The mean age at enrollment was 78.5 years and 30.9%

were male. At the last evaluation, 24.9% met clinical diagnostic criteria for AD and 21.8% had mild cognitive impairment. The summary measure of global cognitive performance was based on annual ATM/ATR inhibitor clinical trial assessments of 17 neuropsychiatric tests. A nested autopsy cohort consisted of 651 deceased subjects (376 ROS and 275 MAP); mean age at death was 81.5 years and 37.6% were male. Proximate to death, 40.9% of subjects included in the autopsy cohort met clinical diagnostic criteria for AD. Bielschowsky silver stain was used to visualize neurofibrillary tangles in tissue sections from the midfrontal, middle temporal, inferior parietal, and entorhinal cortices, and the hippocampal CA1 sector. A quantitative composite score

for neurofibrillary tangle pathologic burden was created by dividing the raw counts in each region by the standard deviation of the region specific counts and then averaging the scaled counts over the five brain regions to create a single standardized summary measure. Additional details of the ROS and MAP cohorts as well Crizotinib price as the cognitive and pathologic phenotypes are described in prior publications (De Jager et al., 2012; Keenan et al., 2012). The Knight-ADRC and UW samples were genotyped with the Illumina 610 or the Omniexpress chip. The ADNI samples were genotyped with the Illumina 610 chip, and the UPenn sample with the Omniexpress. Prior to association analysis, all samples and genotypes underwent stringent quality control (QC). Genotype data were cleaned by applying a minimum call rate for SNPs and individuals (98%) and minimum minor allele frequencies (0.02). SNPs not in Hardy-Weinberg equilibrium (p < 1 × 10−6) were excluded. The QC cleaning steps were applied for each genotyping array separately. We tested for unanticipated duplicates and cryptic relatedness among samples using pairwise genome-wide estimates of proportion identity-by-descent. When a pair of identical samples or a pair of samples with cryptic relatedness was identified, the sample from the Knight-ADRC or samples with a higher

number of SNPs passing QC were prioritized. Eigenstrat (Price et al., 2006) was used to calculate principal old component factors for each sample and confirm the ethnicity of the samples. Rs7412 and rs429358 which define the APOE ε2/ε3/ε4 isoforms were genotyped using Taqman genotyping technology, as previously described ( Koch et al., 2002; Cruchaga et al., 2009, 2010, 2011, 2012; Kauwe et al., 2010). DNA from ROS and MAP subjects was extracted from whole blood, lymphocytes, or frozen postmortem brain tissue and genotyped on the Affymetrix Genechip 6.0 platform, as previously described (Keenan et al., 2012). Following standard QC procedures, imputation was performed using MACH software (version 1.0.16a) and HapMap release 22 CEU (build 36) as a reference.