), or dyslipidemia (OR: 1.08; 95% CI: .91-1.28) and late-life depression. The association with smoking was weak (OR: 1.35; 95% CI: 1.00-1.81), whereas positive associations were found with diabetes (OR: 1.51; 95% CI: 1.30-1.76), cardiovascular disease (OR: 1.76; 95% CI: 1.52-2.04), and stroke (OR: 2.11; 95% CI: 1.61-2.77). Moderate to high heterogeneity was found in the results for RFCS, smoking, hypertension, dyslipidemia, and stroke, whereas publication bias was detected for RFCS and diabetes. We therefore found convincing evidence of a strong relationship between key diseases and depression (cardiovascular disease, diabetes, and stroke) and between composite vascular risk and depression but not between some vascular risk factors (hypertension, smoking, dyslipidemia) and depression. More evidence is needed to be accumulated from large longitudinal epidemiological studies, particularly if complemented by neuroimaging.

There is need to identify targets for preventing or delaying dementia. Social contact is a potential target for clinical and public health studies, but previous observational studies had short follow-up, making findings susceptible to reverse causation bias. We therefore examined the association of social contact with subsequent incident dementia and cognition with 28 years' follow-up.

Whether poorer pulmonary function accelerates progression of arterial stiffness remains unknown as prior observational studies have not examined longitudinal changes in arterial stiffness in relation to earlier pulmonary function. Data (N=5342, 26% female) were drawn from the Whitehall II cohort study. Participants completed repeated assessments of forced expiratory volume in 1 second (FEV1, L) and carotid-femoral pulse wave velocity (cf-PWV, m/s) over 5 years. The effect of FEV1 on later cf-PWV and its progression was estimated using linear mixed-effects modeling. Possible explanatory mechanisms, such as mediation by low-grade systemic inflammation, common-cause explanation by preexisting cardiometabolic risk factors, and reverse-causation bias, were assessed. Poorer pulmonary function was associated with later higher cf-PWV and its subsequent progression (cf-PWV 5-year change 0.09, 95% CI 0.03-0.17 per SD lower FEV1) after adjustment for age, sex, ethnicity, heart rate, and mean arterial pressure. Decrease in pulmonary function was associated with later higher cf-PWV (0.17, 95% CI 0.04-0.30 in the top compared to bottom quartile of decline in FEV1). There was no evidence to support mediation by circulating CRP (C-reactive protein) or IL (interleukin)-6. Furthermore, arterial stiffness was not associated with later FEV1 after accounting for cardiometabolic status. In conclusion, poorer pulmonary function predicted future arterial stiffness. These findings support pulmonary function as a clinically important risk factor for arterial stiffness and provide justification for future intervention studies for pulmonary function based on its relationship with arterial stiffness.

Recognizing dementia in general hospitals allows for tailored care. We aimed to assess hospital dementia diagnosis accuracy, changes over time, and predictors of correct identification.

The ε4 allele of apolipoprotein E (APOE) gene and increasing age are two of the most important known risk factors for developing Alzheimer disease (AD). The diagnosis of AD based on clinical symptoms alone is known to have poor specificity; recently developed diagnostic criteria based on biomarkers that reflect underlying AD neuropathology allow better assessment of the strength of the associations of risk factors with AD. Accordingly, we examined the global and age-specific association between APOE genotype and AD by using the A/T/N classification, relying on the cerebrospinal fluid (CSF) levels of β-amyloid peptide (A, β-amyloid deposition), phosphorylated tau (T, pathologic tau), and total tau (N, neurodegeneration) to identify patients with AD.

Being married is associated with healthier lifestyle behaviours and lower mortality and may reduce risk for dementia due to life-course factors. We conducted a systematic review and meta-analysis of studies of the association between marital status and the risk of developing dementia.

The mediating role of eating behaviors in genetic susceptibility to weight gain during mid-adult life is not fully understood. This longitudinal study aims to help us understand contributions of genetic susceptibility and appetite to weight gain.

The concept of brain maintenance refers to the preservation of brain integrity in older age, while cognitive reserve refers to the capacity to maintain cognition in the presence of neurodegeneration or aging-related brain changes. While both mechanisms are thought to contribute to individual differences in cognitive function among older adults, there is currently no "gold standard" for measuring these constructs. Using machine-learning methods, we estimated brain and cognitive age based on deviations from normative aging patterns in the Whitehall II MRI substudy cohort (N = 537, age range = 60.34-82.76), and tested the degree of correspondence between these constructs, as well as their associations with premorbid IQ, education, and lifestyle trajectories. In line with established literature highlighting IQ as a proxy for cognitive reserve, higher premorbid IQ was linked to lower cognitive age independent of brain age. No strong evidence was found for associations between brain or cognitive age and lifestyle trajectories from midlife to late life based on latent class growth analyses. However, post hoc analyses revealed a relationship between cumulative lifestyle measures and brain age independent of cognitive age. In conclusion, we present a novel approach to characterizing brain and cognitive maintenance in aging, which may be useful for future studies seeking to identify factors that contribute to brain preservation and cognitive reserve mechanisms in older age.

To examine the association between sleep duration trajectories over 28 years and measures of cognition, gray matter volume, and white matter microstructure. We hypothesize that consistently meeting sleep guidelines that recommend at least 7 hours of sleep per night will be associated with better cognition, greater gray matter volumes, higher fractional anisotropy, and lower radial diffusivity values.

Besides its well established susceptibility to ageing, the hippocampus has also been shown to be affected by alcohol consumption. Proton spectroscopy (1H-MRS) of the hippocampus, particularly at high-field 7T MRI, may further our understanding of these associations. Here, we aimed to examine how hippocampal metabolites varied with age and alcohol consumption. Hippocampal metabolite spectra were acquired in 37 older adults using 7T 1H-MRS, from which we determined the absolute concentration of N-acetylaspartate (NAA), creatine, choline, myo-inositol, glutamate and glutamine. Thirty participants (mean age = 70.4 ± 4.7 years) also had self-reported data on weekly alcohol consumption. Total choline inversely correlated with age, although this did not survive multiple comparisons correction. Crucially, adults with a higher weekly alcohol consumption had significantly lower levels of creatine, suggesting a deficit in their hippocampal metabolism. These findings add to an increasing body of evidence linking alcohol to hippocampal function.

Type 2 diabetes is associated with increased risks of cognitive dysfunction and brain abnormalities. The extent to which risk factor modification can mitigate these risks is unclear. We investigated the associations between incident dementia, cognitive performance, and brain abnormalities among individuals with type 2 diabetes, according to the number of risk factors on target, compared with control subjects without diabetes.

Cardiometabolic risk (CMR) factors are associated with accelerated brain aging and increased risk for sex-dimorphic illnesses such as Alzheimer's disease (AD). Yet, it is unknown how CMRs interact with sex and apolipoprotein E-ϵ4 (APOE4), a known genetic risk factor for AD, to influence brain age across different life stages. Using age prediction based on multi-shell diffusion-weighted imaging data in 21,308 UK Biobank participants, we investigated whether associations between white matter Brain Age Gap (BAG) and body mass index (BMI), waist-to-hip ratio (WHR), body fat percentage (BF%), and APOE4 status varied (i) between males and females, (ii) according to age at menopause in females, and (iii) across different age groups in males and females. We report sex differences in associations between BAG and all three CMRs, with stronger positive associations among males compared to females. Independent of APOE4 status, higher BAG (older brain age relative to chronological age) was associated with greater BMI, WHR, and BF% in males, whereas in females, higher BAG was associated with greater WHR, but not BMI and BF%. These divergent associations were most prominent within the oldest group of females (66-81 years), where greater BF% was linked to lower BAG. Earlier menopause transition was associated with higher BAG, but no interactions were found with CMRs. In conclusion, the findings point to sex- and age-specific associations between CMRs and brain age. Incorporating sex as a factor of interest in studies addressing CMR may promote sex-specific precision medicine, consequently improving health care for both males and females.