ACE inhibition increases Alzheimer's disease risk by promoting tau phosphorylation.

Reportedly, over 60% of individuals in the USA aged 65 or older take antihypertensive medications, making it crucial to evaluate their potential impact on dementia. Alzheimer's disease (AD), the most prevalent form of dementia, develops insidiously over decades, effectively precluding clinical trials of antihypertensive drug effects on AD risk. Through a triangulation approach integrating large-scale human genetics, population-based study, and rigorous experimental models, we identified that angiotensin-converting enzyme (ACE) inhibitors were associated with increased AD risk, with no significant associations observed for other antihypertensive classes, including angiotensin II receptor blockers and calcium channel blockers. Multi-omics Mendelian randomization analyses revealed that genetically proxied reductions in ACE expression and ACE protein levels in serum, cerebrospinal fluid, and brain tissues were causally associated with increased AD risk via exacerbated tau phosphorylation. A cohort study of 338,645 UK Biobank participants, followed for more than 10 years, also found an association between genetically predicted low serum ACE levels and the increased incidence of AD. Experimental validation using P301S tau transgenic mice and human iPSC-derived neurons confirmed that pharmacological ACE inhibition intensified tau phosphorylation and aggregation, cognitive impairment, neuroinflammation, and glial activation, predominantly in the hippocampal region. Multiple lines of evidence established a specific link between ACE inhibition and tau-driven neurodegeneration, underscoring the importance of carefully tailored antihypertensive strategies to prevent dementia risk, and identifying ACE as a viable therapeutic target for AD and other tau-related neurodegenerative conditions.