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.

Method: The 5,092 participants, who we re 6 5 y ea r s o l d o r o l d er, we re screened for dementia. Based on the results of this screen, 1,002 participants (329 with dementia and 673 without dementia) underwent comprehensive neuropsychiatric examinations and were rated on the Neuropsychiatric Inventory, a widely used method for ascertainment and classification of dementia-associated mental and behavioral disturbances. Results: Of the 329 participants with dementia, 214 (65%) had Alzheimer's disease, 62 (19%) had vascular dementia, and 53 (16%) had another DSM-IV dementia diagnosis; 201 (61%) had exhibited one or more mental or behavioral disturbances in the past month. Apathy (27%), depression (24%), and agitation/ aggression (24%) were the most com

SUMMARYBackground-Neuropsychiatric symptoms are nearly universal in dementia, yet little is known about their longitudinal course in the community.

Objective: The authors report findings from a study of 5,092 community residents who constituted 90% of the elderly resident population of Cache County, Utah. Method:The 5,092 participants, who we re 6 5 y ea r s o l d o r o l d er, we re screened for dementia. Based on the results of this screen, 1,002 participants (329 with dementia and 673 without dementia) underwent comprehensive neuropsychiatric examinations and were rated on the Neuropsychiatric Inventory, a widely used method for ascertainment and classification of dementia-associated mental and behavioral disturbances. Results:Of the 329 participants with dementia, 214 (65%) had Alzheimer's disease, 62 (19%) had vascular dementia, and 53 (16%) had another DSM-IV dementia diagnosis; 201 (61%) had exhibited one or more mental or behavioral disturbances in the past month. Apathy (27%), depression (24%), and agitation/ aggression (24%) were the most common in participants with dementia. These disturbances were almost four times more common in participants with dementia than in those without. Only modest differences were observed in the prevalence of mental or behavioral disturbances in different types of dementia or at different stages of illness: participants with Alzheimer's disease were more likely to have delusions and less likely to have depression. Agitation/ aggression and aberrant motor behavior were more common in participants with advanced dementia. Conclusions:On the basis of their findings in this large community population of elderly people, the authors conclude that a wide range of dementia-associated mental and behavioral disturbances afflict the majority of individuals with dementia. Because of their frequency and their adverse effects on patients and their caregivers, these disturbances should be ascertained and treated in all cases of dementia.

In participants with no epsilon4 alleles, the age-specific prevalence of AD reached a maximum and then declined after age 95. In epsilon4 heterozygotes a similar maximum was noted earlier at age 87, in homozygotes at age 73. Female sex was a risk factor for AD only in those with epsilon4. The epsilon4 allele accounted for 70% of the population attributable risk for AD.