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Introduction: There is increasing interest in plasma amyloid beta (Aβ) as an endophenotype of Alzheimer's disease (AD). Identifying the genetic determinants of plasma Aβ levels may elucidate important biological processes that determine plasma Aβ measures. Methods: We included 12,369 non‐demented participants from eight population‐based studies. Imputed genetic data and measured plasma Aβ1‐40, Aβ1‐42 levels and Aβ1‐42/Aβ1‐40 ratio were used to perform genome‐wide association studies, and gene‐based and pathway analyses. Significant variants and genes were followed up for their association with brain positron emission tomography Aβ deposition and AD risk. Results: Single‐variant analysis identified associations with apolipoprotein E (APOE) for Aβ1‐42 and Aβ1‐42/Aβ1‐40 ratio, and BACE1 for Aβ1‐40. Gene‐based analysis of Aβ1‐40 additionally identified associations for APP, PSEN2, CCK, and ZNF397. There was suggestive evidence for interaction between a BACE1 variant and APOE ε4 on brain Aβ deposition. Discussion: Identification of variants near/in known major Aβ‐processing genes strengthens the relevance of plasma‐Aβ levels as an endophenotype of AD. [ABSTRACT FROM AUTHOR]

Background: Mild cognitive impairment (MCI) encompasses cognitive deficits beyond normal aging that minimally impact daily functioning. Uncovering the genetic architecture of MCI, which can progress to Alzheimer's disease in some individuals, may facilitate the development of lifestyle and pharmacologic interventions to minimize cognitive impairment or prevent dementia. We conducted a whole exome sequence study of MCI in 1,144 African American (AA) and 3,358 European American (EA) participants aged 67‐90 years from the Atherosclerosis Risk in Communities‐Neurocognitive Study. Methods: For both single‐variant and gene‐based tests, we employed seqMeta to perform race‐stratified analyses of functional (nonsynonymous, splicing, stopgain, stoploss, or frameshift) variants in each sex alone and both sexes combined. Models were adjusted for age, sex (except sex‐stratified models), field center, and population substructure (the first ten principal components). Logistic regression models were fit on autosomal single‐variants with minor allele frequency (MAF) ≥0.01 while SKAT‐O, T1 burden, and SKAT (beta weights and MAF ≤ 0.05) gene‐based tests were conducted. The significance and suggestive p‐value thresholds were 1.13E‐06 and 2.27E‐05 for single‐variant tests and 2.81E‐06 and 5.63E‐05 for gene‐based tests, respectively, after Bonferroni correction. Results: The analysis sample contained 993 MCI cases and 3,509 cognitively normal participants; Table 1 contains the count for each race and sex subgroup. One significant (p‐value=1.06E‐7) single‐variant association (chr6:51712759:T:C in PKHD1) was detected in AA males (Figure 1). This variant had MAF=0.025 in AA males but was monomorphic in EA males. Four significant gene‐based associations with minor allele counts (MAC) ≥ 10 were discovered: CDC27 in AA females (SKAT‐O p‐value=6.63E‐07), C19orf18 in AA males (SKAT‐O p‐value=1.26E‐07), SLC16A10 in EA males and females combined (SKAT p‐value=1.90E‐06), and ZNF804A in EA females (T1 p‐value=2.69E‐07). Twenty‐three suggestive single‐variant and gene‐based associations with MAC ≥ 10 were identified (Figure 2). Conclusions: MCI‐associated genes have diverse biological functions including cell division, sodium‐independent transportation of amino acids, and zinc finger binding. Our findings imply that the genetic underpinnings of MCI may differ by race and sex. External replication of our findings, as well as investigations using large samples in consortia, will provide insight into the pervasiveness of sex‐specific genetic effects in dementia‐related traits. [ABSTRACT FROM AUTHOR]