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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. [ABSTRACT FROM AUTHOR]

Background: Depression has been associated with an increased risk of Alzheimer's disease (AD), but the biological mechanisms are still not fully understood. Plasma biomarkers, such as amyloid‐beta, tau, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL), have been associated with AD pathophysiology. However, the relationship with depression is unclear. Assessing these biomarkers in the blood allows for the opportunity to assess if AD pathology is related to depressive symptoms on a large‐scale. We hypothesized if depression is part of the AD process, then these markers will be associated with depressive symptoms. Method: A two‐stage IPD meta‐analysis was performed based on eight cohorts of individuals without dementia as part of the Netherlands Consortium of Dementia Cohorts (NCDC). We examined the cross‐sectional association between each plasma marker for AD (amyloid‐beta42/40 ratio, p‐tau181, NfL, and GFAP) with depressive symptoms (the GDS‐15, PHQ‐9, CES‐D, and SF‐36). Plasma markers were assessed using Single Molecular Array (Simoa; Quanterix) assays. Both plasma markers and depressive symptoms were standardized. We estimated the effect per plasma marker with depressive symptoms using linear regressions, correcting for age, sex, education, and APOE e4 allele presence, in each cohort. The effect estimates were entered into a random‐effects meta‐analysis. We also performed subgroup analyses assessing sex differences and between those with and without an APOE e4 allele. Result: This study involved 7210 participants with an age range of 38 to 102 years. Based on clinical cut‐offs per questionnaire, high depressive symptomology ranged from one to 22% per cohort. None of the plasma markers were associated with depressive symptoms in the meta‐analysis. However, subgroup analyses found an association with NfL and depressive symptoms in women (beta 0.07; 95% CI: 0.03‐0.10, p < 0.001) and in those with an APOE e4 allele (beta 0.11; 95% CI: 0.05‐0.17, p = 0.001). Conclusion: AD pathology did not show an overall relationship with depressive symptoms. However, in women and in those with a genetic risk for AD, NfL showed an association. As NfL is a marker of overall neurodegeneration, this pathology in plasma may be specific to depressive symptoms in certain subgroups. [ABSTRACT FROM AUTHOR]

Background: Rare TREM2 variants are major risk factors for Alzheimer's disease (AD), but TREM2 variants may also confer a higher risk for other neurodegenerative diseases and a lower probability for cognitively healthy aging. We studied the TREM2 burden associated with different types of dementia and cognitively healthy centenarians (CHCs). Method: We included participants of the 100‐Plus Study, Amsterdam Dementia Cohort, Longitudinal Aging Study Amsterdam and various Dutch memory clinics. TREM2 variants (R47H, R62H, Q33X, R62C, T96K) were genotyped with a high density array or imputed using standard methods (TOPMED reference panel). To avoid family bias and ethnic differences, related individuals and those of non‐European ancestry were excluded. Frequencies of individual variants and the burden of TREM2 variants were compared in AD dementia, dementia with Lewy Bodies (DLB), frontotemporal dementia (FTD), cognitively normal controls and CHCs (correcting for 5 principal components). Result: We identified 242 carriers of TREM2 mutations and 6,683 controls without a TREM2 mutation with a mean age of 69 years (SD ±14 years), 50% female (Table 1). TREM2 variants were significantly associated with AD dementia (OR 1.4, 95%CI 1.1‐1.8, p = 0.01) (Table 2). R47H conferred the highest risk for AD (OR 2.8, 95%CI 1.4‐5.6, p = 0.004), compared to 1.3‐fold increased risk of R62H (95%CI 0.9‐1.7, p = 0.11). The carrier frequency was not increased in DLB (OR 1.4, 95%CI 0.7‐2.6, p = 0.34) and was not increased in FTD compared to controls (OR 0.59, 95%CI 0.3‐1.3, p = 0.18). Of interest, the allele frequency of TREM2 variants in centenarians is half of the expected frequency (OR = 0.46, 95%CI 0.1‐1.1, p = 0.10), and only concerns R62H. Conclusion: We replicate the association of TREM2 with increased risk of AD. In contrast to previous reports no association was observed with DLB or FTD. Cognitively healthy centenarians show a negative trend for TREM2 allele frequency suggesting that carrying a TREM2 variant decreases chances of survival to extreme age. [ABSTRACT FROM AUTHOR]

Background: The prevalence of Alzheimer's Disease (AD) increases with age, yet a small fraction of the population reaches ages beyond 100 years maintaining cognitive abilities, so‐called cognitively‐healthy‐centenarians. We aimed to uncover the genetic factors associated with such protection against AD, and to highlight the effects of AD‐associated variants during advanced aging. Method: Previous Genome‐Wide‐Association‐Studies (GWAS) identified 86 single‐nucleotide‐polymorphisms (SNPs) associated with AD‐risk. We investigated the frequency of each SNP in 346 cognitively‐healthy‐centenarians (mean age 101.05±2.51), compared to 2,281 AD cases (mean age 67.96±9.84), 3,165 middle‐aged healthy controls (mean age 62.57±8.66), and we combined the SNPs into Polygenic Risk Scores (PRS) for each individual. Finally, we characterized the functional properties of the SNPs enriched/depleted the most in the centenarians. Result: At the SNP level, centenarians were depleted with risk‐increasing SNPs and enriched with protective SNPs. The AD‐related PRS (excluding APOE SNPs) was significantly lower in centenarians; not only compared to AD (OR = 1.96, p = 4.07×10−26), but also to middle‐aged controls (OR = 1.29, p = 2.61×10−5). When including APOE SNPs these effects were even stronger (OR = 5.07, p = 6.15×10−71, and OR = 1.87, p = 4.67×10−17, for comparisons with AD and normal controls, respectively). The most depleted/enriched SNPs in centenarians functionally mapped to activation/regulation of immune response and endocytosis/phagocytosis. These SNPs were located near ANKH, TMEM106B, CLNK, EPDR1, WDR12, PLCG2, RIN3, CD2AP, MS4A, TREM2, ABCA7 and MAF. Conclusion: The ability to reach advanced age without cognitive decline is influenced by AD‐associated genetic variants. An advantageous regulation of the brain's immune system, intracellular protein trafficking, and endocytosis/phagocytosis may confer the strongest protection against AD and potentially other age‐related diseases. [ABSTRACT FROM AUTHOR]

Objectives. The aim of this study was to explore self-reported changes in personal development and meaning in life of older adults in the Netherlands during the COVID-19 pandemic and characteristics of the groups that reported these changes. Methods. Older adults from the Longitudinal Aging Study Amsterdam completed a questionnaire on the impact of the COVID-19 pandemic. Participants were asked to rate changes in personal development and meaning in life. These variables were descriptively analysed and logistic regression analyses were used to explore characteristics of the groups that reported these changes. Results. Of the 1099 older adults (aged 62–102 years), 25.7% paid more attention to things one enjoys doing in spare time, 36.6% reflected more on important things in life, and 16.8% made less future plans during the COVID-19 pandemic. Self-reported changes in meaning in life and personal development differed between specific subgroups of older adults. The largest changes in aspects of personal development and meaning in life were reported by older adults who experienced personal adverse experiences such as death of a loved one (ORs 2.03) and/or health problems such as functional limitations (ORs ranging from 1.59 to 2.84) and depression (ORs ranging from 1.69 to 2.77). Discussion and Implications. A substantial share of the participants reported changes in specific aspects of personal development and meaning in life. This was especially true for certain subgroups of older adults. Relatives and caregivers should be aware of changes in personal development and meaning in life since lower scores are known to be associated with poor physical, psychological, and social well-being outcomes. [ABSTRACT FROM AUTHOR]

Mediation analysis is often used to explore the complex relationship between two variables through a third mediating variable. This paper aims to illustrate the performance of the deviance information criterion, the pseudo‐Bayes factor, and the Watanabe–Akaike information criterion in selecting the appropriate multilevel mediation model. Our focus will be on comparing the conditional criteria (given random effects) versus the marginal criteria (averaged over random effects) in this respect. Most of the previous work on the multilevel mediation models fails to report the poor behavior of the conditional criteria. We demonstrate here the superiority of the marginal version of the selection criteria over their conditional counterpart in the mediated longitudinal settings through simulation studies and via an application to data from the Longitudinal Aging Study of the Amsterdam study. In addition, we demonstrate the usefulness of our self‐written R function for multilevel mediation models. [ABSTRACT FROM AUTHOR]

Objective: There is a growing interest in how people living with dementia may achieve good outcomes and be resilient despite their health challenges. Understanding what might be important for resilience in this population is largely untested theory.Methods: The analysis draws a subsample with cognitive impairment (N = 579) from two waves of the Cognitive Function and Ageing Studies Wales study, a nationally representative study of community-dwelling people aged 65+ in Wales. We constructed a measure of mental health resilience (MHR) defined as no depression, no anxiety and high well-being. Drawing on a resilience framework, we tested univariate and cumulative effects models of the factors that enable MHR, and then examined whether MHR is important for reducing loneliness over time.Results: Across both waves of data 22% (n = 121) met the criteria for MHR. The cumulative effects model found the odds of MHR were greater for male gender, higher self-esteem, greater social resources and no subjective memory complaints. Controlling for these significant predictors, MHR significantly predicted lower total and sub-scale scores for loneliness at wave 2. Sensitivity analysis shows these effects held at lower levels of cognitive function when the Mini-Mental State Examination score was <25, but not at <23.Conclusions: This paper addresses a gap in research regarding the conceptualisation and measurement of resilience when facing cognitive impairment. Understanding what aspects of a person's life might enable good mental health despite cognitive impairment-to be resilient-could inform effective strategies for friends and families, along with health, and social policy and practice. [ABSTRACT FROM AUTHOR]

BACKGROUND/OBJECTIVES: Frailty, loneliness, and social isolation are all associated with adverse outcomes in older adults, but little is known about their combined impact on mortality. DESIGN: Prospective cohort study. SETTING: The Longitudinal Aging Study Amsterdam. PARTICIPANTS: Community‐dwelling older adults aged 65 and older (n = 1,427). MEASUREMENTS: Frailty was measured with the frailty phenotype (Fried criteria). Loneliness was assessed with the De Jong Gierveld Loneliness Scale. Social isolation was operationalized using information on partner status, social support, and network size. Two categorical variables were created, for each possible combination regarding frailty and loneliness (FL) and frailty and social isolation (FS), respectively. Mortality was monitored over a period of 22 years (1995–2017). Survival curves and Cox proportional hazard models were used to study the effects of the FL and FS combinations on mortality. Analyses were adjusted for sociodemographic factors, depression, chronic diseases, and smoking. RESULTS: Frailty prevalence was 13%, and 5.9% of the sample were frail and lonely, and 6.2% frail and socially isolated. In fully adjusted models, older adults who were only frail had a higher risk of mortality compared with people without any of the conditions (hazard ratio [HR] range = 1.40–1.48; P <.01). However, the highest risk of mortality was observed in people with a combined presence of frailty and loneliness or social isolation (HRFL = 1.83; 95% confidence interval [CI] = 1.42–2.37; HRFS = 1.77; 95% CI = 1.36–2.30). Sensitivity analyses using a frailty index based on the deficit accumulation approach instead of the frailty phenotype showed similar results, confirming the robustness of our findings. CONCLUSION: Frail older adults are at increased risk of mortality, but this risk is even higher for those who are also lonely or socially isolated. To optimize well‐being and health outcomes in physically frail older adults, targeted interventions focusing on both subjective and objective social vulnerability are needed. [ABSTRACT FROM AUTHOR]

Background: Several collaborative genome‐wide‐association studies (GWAS) have characterized the genetic landscape of Alzheimer's disease (AD), which now counts >70 single‐nucleotide polymorphisms (SNPs) associated with AD‐risk. Method: We linked these SNPs to their affected biological pathways, and combined the effect of multiple SNPs into pathway‐specific polygenic‐risk‐scores (PRS). Using a genetically homogeneous dataset of 2,458 AD‐patients (age=70.2±10.4), 3,848 healthy controls (age=61.1±14.8), 343 cognitively healthy centenarians (age=101.1±1.8) and 705 individuals with mild‐cognitive‐impairment (MCI, age=69.1±8.9), we studied the association between pathway‐PRS and AD‐risk, MCI‐to‐AD conversion, and resilience against AD. Result: With an integrative strategy, we linked 72 AD‐associated SNPs to 5 clusters of biological pathways: beta‐amyloid cluster, immune cluster, vascular cluster, endocytosis cluster and a trafficking cluster (Figure 1). A PRS comprising all 72 SNPs (excluding APOE‐SNPs) was significantly associated with AD‐risk (OR=1.53, p<2e‐16), progression of MCI to AD dementia (OR=1.45, p=5.5e‐4), and, albeit in the opposite direction, resilience against AD in healthy centenarians (OR=0.82, p=6.4e‐4) (Figure 2, Figure 3). At the pathway level, all pathway‐PRS significantly associated with increased AD‐risk while specifically the vascular‐, endocytosis‐ and trafficking‐PRS associated with resilience against AD (p<0.05) (Figure 4). Interestingly, the beta‐amyloid‐, endocytosis and trafficking‐PRSs were significantly associated with MCI‐to‐AD progression (p<0.05), with a higher‐PRS leading up to 1.5‐year shorter conversion time. Conclusion: Our results add on the efficacy of pathway‐specific PRSs to identify individuals at highest or the lowest risk for the development of AD. Further, our results suggest that specific biological pathways are more important at different stages of the disease or in fact, associate with the escape of disease. AD diagnostic procedures may benefit from the identification of individual, pathway‐specific vulnerabilities. In the future, pathway‐specific PRSs may contribute to the selection of patients who may benefit most from pathway‐specific treatment strategies. [ABSTRACT FROM AUTHOR]

Introduction: This study examines the role of educational attainment, an indicator of cognitive reserve, on transitions in later life between cognitive states (normal Mini‐Mental State Examination (MMSE), mild MMSE impairment, and severe MMSE impairment) and death. Methods: Analysis of six international longitudinal studies was performed using a coordinated approach. Multistate survival models were used to estimate the transition patterns via different cognitive states. Life expectancies were estimated. Results: Across most studies, a higher level of education was associated with a lower risk of transitioning from normal MMSE to mild MMSE impairment but was not associated with other transitions. Those with higher levels of education and socioeconomic status had longer nonimpaired life expectancies. Discussion: This study highlights the importance of education in later life and that early life experiences can delay later compromised cognitive health. This study also demonstrates the feasibility and benefit in conducting coordinated analysis across multiple studies to validate findings. Highlights: There are benefits to coordinated analysis across multiple longitudinal studies.Education and socioeconomic status delays the progression to mild cognitive impairment.Higher education and socioeconomic status increases noncognitively impaired life expectancy. [ABSTRACT FROM AUTHOR]

Objectives To examine the effects of decreasing hospital length of stay ( HLOS) on change in functioning from prehospital admission to posthospital discharge in older cohorts. Design Cohort-sequential design. Setting Nationwide, older population-based Longitudinal Aging Study Amsterdam ( LASA). Participants Individuals aged 68 and older with any hospital admission according to national medical registry data: two 10-year age groups (68-77 (younger-old) and 78-87 (older-old)) in two periods (1996-99 (Period 1) and 2006-09 (Period 2)) (N = 1,212). Measurements HLOS was the main independent variable in multinomial logistic models, dichotomized as 1 to 5 days (short) and 6 days or longer (long). Outcomes were change scores in mobility and activities in daily living ( ADLs). Respondents who died during the 3-year period were assigned to a third outcome category. Results Results for both age groups showed more hospital admissions and shorter median HLOS in Period 2 than Period 1 ( P < .05). Lower odds of decline in physical functioning were found in respondents with short HLOS than in those with long HLOS (for mobility: odds ratio ( OR) = 0.36, 95% confidence interval ( CI) = 0.23-0.54 (younger-old) and OR = 0.47, 95% CI = 0.30-0.72 (older-old); for ADLs: OR = 0.30, 95% CI = 0.19-0.48 (younger-old) and OR = 0.30, 95% CI = 0.18-0.53 (older-old)). Adjusting for confounders did not significantly change these estimates. Period did not modify these associations. Conclusion Because the associations of HLOS with change in mobility and ADLs were the same in both periods, hospitalized older adults had neither advantage nor disadvantage from the decrease in HLOS. In addition, in both age groups, a greater percentage experienced the better functional outcomes and lower mortality associated with short admissions, which suggests an advantage of the decrease in HLOS. [ABSTRACT FROM AUTHOR]

Aim Studies have shown better predictive value of self-rated health ( SRH) for mortality when prospective change in SRH is considered. However, retrospective change is more feasible and might have better sensitivity to objective health changes. This study compares the predictive value for mortality of retrospectively measured change in SRH (based on a 'then-test') with current SRH and prospectively measured change in SRH. Methods Data from two waves of the Longitudinal Aging Study Amsterdam (2001-2003 and 2005-2006 [T0], n = 1894) were used. Retrospective change was defined as the difference between SRH at T0 ('current SRH') and SRH measured with a then-test at T0, asking for a renewed judgement of one's health at the previous wave. Prospective change was defined as change in SRH between the two waves. We applied Cox proportional hazards analysis to predict 5-year mortality. Results Having poorer current SRH significantly predicted mortality ( HR poor vs very good SRH = 4.42). Declined SRH was associated with higher mortality risk, but only when measured prospectively (one point decline vs no change HR = 1.33; two points decline HR = 1.95). After adjusting for current SRH, neither change measure predicted mortality. Results were similar in subgroups that did and did not experience incident diseases or limitations between the two waves. Conclusions Neither retrospective, nor prospective changes in SRH improved the prediction of mortality in older adults over current SRH. These results imply that using a standard single indicator for self-rated health in research or clinical practice might suffice to identify those with a high risk of future negative health outcomes. Geriatr Gerontol Int 2013; 13: 678-686. [ABSTRACT FROM AUTHOR]

Background: Developing Alzheimer's disease (AD) is influenced by multiple genetic variants that are involved in five major AD‐pathways: immune response, β‐amyloid metabolism, endocytosis, cholesterol/lipid metabolism and angiogenesis. The extent to which these pathways are involved in the resilience against AD have thus far been poorly addressed. Here, we investigated the association of each molecular mechanism with (i) the increased risk of AD, and (ii) the resilience against AD until extreme old age, by comparing pathway‐specific polygenic risk scores (pathway‐PRS). Method: We focused on 29 genetic variants identified in GWAS studies of AD to calculate a pathway‐PRS for the five major pathways involved in AD. For our pathway‐PRS, we developed an integrative framework that allows multiple genes to associate with a variant, and multiple pathways to associate with a gene. We studied the pathway‐PRSs in the Amsterdam Dementia Cohort of well‐phenotyped AD patients (N = 1,909), Dutch population controls from the Longitudinal Aging Study Amsterdam (N = 1,654), and our unique 100‐plus Study cohort of cognitively healthy centenarians who avoided AD (N = 293). Moreover, we estimated the contribution of each pathway to the genetic risk of AD in the general population. Result: All pathway‐PRSs (except for angiogenesis) significantly associated with increased AD‐risk and, in the opposite direction, with resilience against AD (p < 0.05). The pathway that contributed the most to the overall modulation of AD‐risk was β‐amyloid metabolism (29.6%), which was driven mainly by APOE‐variants. After excluding APOE variants, all pathway‐PRSs (except for angiogenesis) associated with increased AD‐risk (p < 0.05), while specifically immune response (p = 0.003) and endocytosis (p = 2.2 × 10−4) significantly associated, in the opposite direction, with resilience against AD. Indeed, the variants in these pathways were the main contributors to the overall modulation of genetic risk of AD in the general population (45.5% and 19.2%, respectively). Conclusion: The genetic variants associated with the resilience against AD indicate which pathways are involved with maintained cognitive functioning until extreme ages. Our work suggests that a favorable immune response and a maintained endocytosis pathway might be involved in neuro‐protection mechanisms of AD, which highlight the need to investigate these pathways, next to β‐amyloid metabolism. [ABSTRACT FROM AUTHOR]