BACKGROUND
Alzheimer's disease (AD) prevalence increases with age, yet a small fraction of the population reaches ages > 100 years without cognitive decline. We studied the genetic factors associated ...with such resilience against AD.
METHODS
Genome‐wide association studies identified 86 single nucleotide polymorphisms (SNPs) associated with AD risk. We estimated SNP frequency in 2281 AD cases, 3165 age‐matched controls, and 346 cognitively healthy centenarians. We calculated a polygenic risk score (PRS) for each individual and investigated the functional properties of SNPs enriched/depleted in centenarians.
RESULTS
Cognitively healthy centenarians were enriched with the protective alleles of the SNPs associated with AD risk. The protective effect concentrated on the alleles in/near ANKH, GRN, TMEM106B, SORT1, PLCG2, RIN3, and APOE genes. This translated to >5‐fold lower PRS in centenarians compared to AD cases (P = 7.69 × 10−71), and 2‐fold lower compared to age‐matched controls (P = 5.83 × 10−17).
DISCUSSION
Maintaining cognitive health until extreme ages requires complex genetic protection against AD, which concentrates on the genes associated with the endolysosomal and immune systems.
Highlights
Cognitively healthy cent enarians are enriched with the protective alleles of genetic variants associated with Alzheimer's disease (AD).
The protective effect is concentrated on variants involved in the immune and endolysosomal systems.
Combining variants into a polygenic risk score (PRS) translated to > 5‐fold lower PRS in centenarians compared to AD cases, and ≈ 2‐fold lower compared to middle‐aged healthy controls.
Background: Low serum 25-hydroxyvitamin D 25(OH)D concentrations have been associated with insulin resistance, the metabolic syndrome, and type 2 diabetes. Because many non-Western immigrants in the ...Netherlands are vitamin D deficient, obese, and at high risk of diabetes, vitamin D supplementation may contribute to prevent diabetes and insulin resistance.Objective: We examined the effect of vitamin D supplementation on insulin sensitivity and β cell function in overweight, vitamin D–deficient, non-Western immigrants at high risk of diabetes.Design: The study was a 16-wk, randomized, placebo-controlled trial. A total of 130 non-Western immigrants with prediabetes (fasting glucose concentration >5.5 mmol/L or random glucose concentration from 7.8 to 11.1 mmol/L) and vitamin D deficiency (serum 25OHD concentration <50 nmol/L) were randomly assigned after stratification by sex to receive either cholecalciferol (1200 IU/d) or a placebo for 16 wk. All participants received 500 mg Ca/d as calcium carbonate. The primary outcome was the difference in the area under the curve of insulin and glucose after a 75-g oral-glucose-tolerance test after 4 mo of treatment. Secondary outcomes were insulin-sensitivity variables, β cell–function variables, and metabolic syndrome.Results: Mean serum 25(OH)D concentrations increased significantly in the vitamin D compared with placebo groups. After 4 mo of therapy, the mean between-group difference was 38 nmol/L (95% CI: 32.1, 43.9 nmol/L; P < 0.001). There was no significant effect on insulin sensitivity and β cell function. In a post hoc analysis, when patients with diabetes at baseline were excluded, a significant increase in the insulinogenic index was observed in participants who obtained a 25(OH)D concentration ≥60 nmol/L (P = 0.040).Conclusions: Vitamin D supplementation in non-Western vitamin D–deficient immigrants with prediabetes did not improve insulin sensitivity or β cell function or change the incidence of metabolic syndrome. However, after the exclusion of diabetic subjects, an improvement in the insulinogenic index was observed in participants who obtained a 25(OH)D concentration ≥60 nmol/L. This trial was registered at trialregister.nl as NTR1827.
Depressive symptoms and impaired physical functioning are prevalent among older adults. Supplementation with vitamin D might improve both conditions, particularly in persons with low vitamin D ...status.
The D-Vitaal study primarily aimed to investigate the effect of vitamin D supplementation on depressive symptoms, functional limitations, and physical performance in a high-risk older population with low vitamin D status. Secondary aims included examining the effect of vitamin D supplementation on anxiety symptoms, cognitive functioning, mobility, handgrip strength, and health-related quality of life.
This study was a randomized placebo-controlled trial with 155 participants aged 60–80 y who had clinically relevant depressive symptoms, ≥1 functional limitations, and serum 25-hydroxyvitamin D 25(OH)D concentrations of 15–50/70 nmol/L (depending on season). Participants received 1200 IU/d vitamin D3 (n = 77) or placebo tablets (n = 78) for 12 mo. Serum 25(OH)D was measured at baseline and 6 mo; outcomes were assessed at baseline, 6 mo, and 12 mo. Linear mixed-models analyses were conducted to assess the effect of the intervention.
The supplementation increased serum 25(OH)D concentrations in the intervention group to a mean ± SD of 85 ± 16 nmol/L compared with 43 ± 18 nmol/L in the placebo group after 6 mo (P < 0.001). No relevant differences between the treatment groups were observed regarding depressive symptoms, functional limitations, physical performance, or any of the secondary outcomes.
Supplementation with 1200 IU/d vitamin D for 12 mo had no effect on depressive symptoms and physical functioning in older persons with relatively low vitamin D status, clinically relevant depressive symptoms, and poor physical functioning. This trial is registered with the Netherlands Trial Register (www.trialregister.nl) under NTR3845.
The Longitudinal Aging Study Amsterdam (LASA) is an ongoing longitudinal study of older adults in the Netherlands, which started in 1992. LASA is focused on the determinants, trajectories and ...consequences of physical, cognitive, emotional and social functioning. The study is based on a nationally representative sample of older adults aged 55 years and over. The findings of the LASA study have been reported in over 450 publications so far (see www.lasa-vu.nl). In this article we describe the background and the design of the LASA study, and provide an update of the methods. In addition, we provide a summary of the major findings from the period 2011-2015.
Abstract Background Prediction models can identify fall-prone individuals. Prediction models can be based on either data from research cohorts (cohort-based) or routinely collected data (RCD-based). ...We review and compare cohort-based and RCD-based studies describing the development and/or validation of fall prediction models for community-dwelling older adults. Methods Medline and Embase were searched via Ovid until January 2023. We included studies describing the development or validation of multivariable prediction models of falls in older adults (60+). Both risk of bias and reporting quality were assessed using the PROBAST and TRIPOD, respectively. Results We included and reviewed 28 relevant studies, describing 30 prediction models (23 cohort-based and 7 RCD-based), and external validation of two existing models (one cohort-based and one RCD-based). The median sample sizes for cohort-based and RCD-based studies were 1365 interquartile range (IQR) 426–2766 versus 90 441 (IQR 56 442–128 157), and the ranges of fall rates were 5.4% to 60.4% versus 1.6% to 13.1%, respectively. Discrimination performance was comparable between cohort-based and RCD-based models, with the respective area under the receiver operating characteristic curves ranging from 0.65 to 0.88 versus 0.71 to 0.81. The median number of predictors in cohort-based final models was 6 (IQR 5–11); for RCD-based models, it was 16 (IQR 11–26). All but one cohort-based model had high bias risks, primarily due to deficiencies in statistical analysis and outcome determination. Conclusions Cohort-based models to predict falls in older adults in the community are plentiful. RCD-based models are yet in their infancy but provide comparable predictive performance with no additional data collection efforts. Future studies should focus on methodological and reporting quality.
Abstract
Background
Physical activity may be both a risk and protective factor for falls and fall-related fractures. Despite its positive effects on muscle and bone health, physical activity also ...increases exposure to situations where falls and fractures occur. This paradox could possibly be explained by frailty status. Therefore, the aim of this study was to investigate the associations between physical activity and both falls and fractures, and to determine whether frailty modifies the association of physical activity with falls, and fractures.
Methods
Data of 311 community-dwelling participants aged 75 years or older from the Longitudinal Aging Study Amsterdam, who participated in a three-year longitudinal study with five nine-monthly measurements between 2015/2016 and 2018/2019. Their mean age was 81.1 (SD 4.8) years and frailty was present in 30.9% of the participants. Physical activity in minutes per day was objectively assessed with an inertial sensor (Actigraph) for seven consecutive days. Falls and fractures were assessed every nine months using self-report during an interview over a follow-up period of three years. Frailty was determined at baseline using the frailty index. Associations were estimated using longitudinal logistic regression analyses based on generalized estimating equations.
Results
No association between physical activity and falls was found (OR = 1.00, 95% CI: 0.99–1.00). Fall risk was higher in frail compared to non-frail adults (OR = 2.21, 95% CI: 1.33–3.68), but no effect modification was seen of frailty on the association between physical activity and falls. Also no relation between physical activity and fractures was found (OR = 1.00, 95% CI: 0.99–1.01). Fracture risk was higher in frail compared to non-frail adults (OR = 2.81, 95% CI: 1.02–7.75), but also no effect modification of frailty was present in the association between physical activity and fractures.
Conclusions
No association between physical activity and neither falls nor fractures was found, and frailty appeared not to be an effect modifier. However, frailty was a risk factor for falls and fractures in this population of older adults. Our findings suggest that physical activity can be safely recommended in non-frail and frail populations for general health benefits, without increasing the risk of falls.
BACKGROUND: Overweight and obesity impose a considerable individual and social burden, and the urban environments might encompass factors that contribute to obesity. Nevertheless, there is a scarcity ...of research that takes into account the simultaneous interaction of multiple environmental factors. OBJECTIVES: Our objective was to perform an exposome-wide association study of body mass index (BMI) in a multicohort setting of 15 studies. METHODS: Studies were affiliated with the Dutch Geoscience and Health Cohort Consortium (GECCO), had different population sizes (688-141,825), and covered the entire Netherlands. Ten studies contained general population samples, others focused on specific populations including people with diabetes or impaired hearing. BMI was calculated from self-reported or measured height and weight. Associations with 69 residential neighborhood environmental factors (air pollution, noise, temperature, neighborhood socioeconomic and demographic factors, food environment, drivability, and walkability) were explored. Random forest (RF) regression addressed potential nonlinear and nonadditive associations. In the absence of formal methods for multimodel inference for RF, a rank aggregation-based meta-analytic strategy was used to summarize the results across the studies. RESULTS: Six exposures were associated with BMI: five indicating neighborhood economic or social environments (average home values, percentage of high-income residents, average income, livability score, share of single residents) and one indicating the physical activity environment (walkability in 5-km buffer area). Living in high-income neighborhoods and neighborhoods with higher livability scores was associated with lower BMI. Nonlinear associations were observed with neighborhood home values in all studies. Lower neighborhood home values were associated with higher BMI scores but only for values up to euro300,000. The directions of associations were less consistent for walkability and share of single residents. DISCUSSION: Rank aggregation made it possible to flexibly combine the results from various studies, although between-study heterogeneity could not be estimated quantitatively based on RF models. Neighborhood social, economic, and physical environments had the strongest associations with BMI.
•Ghrelin is associated with depressive symptoms after three years of follow-up.•We find effect modification by age and waist-hip-ratio in this association.•In men, leptin is associated with ...depressive symptoms after three years of follow-up.•Both hormones are influenced by lifestyle changes and may therefore provide a novel therapeutic target for treatment.
Ghrelin, leptin and high-molecular-weight (HMW) adiponectin have been linked to depression in middle-aged adults. Pathophysiological mechanisms of depression change as age progresses and it is unclear whether the same associations exist in older adults.
We analyzed the associations between ghrelin, leptin and HMW adiponectin and depressive symptoms (Center for Epidemiologic Studies Depression (CES-D) score ≥ 16) in a community-dwelling cohort of 898 participants in a multivariable logistic regression analysis at baseline and after three years of follow-up, were applicable stratified by sex, age and waist-hip-ratio (WHR).
At baseline no significant associations were found.
After three years of follow-up ghrelin was associated with higher odds for depressive symptoms (fully adjusted continuous analysis OR 2.27, 95% CI 1.42 – 3.61). There was effect modification for age and WHR, with significant associations in participants younger than 69.7 years (median) and with a WHR below 0.9554 (mean). In the sex-stratified analysis for leptin we found significant associations in men (fully adjusted continuous analysis OR 1.07, 95% CI 1.02 – 1.12). For HMW adiponectin there were no significant associations in the multivariable analysis.
As our cohort consisted of relatively healthy participants with intact cognitive function, selection bias may have contributed to lack of significant baseline associations.
Our results show significant associations between ghrelin and – for men only - leptin and depressive symptoms after three years of follow up. This may provide a new therapeutic window for treatment of depressive symptoms in older adults, as both ghrelin and leptin are positively influenced by weight loss.
Background: Falls frequently occur in the elderly and are a major cause of morbidity and mortality.
Objective: The objective of the study was to prospectively investigate the association between ...serum 25-hydroxyvitamin D 25(OH)D levels and risk of recurrent falling in older men and women.
Design: This was a prospective cohort study.
Setting: An age- and sex-stratified random sample of the Dutch older population was determined.
Subjects: Subjects included 1231 men and women (aged 65 yr and older) participating in the Longitudinal Aging Study Amsterdam.
Measurements: Baseline serum 25(OH)D was determined by a competitive protein binding assay. During 1 yr, falls were prospectively recorded by means of a fall calendar.
Results: Low 25(OH)D (<10 ng/ml) was associated with an increased risk of falling. After adjustment for age, sex, education level, region, season, physical activity, smoking, and alcohol intake, the odds ratios (95% confidence interval) were 1.78 (1.06–2.99) for subjects who experienced two falls or more as compared with those who did not fall or fell once and 2.23 (1.17–4.25) for subjects who fell three or more times as compared with those who fell two times or less. There was a statistically significant effect modification by age, and stratified analyses (<75 and ≥ 75 yr) showed that the associations were particularly strong in the younger age group; the odds ratios (95% confidence interval) were 5.21 (2.03–13.40) for two falls or more and 4.96 (1.52–16.23) for three falls or more.
Conclusions: Poor vitamin D status is independently associated with an increased risk of falling in the elderly, particularly in those aged 65–75 yr.
Background: Vitamin D status is currently diagnosed by measuring serum 25-hydroxyvitamin D 25(OH)D.Objective: This study aimed to develop a risk profile that can be used to easily identify older ...individuals at high risk of vitamin D deficiency.Design: This study was performed within the Longitudinal Aging Study Amsterdam, an ongoing cohort study in a representative sample of the Dutch older population (n = 1509 for the development sample and n = 1100 for the validation sample). Prediction models for serum 25(OH)D concentrations <50 and <30 nmol/L were developed by using backward logistic regression. Risk scores were calculated by dividing the individual regression coefficients by the regression coefficient with the lowest β to create simple scores.Results: Serum 25(OH)D concentrations <50 and <30 nmol/L were present in 46.2% and 17.5% of participants, respectively. The model for the prediction of concentrations <50 nmol/L consisted of 13 easily assessable predictors, whereas the model for concentrations <30 nmol/L contained 10 predictors. The resulting areas under the curve (AUCs) were 0.78 and 0.80, respectively. The AUC in the external validation data set was 0.71 for the <50-nmol/L model. At a cutoff of 58 in total risk score (range: 8–97), the model predicted concentrations <50 nmol/L with a sensitivity of 61% and a specificity of 82%, whereas these values were 61% and 84%, respectively, at a cutoff of 110 in the total risk score (range: 6–204) in the model for concentrations <30 nmol/L.Conclusions: Two total risk scores, including 13 or 10 predictors that can easily be assessed, were developed and are able to predict serum 25(OH)D concentrations <50 and <30 nmol/L accurately. These risk scores may be useful in clinical practice to identify persons at risk of vitamin D deficiency.
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