Telmisartan for Apolipoprotein E ε4 Carriers as a Candidate Precision Medicine Strategy in Alzheimer’s Disease

Abstract

The apolipoprotein E ε4 (APOE ε4) allele is the strongest common genetic risk factor for late-onset Alzheimer’s disease and is associated with blood–brain barrier (BBB) dysfunction, cerebrovascular instability, impaired lipid transport, and metabolic dysregulation. These features support investigation of precision medicine approaches targeting neurovascular and metabolic pathways in APOE ε4 carriers. Telmisartan, an angiotensin II type 1 receptor blocker with partial peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist activity, possesses pharmacological properties that may address several of these mechanisms. This narrative review evaluates the mechanistic and translational rationale for telmisartan as a candidate therapeutic strategy in APOE ε4 carriers, with emphasis on BBB integrity, endothelial function, neuroprotection, and metabolic regulation. Preclinical evidence demonstrates reductions in neuroinflammation, oxidative stress, and amyloid-related pathology, while experimental studies support effects on BBB stability and neurovascular function. However, the translational relevance of these findings remains uncertain, as many interventions demonstrating efficacy in animal models of Alzheimer’s disease have failed in human studies. Clinical data, including APOE-genotyped populations, provide indirect support for further investigation but do not establish APOE ε4-specific therapeutic benefit. Telmisartan represents a biologically plausible candidate for APOE ε4-enriched mechanistic investigation; however, definitive evidence requires prospective APOE-stratified clinical trials incorporating neurovascular, BBB-specific, and clinically meaningful cognitive endpoints.