Damaging mutations of the Angiotensin I-converting enzyme (ACE) that result in low ACE levels may increase the risk of developing late-onset Alzheimer’s disease (AD). We quantified blood ACE levels in EDTA-plasma from 147 subjects with 23 different heterozygous ACE mutations (and 70 controls) and estimated the effect of these mutations on ACE phenotype, using a set of monoclonal antibodies (mAbs) to ACE and two ACE substrates. We identified several mutations in both ACE domains (including the most frequent ACE mutation, Y215C), which led to decreased ACE levels in the blood, and thus could be considered as putative risk factors for late-onset AD. The precipitation of several ACE mutants (Q259R, A725P, C734Y) by specific mAbs changed significantly, and therefore, these mAbs could be markers of these mutations. Analysis of 50 of the most frequent ACE mutations demonstrates that more than 1.5% of the adult population may have mutations which lead to decreased ACE levels, and thus, the role of low ACE levels in the development of AD may be underappreciated. Intriguingly, statistical and cluster analyses of longevity patients revealed trends towards higher frequency of cognitive impairment among affected individuals with damaging ACE mutations. Systematic analysis of blood ACE levels in patients with various ACE mutations identifies individuals with low blood ACE levels who may be at increased risk for late-onset AD. Patients with transport-deficient ACE mutations theoretically could benefit from therapeutic treatment with a combination of chemical and pharmacological chaperones and proteasome inhibitors, as was demonstrated previously on a cell model of the transport-deficient ACE mutation Q1069R. Moreover, clinical association analysis suggests a trend linking damaging ACE mutations with increased risk of cognitive impairment.

Background: The ACE 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. Methods: Circulating ACE levels and activity were measured in EDTA plasma obtained from 84 carriers of the ACE 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. Results: Most carriers of the Y215C ACE 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. Conclusions: The presence of the damaging ACE 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.

Aging induces profound physiological changes that alter drug disposition and response, narrowing therapeutic windows and increasing susceptibility to adverse drug reactions (ADRs). This review synthesizes current evidence on age-related pharmacokinetic and pharmacodynamic changes, with a focus on pharmacogenomic determinants of drug response in older adults. Progressive decline in renal function, hepatic metabolic capacity, and alterations in body composition collectively necessitate age-appropriate dose adjustments. Polypharmacy, prevalent in community-dwelling and hospitalized older adults, compounds these challenges through drug–drug and drug–drug–gene interactions. Pharmacogenomic testing—particularly for CYP2D6, CYP2C19, CYP2C9, and SLCO1B1—offers a promising strategy to personalize therapy, while deprescribing frameworks provide practical approaches to mitigate medication-related risks. This review presents a comprehensive framework for understanding the mechanistic basis of altered drug response in older adults and proposes actionable strategies for optimizing pharmacotherapy in this vulnerable population.

Aging induces profound physiological changes that alter drug disposition and response, narrowing therapeutic windows and increasing susceptibility to adverse drug reactions (ADRs). This review synthesizes current evidence on age-related pharmacokinetic and pharmacodynamic changes, with a focus on pharmacogenomic determinants of drug response in older adults. Progressive decline in renal function and hepatic metabolic capacity and alterations in body composition collectively necessitate age-appropriate dose adjustments. Polypharmacy, prevalent in community-dwelling and hospitalized older adults, compounds these challenges through drug–drug and drug–drug–gene interactions. Pharmacogenomic testing—particularly for CYP2D6, CYP2C19, CYP2C9, and SLCO1B1—offers a promising strategy with which to personalize therapy, while deprescribing frameworks provide practical approaches to mitigating medication-related risks. This review provides a comprehensive framework for understanding the mechanistic basis of altered drug response in older adults and proposes actionable strategies for optimizing pharmacotherapy in this vulnerable population. Throughout, pharmacogenomic claims are graded across four levels: biological plausibility, measured pharmacokinetic effect, pharmacogenetic actionability, and demonstrated clinical utility. Furthermore, selected gene–drug examples are explicitly identified as either geriatric-specific evidence or extrapolations from general adult pharmacogenomics, clarifying which findings are truly modified by the aging process.