Big Patient Data Analyses Pinpoint Telmisartan as a Candidate Drug for Alzheimer’s in Black Adults

Use of the angiotensin II receptor blocker telmisartan is associated with a significantly reduced risk of Alzheimer’s disease (AD) in Black adults over age 60, according to a patient data analysis by a team of researchers led by Feixiong Cheng, PhD, associate staff in Cleveland Clinic’s Genomic Medicine Institute.

The finding, published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association [Epub 4 Nov 22], is from an investigation combining retrospective pharmacoepidemiologic studies and Mendelian randomization genetic analysis. Results of the investigation support randomized controlled trials with racially diverse patient cohorts to prospectively evaluate telmisartan’s potential effects in AD prevention/treatment and explore underlying mechanisms, the authors conclude.

“We identified telmisartan as a drug that might be repurposed for use against AD in Black adults,” says Dr. Cheng, noting that Black adults over age 60 are 1.5 to two times as likely to develop AD as age-matched white adults. “More broadly, consideration of race-specific drug responses holds potential for significantly improving patient care. Identifying candidate drugs can also reveal more information about the disease itself through referencing the medicine’s targets.”

Backdrop to the investigation

The study was prompted by telmisartan’s status as the only drug in the angiotensin II receptor blocker (ARB) class — a group of antihypertensive medications with established favorable tolerability — that acts as a partial agonist of peroxisome proliferator-activated receptor gamma (PPAR-γ). Meta-analyses have shown that telmisartan had positive clinical effects, relative to other ARBs, for patients with type 2 diabetes and chronic kidney disease, and animal models found telmisartan’s PPAR agonistic activity to reduce cognitive decline.

“This caused us to speculate whether telmisartan might protect against AD, particularly among Black adults, who have an elevated prevalence of hypertension, type 2 diabetes and chronic kidney disease,” Dr. Cheng explains. The investigation aligns with several ongoing interventional clinical trials evaluating potential neuroprotective effects of telmisartan in multiple racial groups.

Preferential protection among Black individuals

For the pharmacoepidemiologic part of their investigation, the researchers used a U.S. insurance database including more than 5.6 million ethnically diverse adults aged 60 or older who were continuously enrolled for at least three years. Within this big patient data set, they identified individuals using telmisartan and stratified them by race (non-Hispanic white and non-Hispanic Black).

After adjusting for multiple confounding factors using propensity score and nearest-neighbor matching methods, they found that, among Black adults, moderate or high telmisartan exposure was associated with a decreased risk of AD (hazard ratio [HR] = 0.77, 95% CI, 0.65-0.91; P = 0.0022) and dementia (HR = 0.82, 95% CI, 0.74-0.91; P = 0.0003) relative to low or no telmisartan exposure. In contrast, among white adults, moderate/high telmisartan exposure conferred no reduced risk of AD (HR = 0.97, 95% CI, 0.89-1.05; P = 0.411) or dementia (HR = 0.98, 95% CI, 0.93-1.04; P = 0.542) relative to low/no telmisartan exposure.

Sensitivity analyses and sex- and age-stratified subgroup analyses revealed that individuals’ medication possession ratio for telmisartan and average daily dosage were significantly associated with greater reductions in the incidence of both AD and dementia in the study’s Black population. Moreover, comparison with an active-user cohort from the database showed that telmisartan use among Black adults was associated with a stronger reduction in AD risk than use of the angiotensin-converting enzyme inhibitor lisinopril.

Supportive results from Mendelian analysis

To better assess a potential causal relationship between telmisartan use and AD risk reduction, the researchers then used Mendelian randomization analysis from ethnically diverse genome-wide association studies (GWAS) across AD, hypertension and diabetes. They found that PPAR-γ — the nuclear receptor targeted only by telmisartan among the ARB drug class — was significantly associated with a protective effect against AD in Black individuals with type 2 diabetes, hypertension and/or chronic kidney disease, whereas no such association was found among white individuals.

“This finding further supports a protective effect for telmisartan against AD specifically in Black individuals,” Dr. Cheng observes. He notes that this effect may be attributable to the drug’s multitarget effects against comorbidities — namely, hypertension, diabetes and chronic kidney disease — that are more prevalent among Black adults.

“Our population-based discovery analysis and our Mendelian randomization analysis together suggest that telmisartan may be a potential therapy for AD and dementia that holds uniquely specific efficacy in Black adults,” Dr. Cheng concludes. “Further clinical investigation of telmisartan for AD is highly warranted, and future trials should prioritize inclusion of patients from minority populations to refine or reinforce the associations we have identified.”

Dr. Cheng’s team is applying innovative research techniques using artificial intelligence and de-identified data from Cleveland Clinic’s expansive electronic medical record systems and large genetic data (e.g., whole genome sequencing) from the Alzheimer’s Disease Sequencing Project (ADSP) to identify novel targets and repurposable medicines for AD treatment.

The study was supported by the National Institute on Aging and the Translational Therapeutics Core of the Cleveland Alzheimer’s Disease Research Center.