Context Genome wide association studies (GWAS) have recently identified CLU, PICALM and CR1 as novel genes for late-onset Alzheimer’s disease (AD). Objective In a three-stage analysis of new and previously published GWAS on over 35000 persons (8371 AD cases), we sought to identify and strengthen additional loci associated with AD and confirm these in an independent sample. We also examined the contribution of recently identified genes to AD risk prediction. Design, Setting, and Participants We identified strong genetic associations (p<10−3) in a Stage 1 sample of 3006 AD cases and 14642 controls by combining new data from the population-based Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium (1367 AD cases (973 incident)) with previously reported results from the Translational Genomics Research Institute (TGEN) and Mayo AD GWAS. We identified 2708 single nucleotide polymorphisms (SNPs) with p-values<10−3, and in Stage 2 pooled results for these SNPs with the European AD Initiative (2032 cases, 5328 controls) to identify ten loci with p-values<10−5. In Stage 3, we combined data for these ten loci with data from the Genetic and Environmental Risk in AD consortium (3333 cases, 6995 controls) to identify four SNPs with a p-value<1.7×10−8. These four SNPs were replicated in an independent Spanish sample (1140 AD cases and 1209 controls). Main outcome measure Alzheimer’s Disease. Results We showed genome-wide significance for two new loci: rs744373 near BIN1 (OR:1.13; 95%CI:1.06–1.21 per copy of the minor allele; p=1.6×10−11) and rs597668 near EXOC3L2/BLOC1S3/MARK4 (OR:1.18; 95%CI1.07–1.29; p=6.5×10−9). Associations of CLU, PICALM, BIN1 and EXOC3L2 with AD were confirmed in the Spanish sample (p<0.05). However, CLU and PICALM did not improve incident AD prediction beyond age, sex, and APOE (improvement in area under receiver-operating-characteristic curve <0.003). Conclusions Two novel genetic loci for AD are reported that for the first time reach genome-wide statistical significance; these findings were replicated in an independent population. Two recently reported associations were also confirmed, but these loci did not improve AD risk prediction, although they implicate biological pathways that may be useful targets for potential interventions.

Importance-It is unclear if female carriers of the Apolipoprotein E (APOE) ε4 allele are at greater risk of developing Alzheimer's disease (AD) than men, and the sex-dependent association of mild cognitive impairment (MCI) and APOE has not been established.Objective-To determine how sex and APOE genotype affect the risks for developing MCI and AD.Data Sources-Twenty-seven independent research studies in the Global Alzheimer's Association Interactive Network with data on nearly 58,000 subjects.Neu et al.

Depression symptoms before the onset of AD are associated with the development of AD, even in families where first depression symptoms occurred more than 25 years before the onset of AD. These data suggest that depression symptoms are a risk factor for later development of AD.

Head injury is a risk factor for AD. The magnitude of the risk is proportional to severity and heightened among first-degree relatives of AD patients. The influence of head injury on the risk of AD appears to be greater among persons lacking APOE-epsilon4 compared with those having one or two epsilon4 alleles, suggesting that these risk factors may have a common biologic underpinning.

Depression is associated with an increased risk of dementia and AD in older men and women over 17 years of follow-up.

Despite recent advances in the molecular genetics of Alzheimer's disease (AD), several fundamental questions concerning risk of illness are unresolved, namely, if Mendelian factors account for the incidence of the disease, and if AD is an inevitable consequence of the aging process. This study was designed to address these issues and other aspects of familial aggregation of the disorder. A consecutive sample of 1,694 patients who met criteria for a diagnosis of probable or definite AD were ascertained in 13 centers participating in the Multi-Institutional Research in Alzheimer Genetic Epidemiology (MIRAGE) project. Lifetime risk and age at onset of AD among various strata of 12,971 first-degree relatives was estimated using survival analysis procedures. The lifetime risk of AD in first-degree relatives was 39.0% +/- 2.1% by age 96 years. Age-specific risk of AD declined after age 90 and the data set included 61 apparently unaffected persons who survived to age 96 without becoming demented. Female relatives had a higher risk of AD than male relatives at all ages. By age 80, children of conjugal AD couples had a cumulative risk of 54%, 1.5 times greater than the sum of the risks to children having affected mothers or fathers, and nearly 5 times greater than the risk to children having normal parents. Children of affected fathers had a cumulative risk that was 1.4 times the corresponding risk to children of affected mothers. Risk assessment in early-onset and late-onset families, using various strategies for determining the age cut-off, yielded contradictory results. These data suggest the following: (1) the lifetime risk among relatives does not support a simple autosomal dominant inheritance pattern of disease; (2) women are innately more susceptible to AD than men; (3) the proportion of hereditary cases may be higher in men than women; (4) distinction between early- onset and late-onset forms of AD has little meaning in the absence of a biological marker; (5) the risk of AD decreases after age 90; and (6) AD therefore may not be an inevitable concomitant of the aging process, a conclusion that has profound implications for basic and applied AD research. The age- and sex-specific lifetime risks derived from this study are sufficiently robust to be a reliable source of information for counseling relatives of AD patients.

SDB symptoms are common in 5-year-old children and are associated with an increased risk of daytime sleepiness and with problem behaviors suggestive of attention-deficit/hyperactivity disorder.

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