ACE-Dependent Alzheimer’s Disease: Blood ACE Phenotyping of the Most Prevalent and Damaging ACE Missense Mutation—Y215C (rs3730025)

<b>Background</b>: The <i>ACE</i> Y215C mutation is a common, functionally damaging missense variant (~1.5% allele frequency) associated with reduced plasma ACE levels and increased Alzheimer's disease (AD) risk. In CHO and HEK cell models, this mutation caused a ~3-6-fold decrease in ACE surface expression, soluble ACE levels, and ACE enzymatic activity compared to those of wild-type ACE. <b>Methods</b>: Circulating ACE levels and activity were measured in EDTA plasma obtained from 84 carriers of the <i>ACE</i> Y215C mutation using a set of mAbs to the ACE. The mAbs 5B3/1G12 binding ratio was revealed as a sensitive marker for the circulating Y215C ACE mutant. Whole-exome and whole-genome sequencing (WES/WGS) were performed to identify genetic variants potentially modifying circulating ACE levels. In parallel, published sequencing and proteomic data from 35,559 Icelanders participants were analyzed to identify genes influencing ACE shedding. Sequence comparison was performed between carriers with elevated and reduced ACE concentrations to identify the potential protective variants that may compensate for decreased ACE levels due to the Y215C mutation itself. <b>Results</b>: Most carriers of the Y215C <i>ACE</i> mutation demonstrated significantly decreased ACE levels (median is 62% of control ACE levels). However, substantial inter-individual variability was observed in plasma ACE activity among carriers. Comparative sequencing analysis revealed 9648 variants unique to individuals with elevated ACE, mapping to 5779 protein-coding genes and enriched for pathways related to intracellular and transmembrane transport. <b>Conclusions</b>: The presence of the damaging <i>ACE</i> mutation Y215C does not invariably result in low plasma ACE or, likely, elevated AD risk. Therefore, combined blood ACE phenotyping and whole-exome sequencing are recommended to more accurately assess ACE-related AD susceptibility in mutation carriers.