Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. We thank Drs. D. Stephen Snyder and Marilyn Miller from NIA who are ex-officio ADGC members. EADI. This work has been developed and supported by the LABEX (laboratory of excellence program investment for the future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease) including funding from MEL (Metropole européenne de Lille), ERDF (European Regional Development Fund) and Conseil Régional Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The authors are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. The generation and management of GWAS genotype data for the Rotterdam Study (RS-I, RS-II, RS-III) was executed by the Human Genotyping Facility of the Genetic Laboratory of the

The Memory and Aging Project is a longitudinal, epidemiologic clinical-pathologic cohort study of common chronic conditions of aging with an emphasis on decline in cognitive and motor function and risk of Alzheimer's disease (AD). In this manuscript, we first summarize the study design and methods. Then, we present data on: 1) the relation of motor function to cognition, disability, and death; 2) the relation of risk factors to cognitive and motor outcomes, disability and death; 3) the relation of neuropathologic indices to cognitive outcomes; 4) the relation of risk factors to neuropathologic indices; and 5) additional study findings. The findings are discussed and contextualized.

Complexity at multiple levels needs to be understood and overcome to develop effective treatments and preventions for cognitive decline and AD dementia.

Mild cognitive impairment is associated with an increased risk of death and incident AD, and a greater rate of decline in selected cognitive abilities.

These results suggest that frequent participation in cognitively stimulating activities is associated with reduced risk of AD.

Context: Social isolation in old age has been associated with risk of developing dementia, but the risk associated with perceived isolation, or loneliness, is not well understood.Objective: To test the hypothesis that loneliness is associated with increased risk of Alzheimer disease (AD).Design: Longitudinal clinicopathologic cohort study with up to 4 years of annual in-home follow-up.Participants: A total of 823 older persons free of dementia at enrollment were recruited from senior citizen facilities in and around Chicago, Ill. Loneliness was assessed with a 5-item scale at baseline (mean±SD, 2.3±0.6) and annually thereafter. At death, a uniform postmortem examination of the brain was conducted to quantify AD pathology in multiple brain regions and the presence of cerebral infarctions. Main Outcome Measures:Clinical diagnosis of AD and change in previously established composite measures of global cognition and specific cognitive functions.Results: During follow-up, 76 subjects developed clinical AD. Risk of AD was more than doubled in lonely persons (score 3.2, 90th percentile) compared with persons who were not lonely (score 1.4, 10th percentile), and controlling for indicators of social isolation did not affect the finding. Loneliness was associated with lower level of cognition at baseline and with more rapid cognitive decline during follow-up. There was no significant change in loneliness, and mean degree of loneliness during the study was robustly associated with cognitive decline and development of AD. In 90 participants who died and in whom autopsy of the brain was performed, loneliness was unrelated to summary measures of AD pathology or to cerebral infarction. Conclusion:Loneliness is associated with an increased risk of late-life dementia but not with its leading causes.

The authors examined change in cognitive abilities in older Catholic clergy members. For up to 6 years, participants underwent annual clinical evaluations, which included a battery of tests from which summary measures of 7 abilities were derived. On average, decline occurred in each ability and was more rapid in older persons than in younger persons. However, wide individual differences were evident at all ages. Rate of change in a given domain was not strongly related to baseline level of function in that domain but was moderately associated with rates of change in other cognitive domains. The results suggest that change in cognitive function in old age primarily reflects person-specific factors rather than an inevitable developmental process.

Introduction We identified rare coding variants associated with Alzheimer’s disease (AD) in a 3-stage case-control study of 85,133 subjects. In stage 1, 34,174 samples were genotyped using a whole-exome microarray. In stage 2, we tested associated variants (P<1×10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, an additional 14,997 samples were used to test the most significant stage 2 associations (P<5×10-8) using imputed genotypes. We observed 3 novel genome-wide significant (GWS) AD associated non-synonymous variants; a protective variant in PLCG2 (rs72824905/p.P522R, P=5.38×10-10, OR=0.68, MAFcases=0.0059, MAFcontrols=0.0093), a risk variant in ABI3 (rs616338/p.S209F, P=4.56×10-10, OR=1.43, MAFcases=0.011, MAFcontrols=0.008), and a novel GWS variant in TREM2 (rs143332484/p.R62H, P=1.55×10-14, OR=1.67, MAFcases=0.0143, MAFcontrols=0.0089), a known AD susceptibility gene. These protein-coding changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified AD risk genes. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to AD development.