Antihypertensive Choice May Affect Dementia Risk, Studies Show

Blood–brain barrier (BBB)-crossing antihypertensive medications are associated with a lower risk of new-onset dementia and mortality, while angiotensin II receptor-stimulating drugs are associated with lower levels of dementia biomarkers, according to new research. The findings add to accumulating evidence that the choice of blood pressure medication may influence dementia risk.

In a prospective study using the 45 and Up Study cohort, researchers included participants aged ≥ 45 years with hypertension who initiated either BBB-crossing or non-crossing antihypertensive medications (AHMs) between January 2004 and June 2022. They were followed from the index date until dementia diagnosis, death, or 30 June 2023. After propensity matching, 66,610 participants were included (mean age 66.9 years; 53.2% women; mean follow-up 11.9 years). Compared with non-BBB-crossing AHMs, use of BBB-crossing AHMs was associated with a lower risk of new-onset dementia (HR, 0.84; 95% CI 0.80–0.88), all-cause mortality (HR, 0.83; 95% CI 0.82–0.86), and dementia-related mortality (HR, 0.85; 95% CI 0.79–0.92). Subgroup analyses revealed a significant reduction in dementia risk for both females and males, with no significant sex interaction (p = 0.067). Based on the AHM class, only angiotensin II receptor blockers (HR, 0.89; 95% CI 0.80–0.99) and β-blockers (HR, 0.76; 95% CI 0.63–0.93) were found to significantly reduce the risk of dementia. With sensitivity analyses, the dementia-protective effect remained significant after excluding individuals with hypertension identified solely by AHM use (HR, 0.84; 95% CI 0.79–0.89) and when accounting for competing mortality risk (HR, 0.84; 95% CI 0.80–0.89). The findings highlight BBB crossing as a potentially relevant pharmacokinetic property of AHMs influencing dementia prevention, warranting further investigation in randomised controlled trials.

A separate autopsy cohort study published in JAMA Network Open found that angiotensin II receptor stimulating drugs were associated with lower levels of a biomarker for Alzheimer’s disease in several brain regions than drugs that inhibit angiotensin II. The risk reductions ranged from 14% to 21%. Most notably, use of these drugs for 15 years or more was associated with a 24% lower risk for arteriolosclerosis. Angiotensin II is a hormone responsible for controlling blood pressure by constricting blood vessels. The study analyzed data from a cohort of 756 patients (mean age at death, 89.2 years; 93.9% White) who participated in ongoing prospective research that began in 1994 and had since died. Angiotensin II-stimulating drugs were linked to lower levels of several markers of neurodegeneration — including neocortical Lewy bodies and arteriolosclerosis — than angiotensin II-inhibiting drugs. They also observed 14%-21% lower levels of the tau biomarker in those who received the stimulating drugs. No significant differences were observed in amyloid-beta 42, a biomarker for Alzheimer’s disease, between the regimens.

The study author, a professor of medicine at the University of Washington in Seattle, said clinicians should not make prescription choices based on these findings and instead look to future guidelines that might recommend a drug class over another. Last year, the American Heart Association (AHA) and the American College of Cardiology (ACC) issued a new joint guideline for the prevention and management of high blood pressure. They noted that observational studies and clinical trials suggest improved control of systolic blood pressure reduces Alzheimer’s disease and related dementia. They recommended initial first-line medications for treatment of primary hypertension in this patient population but did not recommend specific treatments that could prevent or slow dementia. The chair of the AHA/ACC guideline writing committee said the new study may be useful for generating hypotheses for future clinical trials, but it "is not possible to draw firm conclusions relevant to clinical practice" because of its retrospective nature. Other studies also have found that drugs that stimulate angiotensin II have beneficial effects on the brain, including a 25% lower risk for mild cognitive impairment or probable dementia at 5 years of follow-up. A 2025 systematic review and meta-analysis showed that use of stimulating medications reduced the risk for all-cause dementia by 13% compared with inhibiting antihypertensives.

In related research, the Guidelines for the Management of Elevated Blood Pressure and Hypertension 2025 (JSH2025) were published in August 2025. The number of PubMed articles found by searching for "high blood pressure" and "dementia" reached nearly 800 last year and has already exceeded 220 this year (as of the end of March). Reports indicate that blood pressure variability, rather than absolute blood pressure levels, is gaining attention as a factor inducing dementia. A study conducted across 116 regions in China followed hypertensive patients at risk for cardiovascular disease for three years, comparing a group receiving very intensive antihypertensive treatment targeting systolic blood pressure below 120 mmHg with a group receiving standard treatment targeting below 140 mmHg. The results showed that, regardless of age, sex, blood pressure levels, or comorbidities, the intensive treatment strategy did not adversely affect the overall cognitive function of adults with hypertension. An analysis of data from the Health and Retirement Study involving 11,835 participants, of whom 1136 developed dementia, showed that hypertensive patients who continuously took antihypertensive medications during the follow-up period had a 27% lower risk of dementia compared to those with low medication adherence. Using data from the ADVANCE study, researchers demonstrated that in patients with type 2 diabetes, increased blood pressure variability and baseline pulse pressure—rather than mean BP or BP load—were associated with an increased risk of cognitive decline and dementia. A prospective study of more than 3,200 community-dwelling older adults showed that those who used antihypertensive medications during the study period experienced a slower decline in cognitive function, particularly in episodic and semantic memory, compared to those who did not use them. Antihypertensive medication use was also associated with a reduction in paired helical filament-positive tau tangles. An evaluation of four multicenter randomized controlled trials (Syst-Eur, PROGRESS, SCOPE, and HYVET-COG) involving 16,685 elderly individuals with hypertension who did not have dementia at baseline found that antihypertensive therapy significantly improved cognitive function scores and showed a trend toward a lower incidence of dementia, although this was not statistically significant. In an exploratory network meta-analysis, calcium channel blockers showed the highest rating for dementia prevention.