Late-life depression and risk of vascular dementia and Alzheimer's disease: systematic review and meta-analysis of community-based cohort studies

This study examined the relationship between sleep disorders and the risk of dementia in patients with newly diagnosed type 2 diabetes. This study used the Korean Health Screening Cohort data and included 39 135 subjects aged ≥40 years with new-onset type 2 diabetes between 2004 and 2007, with follow-up throughout 2013. Sleep disorders were measured by F51(sleep disorders not due to a substance or known physiological condition) or G47(sleep disorders) under International Classification of Diseases, Tenth Revision (ICD-10) codes as a primary diagnosis, and the adjusted hazard ratio (AHR) and 95% CI of all-cause dementia, Alzheimer disease, vascular dementia, and other dementia were estimated using multivariable Cox proportional hazards regression models. In the patients with type 2 diabetes with an age range between 42 and 84 years (M = 57.8, SD = 9.5), this study identified 2059 events of dementia during an average follow-up time of 5.7 years. In patients with type 2 diabetes, subjects with sleep disorders were associated with an increased risk of all-cause dementia (AHR, 1.46; 95% CI, 1.19-1.80), Alzheimer disease (AHR, 1.39; 95% CI, 1.02-1.88), and other dementia (AHR, 1.69; 95% CI, 1.23-2.31) compared to those without sleep disorders. Men (AHR, 1.93; 95% CI, 1.42-2.62) and older adults (AHR, 1.70; 95% CI, 1.35-2.15) with sleep disorders were associated with an increased risk of dementia than their counterparts without sleep disorders among patients with type 2 diabetes. These findings suggest that sleep disorders are significantly associated with an increased risk of dementia in patients with new-onset type 2 diabetes.

Serum 25-hydroxyvitamin D concentrations, sleep characteristics and the risk of incident dementia.

Now more than two-thirds of cancer survivors are aged 65 years or older, but evidence about their long-term health is thin. Cancer and its treatments have been linked to accelerated aging, so there is a concern that aging cancer survivors have an increased risk of age-related diseases, including dementia. We examined the risk of dementia among 5-year breast cancer survivors using a matched cohort study design. We included breast cancer survivors aged 50 years and older at diagnosis (n = 26,741) and cancer-free comparison participants (n = 249,540). Women eligible for inclusion in the study were those born 1935-1975 and registered in the Swedish Total Population Register between January 1, 1991, and December 31, 2015. We defined breast cancer survivors as women with an initial breast cancer diagnosis between 1991 and 2005 who survived 5 or more years after their first diagnosis. We assessed all-cause dementia, Alzheimer disease (AD), and vascular dementia (VaD) using International Classification of Diseases codes. Survival analyses were conducted using age-adjusted subdistribution hazard models accounting for competing risk of death. We did not observe an association between breast cancer survivorship and risk of all-cause dementia, AD, or VaD. However, in models stratified by age at cancer diagnosis, women diagnosed with cancer after age 65 years had a higher risk of all-cause dementia (subdistribution hazard ratio [SHR] = 1.30, 95% CI 1.07-1.58), AD (SHR = 1.35, 95% CI 1.05-1.75), and VaD (SHR = 1.64, 95% CI 1.11-2.43) in models adjusted for age, education, and country of origin. Older breast cancer survivors who survive cancer have a higher risk for dementia than their peers without a cancer diagnosis, in contrast to earlier studies showing that prevalent or incident cancer is associated with a lower risk of dementia. With the older adult population growing rapidly and because cancer and dementia are 2 of the most common and debilitating diseases among older adults, it is critical that we understand the link between the 2.

Previous studies relating smoking with the risk of dementia have been inconsistent and limited in their validity by short follow-up times, large intervals between baseline and follow-up assessments, and unspecific determination of dementia diagnosis. We re-assessed after longer follow-up time in the large population-based cohort of the Rotterdam Study whether smoking habits and pack-years of smoking are associated with the risk of dementia, Alzheimer disease (AD), and vascular dementia (VaD). Prospective population-based cohort study in 6,868 participants, 55 years or older and free of dementia at baseline. First, Cox proportional hazard models were used to relate smoking status at baseline with the risks of incident dementia, VaD, and AD, using never smokers as the reference category in all analyses. Then Cox proportional hazard models were used to relate pack-years of smoking with the risks of incident dementia, VaD, and AD. To explore the impact of the APOEepsilon4 allele, sex, and age on the association between smoking status and dementia, we repeated all analyses stratifying, in separate models, by APOEepsilon4 genotype, sex, and median of age. After a mean follow-up time of 7.1 years, current smoking at baseline was associated with an increased risk of dementia (HR 1.47, 95% CI 1.18 to 1.86) and AD (HR 1.56, 95% CI 1.21 to 2.02). This increase in disease risk was restricted to persons without the APOEepsilon4 allele. There was no association between current smoking and risk of VaD, and there was no association between past smoking and risk of dementia, AD, or VaD. Current smoking increases the risk of dementia. This effect is more pronounced in persons without the APOEepsilon4 allele than APOEepsilon4 carriers.

We investigated the association between glucose tolerance status defined by a 75-g oral glucose tolerance test (OGTT) and the development of dementia. A total of 1,017 community-dwelling dementia-free subjects aged ≥60 years who underwent the OGTT were followed up for 15 years. Outcome measure was clinically diagnosed dementia. The age- and sex-adjusted incidence of all-cause dementia, Alzheimer disease (AD), and vascular dementia (VaD) were significantly higher in subjects with diabetes than in those with normal glucose tolerance. These associations remained robust even after adjustment for confounding factors for all-cause dementia and AD, but not for VaD (all-cause dementia: adjusted hazard ratio [HR] = 1.74, 95% confidence interval [CI] = 1.19 to 2.53, p = 0.004; AD: adjusted HR = 2.05, 95% CI = 1.18 to 3.57, p = 0.01; VaD: adjusted HR = 1.82, 95% CI = 0.89 to 3.71, p = 0.09). Moreover, the risks of developing all-cause dementia, AD, and VaD significantly increased with elevated 2-hour postload glucose (PG) levels even after adjustment for covariates, but no such associations were observed for fasting plasma glucose (FPG) levels: compared with those with 2-hour PG levels of <6.7 mmol/L, the multivariable-adjusted HRs of all-cause dementia and AD significantly increased in subjects with 2-hour PG levels of 7.8 to 11.0 mmol/L or over, and the risk of VaD was significantly higher in subjects with levels of ≥11.1 mmol/L. Our findings suggest that diabetes is a significant risk factor for all-cause dementia, AD, and probably VaD. Moreover, 2-hour PG levels, but not FPG levels, are closely associated with increased risk of all-cause dementia, AD, and VaD.

BackgroundRestless leg syndrome (RLS) is associated with poor sleep quality, depression or anxiety, poor dietary patterns, microvasculopathy, and hypoxia, all of which are known risk factors for dementia. However, the relationship between RLS and incident dementia remains unclear. This retrospective cohort study aimed to explore the possibility that RLS could be deemed as a non-cognitive prodromal feature of dementia.MethodsThis was a retrospective cohort study using the Korean National Health Insurance Service-Elderly Cohort (aged ≥ 60). The subjects were observed for 12 years, from 2002 to 2013. Identifying patients with RLS and dementia was based on the 10th revised code of the International Classification of Diseases (ICD-10). We compared the risk of all-cause dementia, Alzheimer’s disease (AD), and vascular dementia (VaD) in 2501 subjects with newly diagnosed RLS and 9977 matched controls based on age, sex, and index date. The association between RLS and the risk of dementia was assessed using Cox regression hazard regression models. The effect of dopamine agonists on the risk of dementia among RLS patients was also explored.ResultsThe baseline mean age was 73.4, and the subjects were predominantly females (63.4%). The incidence of all-cause dementia was higher in the RLS group than that in the control group (10.4% vs 6.2%). A baseline diagnosis of RLS was associated with an increased risk of incident all-cause dementia (adjusted hazard ratio [aHR] 1.46, 95% confidence interval [CI] 1.24–1.72). The risk of developing VaD (aHR 1.81, 95% CI 1.30–2.53) was higher than that of AD (aHR 1.38, 95% CI 1.11–1.72). The use of dopamine agonists was not associated with the risk of subsequent dementia among patients with RLS (aHR 1.00, 95% CI 0.76–1.32).ConclusionsThis retrospective cohort study suggests that RLS is associated with an increased risk of incident all-cause dementia in older adults, providing some evidence that requires confirmation through prospective studies in the future. Awareness of cognitive decline in patients with RLS may have clinical implications for the early detection of dementia.

Type 2 diabetes mellitus and risk of dementia: A population-based 14-year follow-up study in Germany

BackgroundSeveral epidemiological studies have suggested that vitamin D status is associated with risk of dementia in general populations. However, due to the synergistic effect between diabetic pathology and neuroinflammation, and the prothrombotic profile in patients with diabetes, whether vitamin D is associated with risk of dementia among patients with diabetes is unclear. This study aimed to investigate the associations of circulating vitamin D levels with risks of all-cause dementia, Alzheimer disease (AD), and vascular dementia (VD) among adults with type 2 diabetes (T2D).Methods and findingsThis study included 13,486 individuals (≥60 years) with T2D and free of dementia at recruitment (2006–2010) from the UK Biobank study. Serum 25-hydroxyvitamin D (25[OH]D) concentrations were measured using the chemiluminescent immunoassay method at recruitment. Serum 25(OH)D ≥ 75 nmol/L was considered sufficient, according to the Endocrine Society Clinical Practice Guidelines. Incidence of all-cause dementia, AD, and VD cases was ascertained using electronic health records (EHRs). Each participant’s person-years at risk were calculated from the date of recruitment to the date that dementia was reported, date of death, date of loss to follow-up, or 28 February 2018, whichever occurred first. Among the 13,486 individuals with T2D (mean age, 64.6 years; men, 64.3%), 38.3% had vitamin D ≥ 50 nmol/L and only 9.1% had vitamin D ≥ 75 nmol/L. During a mean follow-up of 8.5 years, we observed 283 cases of all-cause dementia, including 101 AD and 97 VD cases. Restricted cubic spline analysis demonstrated a nonlinear relationship between serum 25(OH)D and risk of all-cause dementia (Pnonlinearity < 0.001) and VD (Pnonlinearity = 0.007), and the nonlinear association reached borderline significance for AD (Pnonlinearity = 0.06), with a threshold at around a serum 25(OH)D value of 50 nmol/L for all the outcomes. Higher serum levels of 25(OH)D were significantly associated with a lower risk of all-cause dementia, AD, and VD. The multivariate hazard ratios and 95% confidence intervals for participants who had serum 25(OH)D ≥ 50 nmol/L, compared with those who were severely deficient (25[OH]D < 25 nmol/L), were 0.41 (0.29–0.60) for all-cause dementia (Ptrend < 0.001), 0.50 (0.27–0.92) for AD (Ptrend = 0.06), and 0.41 (0.22–0.77) for VD (Ptrend = 0.01). The main limitation of the current analysis was the potential underreporting of dementia cases, as the cases were identified via EHRs.ConclusionsIn this study, we observed that higher concentrations of serum 25(OH)D were significantly associated with a lower risk of all-cause dementia, AD, and VD among individuals with T2D. Our findings, if confirmed by replication, may have relevance for dementia prevention strategies that target improving or maintaining serum vitamin D concentrations among patients with T2D.

BackgroundAdipokines secreted from adipose tissue may contribute to dementia pathogenesis.Objective: Our study investigated the associations between plasma levels of leptin, resistin, TNF-α, and IL-6 and the risk of all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VaD).MethodsPlasma protein levels were measured using the Olink Proximity Extension Assay, and dementia was ascertained from hospital admissions and death registries in the UK Biobank. Multivariable Cox proportional hazards models with stepwise covariate adjustments were used to assess associations. Subgroup analyses were conducted to examine whether the associations differed by sociodemographic characteristics, lifestyle factors, and major diseases.ResultsAmong 32,002 participants, 793 developed all-cause dementia, including 260 with AD and 96 with VaD. Plasma levels of resistin and IL-6 were positively associated with risks of all-cause dementia, with hazard ratios (95% confidence intervals) of 1.10 (1.03, 1.18) and 1.10 (1.04, 1.17), respectively. Leptin (0.98; 0.86, 1.12) and TNF-α levels (1.06; 0.98, 1.13) were not significantly associated with all-cause dementia. Resistin (1.28; 1.08, 1.53) and TNF-α levels (1.21; 1.04, 1.40) were associated with VaD risk. There was a lack of evidence for the associations between four adipokines and AD. Subgroup analyses showed stronger associations between resistin and all-cause dementia in those with high body mass index, diabetes, or stroke.ConclusionsPlasma levels of resistin and IL-6 were positively associated with risks of all-cause dementia, with resistin and TNF-α strongly linked to VaD. These findings support a potential role of adipokines in dementia pathogenesis, particularly for VaD.

BackgroundPrevious studies showed inconsistent results on the association of smoking with all-cause dementia and vascular dementia (VaD), and are limited by inclusion of a small number of studies and unexplained heterogeneity. Our review aimed to assess the risk of all-cause dementia, Alzheimer’s disease (AD) and VaD associated with smoking, and to identify potential effect modifiers.Methods and FindingsThe PubMed, Embase, Cochrane Library and Psychinfo databases were searched to identify studies that provided risk estimates on smoking and incidence of dementia. A random-effects model was used to yield pooled results. Thirty-seven studies were included. Compared with never smokers, current smokers showed an increased risk of all-cause dementia (risk ratio (RR) 1.30, 95% confidence interval (CI) 1.18–1.45), AD (RR 1.40, 95% CI 1.13–1.73) and VaD (RR 1.38, 95% CI 1.15–1.66). For all-cause dementia, the risk increased by 34% for every 20 cigarettes per day (RR 1.34, 95% CI 1.25–1.43). Former smokers did not show an increased risk of all-cause dementia (RR 1.01, 95% CI 0.96–1.06), AD (RR 1.04, 95% CI 0.96–1.13) and VaD (RR 0.97, 95% CI 0.83–1.13). Subgroup analyses indicated that (1) the significantly increased risk of AD from current smoking was seen only in apolipoprotein E ε4 noncarriers; (2) current smokers aged 65 to 75 years at baseline showed increased risk of all-cause dementia and AD compared to those aged over 75 or under 65 years; and (3) sex, race, study location and diagnostic criteria difference in risk of dementia was not found.ConclusionsSmokers show an increased risk of dementia, and smoking cessation decreases the risk to that of never smokers. The increased risk of AD from smoking is more pronounced in apolipoprotein E ε4 noncarriers. Survival bias and competing risk reduce the risk of dementia from smoking at extreme age.

osteoporosis significantly increases the risk of all-cause dementia, Alzheimer's disease dementia, and vascular dementia in Korean older women. Significance of the paper: early detection and treatment of osteoporosis may reduce dementia risk. Dementia and osteoporosis share common risk factors and are increasing in prevalence in the aging population. This study aimed to investigate the impact of osteoporosis on dementia and its subtypes in women using data from a population-based, health-screening cohort, with a follow-up period of more than 10years. This retrospective study included 66-year-old Korean women who participated in the "National Screening Program for Transitional Ages" from 2010 to 2011. Participants were categorized based on spine bone mineral density T-scores into three groups: normal (T-score ≥ - 1.0 standard deviation [SD]; 18.7%), osteopenia (- 2.5 SD < T-score < - 1.0 SD; 42.5%), and osteoporosis (T-score ≤ - 2.5 SD; 38.8%). Incident dementia cases were evaluated until 2021 using national healthcare claims databases. Fine-Gray subdistribution hazard models were used to assess the risks of all-cause dementia including Alzheimer's disease (AD) dementia and vascular dementia (VaD), accounting for death as a competing risk. The study included 131,872 dementia-free women aged 66years. Over an average follow-up of 10.4 ± 1.8years, 9399 individuals developed all-cause dementia (7.1%). Osteoporosis was associated with increased risks for all-cause dementia (adjusted subdistribution hazard ratio [asHR] 1.14; 95% confidence interval [CI] 1.08-1.21; p < 0.001), AD dementia (asHR 1.14; 95% CI 1.08-1.22; p < 0.001), and VaD (asHR 1.42; 95% CI 1.08-1.87; p = 0.013), compared to normal. Our findings highlight an association between osteoporosis and increased risks of developing all-cause dementia, AD dementia, and VaD. Further research is needed to explore the effects of early identification and treatment of osteoporosis in preventing dementia.

Being physically active is protective against dementia. Yet, it is unknown when during the adult life course physical activity is most associated with dementia risk. To determine whether higher physical activity levels in early adult life, midlife, or late life are associated with lower risk of all-cause or Alzheimer disease (AD) dementia. This prospective cohort study used data from the Framingham Heart Study Offspring cohort. The offspring of participants in the original Framingham Heart Study cohort who were dementia free and had physical activity measured at baseline (early adult life [1979-1983], midlife [1987-1991], or late life [1998-2001]) were followed up for a mean (SD) of 37.2 (7.1), 25.9 (8.5), or 14.5 (6.6) years for the development of incident all-cause or AD dementia until December 31, 2023. Physical activity was self-reported using the physical activity index, a composite score weighted by hours spent sleeping and in sedentary, slight, moderate, or heavy activities. Physical activity was divided into quintiles (Q). All-cause and AD dementia were classified by expert consensus based on established diagnostic criteria. This study included 1526 early adult-life (mean [SD] age, 36.7 [4.7] years; 821 [53.8%] female), 1943 midlife (mean [SD] age, 54.0 [5.8] years; 1010 [52.0%] female), and 885 late-life (mean [SD] age, 71.0 [4.5] years; 473 [53.4%] female) participants. There were 567 cases of incident all-cause dementia during follow-up. Higher levels of midlife and late-life physical activity were associated with lower risk of all-cause dementia. Midlife and late-life physical activity levels in Q4 or Q5 were associated with lower risk of all-cause dementia compared with Q1 (midlife Q4: HR, 0.60; 95% CI, 0.41-0.89; midlife Q5: HR, 0.59; 95% CI, 0.40-0.88; late-life Q4: HR, 0.64; 95% CI, 0.42-1.00; late-life Q5: HR, 0.55; 95% CI, 0.35-0.87). There were no associations between early adult-life physical activity and dementia risk. Findings were similar for incident AD (369 cases). In this cohort study of adults in the Framingham Heart Study Offspring cohort, higher levels of midlife and late-life physical activity were associated with similar reductions in risk of all-cause and AD dementia. These findings may inform future efforts to delay or prevent dementia through timing interventions during the most relevant stages of the adult life course.

Cardiovascular diseases (CVDs) have been linked to increased risk of dementia in observational studies, whereas genetic studies have yielded inconsistent findings. We aimed to determine whether nine CVDs are causally associated with the risk of all-cause dementia, Alzheimer's disease, and vascular dementia. We performed time-dependent Cox regression analyses in three prospective cohorts, the Copenhagen City Heart Study (N=10,373), the Copenhagen General Population Study (N=101,582), and the UK Biobank (N=377,706), and meta-analyzed individual estimates. Furthermore, we assessed genetic susceptibility for CVDs and the risk of dementia using individual-level data from the UK Biobank and summary statistics from the FinnGen study. Observationally, CVDs were associated with risk of all incident outcomes in meta-analyses, with hazard ratios up to 7.00 (95% confidence interval [CI]: 6.20, 7.92). Genetically, in the UK Biobank, susceptibility for ischemic stroke was associated with risk of all-cause dementia, Alzheimer's disease, and vascular dementia, and odds ratios (ORs) were 1.64 (1.35, 1.98), 1.44 (1.10, 1.89), and 2.06 (1.41, 3.01), respectively, with similar estimates for ischemic stroke; genetic susceptibility for ischemic heart disease was associated with risk of vascular dementia (OR: 1.24 [1.03, 1.50]). Genetic summary statistics from the FinnGen study confirmed the associations between ischemic stroke and stroke. Associations between stroke and all-cause dementia and its major subtypes are likely to be causal. Moreover, genetic susceptibility for ischemic heart disease is associated with incident vascular dementia. These findings underscore the importance of integrating CVD prevention into interventions to enable early prevention and reduce the risk of dementia.

Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) reduce cardiovascular risk through mechanisms that might affect the development of dementia. To evaluate whether statin use is associated with a lower risk of dementia compared with never use of lipid-lowering agents (LLAs). Cohort study of community-dwelling adults 65 years and older. The analysis included 2798 participants free of dementia at baseline. Using Cox proportional hazards regression analysis, we estimated the risk of incident all-cause and type-specific dementia associated with time-dependent statin therapy compared with never use of LLAs. The primary analyses incorporated a 1-year lag between exposure and outcome. Secondary analyses included the final year of exposure and modeled statin use as current use vs nonuse to simulate a case-control approach. Compared with never use of LLAs, ever use of statins was not associated with the risk of all-cause dementia (multivariable-adjusted hazard ratio [HR], 1.08; 95% confidence interval [CI], 0.77-1.52), Alzheimer disease alone (HR, 1.21; 95% CI, 0.76-1.91), mixed Alzheimer disease and vascular dementia (HR, 0.87; 95% CI, 0.44-1.72), or vascular dementia alone (HR, 1.36; 95% CI, 0.61-3.06). In contrast, in secondary analyses, current use of statins compared with nonuse of LLAs was associated with HRs of 0.69 (95% CI, 0.46-1.02) for all-cause dementia and 0.56 (95% CI, 0.35-0.92) for any Alzheimer disease. In this cohort study, statin therapy was not associated with a decreased risk of dementia. Methodological differences may explain why results of this cohort investigation differ from those of prior case-control studies. Additional investigation is needed to determine whether and for whom statin use may affect dementia risk.

Assessing Late Life Major Depression: Does Brain Disease Affect Measurement of Severity and Treatment Response?