Seasonality of cognitive function in the general population:the Rotterdam Study

Seasonal variation in cognitive function and underlying cerebral hemodynamics in humans has been suggested, but not consistently shown in previous studies. We assessed cognitive function in 10,276 participants from the population-based Rotterdam Study, aged 45 years and older without dementia, at baseline and at subsequent visits between 1999 and 2016. Seasonality of five cognitive test scores and of a summary measure of global cognition were determined, as well as of brain perfusion. Using linkage with medical records, we also examined whether a seasonal variation was present in clinical diagnoses of dementia. We found a seasonal variation of global cognition (0.05 standard deviations [95% confidence interval: 0.02–0.08]), the Stroop reading task, the Purdue Pegboard test, and of the delayed world learning test, with the best performance in summer months. In line with these findings, there were fewer dementia diagnoses of dementia in spring and summer than in winter and fall. We found no seasonal variation in brain perfusion. These findings support seasonality of cognition, albeit not explained by brain perfusion. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11357-021-00485-0

Lung function impairment and the risk of incident dementia : the Rotterdam study

Background: The etiology of dementia may partly be underpinned by impaired lung function via systemic inflammation and hypoxia. Objective: To prospectively examine the association between chronic obstructive pulmonary disease (COPD) and subclinical impairments in lung function and the risk of dementia. Methods: In the Rotterdam Study, we assessed the risk of incident dementia in participants with Preserved Ratio Impaired Spirometry (PRISm; FEV1/FVC≥0.7, FEV1 <  80%) and in participants with COPD (FEV1/FVC <  0.7) compared to those with normal spirometry (controls; FEV1/FVC≥0.7, FEV1≥80%). Hazard ratios (HRs) with 95%confidence intervals (CI) for dementia were adjusted for age, sex, education attainment, smoking status, systolic blood pressure, body mass index, triglycerides, comorbidities and Apolipoprotein E (APOE) genotype. Results: Of 4,765 participants, 110 (2.3%) developed dementia after 3.3 years. Compared to controls, participants with PRISm, but not COPD, had an increased risk for all-type dementia (adjusted HRPRISm 2.70; 95%CI, 1.53-4.75; adjusted HRCOPD 1.03; 95%CI, 0.61-1.74). These findings were primarily driven by men and smokers. Similarly, participants with FVC%predicted values in the lowest quartile compared to those in the highest quartile were at increased risk of all-type dementia (adjusted HR 2.28; 95%CI, 1.31-3.98), as well as Alzheimer's disease (AD; adjusted HR 2.13; 95%CI, 1.13-4.02). Conclusion: Participants with PRISm or a low FVC%predicted lung function were at increased risk of dementia, compared to those with normal spirometry or a higher FVC%predicted, respectively. Further research is needed to elucidate whether this association is causal and how PRISm might contribute to dementia pathogenesis

Cognitive Impairment, Sexual Activity and Physical Tenderness in Community-Dwelling Older Adults: A Cross-Sectional Exploration

Background: The ability to engage in sexual activity and better cognitive functioning are both associated with better health. However, the association between cognitive functioning and sexual activity is understudied. Objective: To examine the association between cognitive functioning with sexual activity and physical tenderness among community-dwelling older adults. Methods: From the Rotterdam Study, cognitive imp

Quantitative gait, cognitive decline, and incident dementia: The Rotterdam Study

Introduction: Poor gait has recently emerged as a potential prodromal feature of cognitive decline and dementia. We assessed to what extent various aspects of poor gait are independently associated with cognitive decline and incident dementia. Methods: We leveraged detailed quantitative gait (GAITRite™) and cognitive assessments in 4258 dementia-free participants (median age 67 years, 55% women) of the population-based Rotterdam Study (baseline 2009–2013). We summarized 30 gait parameters into seven mutually independent gait domains and a Global Gait score. Participants underwent follow-up cognitive assessments between 2014 and 2016 and were followed up for incident dementia until 2016 (median 4 years). Results: Three independent gait domains (Base of Support, Pace, and Rhythm) and Global Gait were associated with cognitive decline. Two independent gait domains (Pace and Variability) and Global Gait were associated with incident dementia. Associations of gait with cognitive decline and incident dementia were only present in individuals who had been cognitively unimpaired at baseline. Discussion: Poor performance on several independent gait domains precedes cognitive decline and incident dementia

Hearing loss and cognitive decline in the general population: a prospective cohort study

Background: Previous studies identifying hearing loss as a promising modifiable risk factor for cognitive decline mostly adjusted for baseline age solely. As such a faster cognitive decline at a higher age, which is expected considering the non-linear relationship between cognition and age, may have been overlooked. Therefore it remains uncertain whether effects of hearing loss on cognitive decline extend beyond age-related declines of cognitive function. Methods: 3,590 non-demented participants were eligible for analysis at baseline, and a maximum of 837 participants were eligible for the longitudinal analysis. Hearing loss was defined at baseline. Cognitive function was measured at baseline and at follow-up (4.4 years [SD: 0.2]). Multivariable linear regression analysis was used for the cross-sectional analysis. Linear mixed models were used to assess the longitudinal association between hearing loss and cognitive decline over time while adjusting for confounders and the interaction of age and follow-up time. Results: Hearing loss was associated with lower cognitive function at baseline. Moreover, hearing loss was associated with accelerated cognitive decline over time on a memory test. After additionally adjusting for the interaction between age and follow-up time, we found that hearing loss did not accelerate cognitive decline anymore. Conclusions: Hearing loss was associated with lowe

Telomere Length and the Risk of Alzheimer's Disease: The Rotterdam Study

There is a wide interest in biomarkers that capture the burden of detrimental factors as these accumulate with the passage of time, i.e., increasing age. Telomere length has received considerable attention as such a marker, because it is easily quantified and it may aid in disentangling the etiology of dementia or serve as predictive marker. We determined the association of telomere length with risk of Alzheimer's disease and all-cause dementia in a population-based setting. Within the Rotterdam Study, we performed quantitative PCR to measure mean leukocyte telomere length in blood. We determined the association of telomere length with risk of Alzheimer's disease until 2016, using Cox regression models. Of 1,961 participants (mean age 71.4±9.3 years, 57.1% women) with a median follow-up of 8.3 years, 237 individuals were diagnosed with Alzheimer's disease. We found a U-shaped associa

Development and Validation of a Dementia Risk Prediction Model in the General Population: An Analysis of Three Longitudinal Studies

© 2019 American Psychiatric Association. All rights reserved. Objective: Identification of individuals at high risk of dementia is essential for development of prevention strategies, but reliable tools are lacking for risk stratification in the population. The authors developed and validated a prediction model to calculate the 10-year absolute risk of developing dementia in an aging population. Methods: In a large, prospective population-based cohort, data were collected on demographic, clinical, neuropsychological, genetic, and neuroimaging parameters from 2,710 nondemented individuals age 60 or older, examined between 1995 and 2011. A basic and an extended model were derived to predict 10-year risk of dementia while taking into account competing risks from death due to other causes. Model performance was assessed using optimism-corrected C-statistics and calibration plots, and the models were externally validated in the Dutch population-based Epidemiological Prevention Study of Zoetermeer and in the Alzheimer’s Disease Neuroimaging Initiative cohort 1 (ADNI-1). Results: During a follow-up of 20,324 person-years, 181 participants developed dementia. A basic dementia risk model using age, history of stroke, subjective memory decline, and need for assistance with finances or medication yielded a C-statistic of 0.78 (95% CI=0.75, 0.81). Subsequently, an extended model incorporating the basic model and additional cognitive, genetic, and imaging predictors yielded a C-statistic of 0.86 (95% CI=0.83, 0.88). The models performed well in external validation cohorts from Europe and the United States. Conclusions: In community-dwelling individuals, 10-year dementia risk can be accurately predicted by combining information on readily available predictors in the primary care setting. Dementia prediction can be further improved by using data on cognitive performance, genotyping, and brain imaging. These models can be used to identify individuals at high risk of dementia in the population and are able to inform trial design

Prediction of dementia risk in low-income and middle-income countries (the 10/66 Study): an independent external validation of existing models

BackgroundTo date, dementia prediction models have been exclusively developed and tested in high-income countries (HICs). However, most people with dementia live in low-income and middle-income countries (LMICs), where dementia risk prediction research is almost non-existent and the ability of current models to predict dementia is unknown. This study investigated whether dementia prediction models developed in HICs are applicable to LMICs.MethodsData were from the 10/66 Study. Individuals aged 65 years or older and without dementia at baseline were selected from China, Cuba, the Dominican Republic, Mexico, Peru, Puerto Rico, and Venezuela. Dementia incidence was assessed over 3–5 years, with diagnosis according to the 10/66 Study diagnostic algorithm. Discrimination and calibration were tested for five models: the Cardiovascular Risk Factors, Aging and Dementia risk score (CAIDE); the Study on Aging, Cognition and Dementia (AgeCoDe) model; the Australian National University Alzheimer's Disease Risk Index (ANU-ADRI); the Brief Dementia Screening Indicator (BDSI); and the Rotterdam Study Basic Dementia Risk Model (BDRM). Models were tested with use of Cox regression. The discriminative accuracy of each model was assessed using Harrell's concordance (c)-statistic, with a value of 0·70 or higher considered to indicate acceptable discriminative ability. Calibration (model fit) was assessed statistically using the Grønnesby and Borgan test.Findings11 143 individuals without baseline dementia and with available follow-up data were included in the analysis. During follow-up (mean 3·8 years [SD 1·3]), 1069 people progressed to dementia across all sites (incidence rate 24·9 cases per 1000 person-years). Performance of the models varied. Across countries, the discriminative ability of the CAIDE (0·52≤c≤0·63) and AgeCoDe (0·57≤c≤0·74) models was poor. By contrast, the ANU-ADRI (0·66≤c≤0·78), BDSI (0·62≤c≤0·78), and BDRM (0·66≤c≤0·78) models showed similar levels of discriminative ability to those of the development cohorts. All models showed good calibration, especially at low and intermediate levels of predicted risk. The models validated best in Peru and poorest in the Dominican Republic and China.InterpretationNot all dementia prediction models developed in HICs can be simply extrapolated to LMICs. Further work defining what number and which combination of risk variables works best for predicting risk of dementia in LMICs is needed. However, models that transport well could be used immediately for dementia prevention research and targeted risk reduction in LMICs

External validation of four dementia prediction models for use in the general community-dwelling population: a comparative analysis from the Rotterdam Study

To systematically review the literature for dementia prediction models for use in the general population and externally validate their performance in a head-to-head comparison. We selected four prediction models for validation: CAIDE, BDSI, ANU-ADRI and DRS. From the Rotterdam Study, 6667 non-demented individuals aged 55 years and older were assessed between 1997 and 2001. Subsequently, participants were followed for dementia until 1 January, 2015. For each individual, we computed the risk of dementia using the reported scores from each prediction model. We used the C-statistic and calibration plots to assess the performance of each model to predict 10-year risk of all-cause dementia. For comparisons, we also evaluated discriminative accuracy using only the age component of these risk scores for each model separately. During 75,581 person-years of follow-up, 867 participants developed dementia. C-statistics for 10-year dementia risk prediction were 0.55 (95% CI 0.53–0.58) for CAIDE, 0.78 (0.76–0.81) for BDSI, 0.75 (0.74–0.77) for ANU-ADRI, and 0.81 (0.78–0.83) for DRS. Calibration plots showed that predicted risks were too extreme with underestimation at low risk and overestimation at high risk. Importantly, in all models age alone already showed nearly identical discriminative accuracy as the full model (C-statistics: 0.55 (0.53–0.58) for CAIDE, 0.81 (0.78–0.83) for BDSI, 0.77 (0.75–0.79) for ANU-ADRI, and 0.81 (0.78–0.83) for DRS). In this study, we found high variability in discriminative ability for predicting dementia in an elderly, community-dwelling population. All models showed similar discriminative ability when compared to prediction based on age alone. These findings highlight the urgent need for updated or new models to predict dementia risk in the general population

Assessment of Advanced Glycation End Products and Receptors and the Risk of Dementia

Importance: Advanced glycation end products (AGEs) and their receptor (RAGE) are implicated in the pathophysiological processes of dementia and potentially underlie the association of diabetes with neurodegeneration. However, longitudinal studies examining this association are lacking. Objective: To determine whether markers of the AGE-RAGE system are associated with prevalent and incident dementia and with cognition. Design, Setting, and Participants: In this population-based cohort study including participants from the prospective Rotterdam Study, extracellular newly identified RAGE binding protein (EN-RAGE) and soluble RAGE (S-RAGE) were measured in plasma collected between 1997 and 1999 in a random selection of participants, and additionally in participants with prevalent dementia. Participants without dementia were followed up for dementia until 2016. Skin AGEs, measured as skin autofluorescence, and cognition were measured between 2013 and 2016 in participants without dementia. Data analysis was performed from June 2019 to December 2019. Exposures: EN-RAGE, S-RAGE, and skin autofluorescence. Main Outcomes and Measures: Prevalent and incident dementia and cognition, adjusted for potential confounders, including age, sex, diabetes, educational level, APOE ε4 carrier status, smoking, and estimated glomerular filtration rate. Results: Of 3889 included participants (mean [SD] age, 72.5 [8.9] years; 2187 [56.2%] women), 1021 participants had data on plasma markers (mean [SD] age 73.6 [7.8] years; 564 [55.2%] women), 73 participants had dementia at baseline, and during 10 711 person-years of follow-up, 161 participants developed incident dementia. Compared with low levels, high EN-RAGE level was associated with a higher prevalence of dementia (odds ratio [OR], 3.68 [95% CI, 1.50-8.03]; P = .003), while high S-RAGE level was associated with a lower prevalence of dementia (OR, 0.37 [95% CI, 0.17-0.78]; P = .01). These associations attenuated in a longitudinal setting, with hazard ratios of 0.65 (95% CI, 0.42-1.01) for high EN-RAGE (P = .05) and 1.22 (95% CI, 0.82-1.81) for high S-RAGE (P = .33). Among 2890 participants without dementia (mean [SD] age, 72.5 [9.4] years; 1640 [57%] women), higher skin autofluorescence was associated with lower global cognitive function (adjusted difference in z score per 1-SD higher skin autofluorescence, -0.07 [95% CI, -0.11 to -0.04]), especially among carriers of the APOE ε4 allele (adjusted difference in z score per 1-SD higher skin autofluorescence, -0.15 [95% CI, -0.22 to -0.07]). Conclusions and Relevance: These findings suggest that the AGE-RAGE system is associated with cognitive decline and dementia cross-sectionally but not longitudinally. This indicates either a short-term association or reverse causality. Findings of cross-sectional associations between higher skin autofluorescence and lower cognitive function and an association with APOE status also warrant replication and prospective studies