Alzheimer's disease (AD) is highly heritable and recent studies have identified over 20 diseaseassociated genomic loci. Yet these only explain a small proportion of the genetic variance, indicating that undiscovered loci remain. Here, we performed the largest genome-wide association study of clinically diagnosed AD and AD-by-proxy (71,880 cases, 383,378 controls). AD-by-proxy, based on parental diagnoses, showed strong genetic correlation with AD (rg=0.81). Meta-analysis identified 29 risk loci, implicating 215 potential causative genes. Associated genes are strongly expressed in immune-related tissues and cell types (spleen, liver and microglia). Gene-set analyses indicate biological mechanisms involved in lipid-related processes and degradation of amyloid precursor proteins. We show strong genetic correlations with multiple health-related outcomes, and Mendelian randomisation results suggest a protective effect of cognitive ability on AD risk. These results are a step forward in identifying the genetic factors that contribute to AD risk and add novel insights into the neurobiology of AD.

Importance: The strongest genetic risk factor for AD, the apolipoprotein E (APOE) gene, has a stronger association among females compared to males. Yet, limited work has evaluated the association between APOE alleles and markers of AD neuropathology in a sex-specific manner. Objective: Evaluate sex differences in the association between APOE and markers of AD neuropathology measured in cerebrospinal fluid (CSF) during life or in brain tissue at autopsy. Design, Setting, Participants: This meta-analysis selected data from 10 longitudinal cohort studies of normal aging and AD. Cohorts had variable recruitment criteria and follow-up intervals, and included population based and clinic based samples. Inclusion in our analysis required APOE genotype data and either CSF data (n=1798, 48% female, 13% AD, 94% Caucasian, 70±9 years) or autopsy data (n=5,109, 56% female, 97% Caucasian, 84±9 years) available for analysis. Main Outcome and Measures: Biomarker analyses included levels of Aβ−42, total tau (t-tau), and phosphorylated tau (p-tau) measured in CSF. Autopsy analyses included CERAD staging for neuritic plaques and Braak staging for neurofibrillary tangles. Results: After correcting for multiple comparisons using the Bonferroni procedure, we observed a statistically significant interaction between APOE-ε4 and sex on CSF t-tau (β=0.41 [95% CI: 0.27, 0.55], p<0.001) and p-tau (β=0.24 [0.09, 0.38], p=0.001), whereby APOE showed a stronger association among females compared to males. Post hoc analyses suggested this sex difference was present in amyloid positive individuals (β=0.41 [0.20, 0.62], p<0.001), but not among amyloid negative individuals (β=0.06 [−0.18, 0.31], p=0.62). We did not observe sex differences in the association between APOE and Aβ−42, neuritic plaque burden, or neurofibrillary tangle burden. Conclusions and Relevance: We provide robust evidence of a stronger association between APOE-ε4 and CSF tau levels among females compared to males across multiple independent datasets. Interestingly, APOE-ε4 is not differentially associated with autopsy measures of neurofibrillary tangles. Together, the sex difference in the association between APOE and CSF measures of tau, and the lack of a sex difference in the association with neurofibrillary tangles at autopsy, suggests that APOE may modulate risk for neurodegeneration in a sex-specific manner, particularly in the presence of amyloidosis.

A multi-ethnic study demonstrates that the extrapolation of genetic disease risk models from European populations to other ethnicities is compromised more strongly by genetic structure than by environmental or global genetic background in differential genetic risk associations across ethnicities.

For the past five years, genome-wide association studies (GWAS) have identified hundreds of common variants associated with human diseases and traits, including high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels. Approximately 95 loci associated with lipid levels have been identified primarily among populations of European ancestry. The Population Architecture using Genomics and Epidemiology (PAGE) study was established in 2008 to characterize GWAS–identified variants in diverse population-based studies. We genotyped 49 GWAS–identified SNPs associated with one or more lipid traits in at least two PAGE studies and across six racial/ethnic groups. We performed a meta-analysis testing for SNP associations with fasting HDL-C, LDL-C, and ln(TG) levels in self-identified European American (∼20,000), African American (∼9,000), American Indian (∼6,000), Mexican American/Hispanic (∼2,500), Japanese/East Asian (∼690), and Pacific Islander/Native Hawaiian (∼175) adults, regardless of lipid-lowering medication use. We replicated 55 of 60 (92%) SNP associations tested in European Americans at p<0.05. Despite sufficient power, we were unable to replicate ABCA1 rs4149268 and rs1883025, CETP rs1864163, and TTC39B rs471364 previously associated with HDL-C and MAFB rs6102059 previously associated with LDL-C. Based on significance (p<0.05) and consistent direction of effect, a majority of replicated genotype-phentoype associations for HDL-C, LDL-C, and ln(TG) in European Americans generalized to African Americans (48%, 61%, and 57%), American Indians (45%, 64%, and 77%), and Mexican Americans/Hispanics (57%, 56%, and 86%). Overall, 16 associations generalized across all three populations. For the associations that did not generalize, differences in effect sizes, allele frequencies, and linkage disequilibrium offer clues to the next generation of association studies for these traits.