Classification of ACE variants related to Alzheimer's disease (AD): the ACE mutations -- AD browser

Abstract

BackgroundACE variants are genetic risk factors for Alzheimers disease (AD), potentially through reduced enzymatic activity and impaired amyloid-{beta} hydrolysis. ObjectivesTo create a publicly available database of ACE variants relevant to ACE deficiency and AD, and to estimate the population frequency of damaging ACE variants and their impact on blood ACE levels. MethodsACE variants were compiled from literature, public databases (VarSome, dbSNP, ClinVar, gnomAD), and sequencing data (WES/WGS) from 5147 Russian individuals. Variants were classified using a consensus in silico score (AlphaMissense, MetaRNN, EVE). Blood ACE levels were measured in 330 carriers of 64 different ACE mutations. ResultsWe identified 1682 unique ACE variants. Of these, 608 (36.2%) were classified as functionally damaging, including 17 signal peptide, 210 loss-of-function, and 381 missense variants. The estimated carrier frequency of damaging ACE variants was 2 % (1/50). Notably, 24 variants associated with experimentally confirmed reductions in blood ACE levels had a combined estimated carrier frequency of 3.9 % in the general population, calculated from cumulative gnomAD v4.1.0 allele frequencies under a rare-variant independence model. An open-access browser is available at https://ace-browser.com/. ConclusionsVariants associated with reduced blood ACE levels were estimated to be carried by approximately 1 in 25 individuals in the general population. This frequency is of the same order of magnitude as the 13.2% prevalence of Alzheimers dementia in individuals aged 75-84 years (Alzheimers Association, 2025), consistent with the hypothesis that ACE deficiency may represent an underrecognized contributor to late-onset AD susceptibility. The ACE mutations-AD browser and integrated genotype-phenotype data presented here provide a novel resource for future basic, translational, and clinical research on ACE-dependent AD.