Antihypertensives Tied to Lower Alzheimer’s Pathology


Certain antihypertensive medications, particularly diuretics, are linked to lower Alzheimer’s disease neuropathology (ADNP) and other brain disease processes, new research shows.

Investigators found that use of any antihypertensive was associated with an 18% decrease in ADNP, a 22% decrease in Lewy bodies (LBs), and a 40% decrease in TAR DNA-binding protein 43 (TDP-43), a protein relevant to several neurodegenerative diseases. Diuretics in particular appear to be driving the association.

Although diuretics might be a better option for preventing brain neuropathology, it’s too early to make firm recommendations solely on the basis of these results as to what blood pressure–lowering agent to prescribe a particular patient, study investigator Ahmad Sajjadi, MD, assistant professor of neurology, University of California, Irvine, told Medscape Medical News.

“This is early stages and preliminary results,” said Sajjadi, “but it’s food for thought.”

The findings were presented at the ANA 2021: 146th Annual Meeting of the American Neurological Association, which was held online

Autopsy Data

The study included 3315 individuals who had donated their brains to research. The National Alzheimer’s Coordinating Center maintains a database that includes data from 32 AD research centers in the United States. Participants in the study must have visited one of these centers within 4 years of death. Each person whose brain was included in the study underwent two or more blood pressure (BP) measurements on at least 50% of visits.

The mean age at death was 81.7 years, and the mean time between last visit and death was 13.1 months. About 44.4% of participants were women, 57.0% had at least a college degree, and 84.7% had cognitive impairment.

Researchers defined hypertension as systolic BP (SBP) ≥130 mm Hg, diastolic BP (DBP) ≥80 mm Hg, mean arterial pressure (MAP) ≥100 mm Hg, and pulse pressure (PP) ≥60 mm Hg.

Antihypertensive medications that were evaluated included antiadrenergic agents, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers (ARBs), beta blockers, calcium channel blockers, diuretics, vasodilators, and combination therapies.

The investigators assessed the number of neuropathologies. In addition to ADNP, which included amyloid beta, tau, LB, and TDP-43, they also assessed for atherosclerosis, arteriolosclerosis, cerebral amyloid angiopathy, frontotemporal lobar degeneration (FTLD), and hippocampal sclerosis (HS).

Results showed that use of any antihypertensive was associated with a lower likelihood of ADNP (odds ratio [OR], 0.822), LB (OR, 0.786), and TDP 43 (OR, 0.597). Use of antihypertensives was also associated with increased odds of atherosclerosis (OR, 1.217) (all P < .5.)

The study showed that hypertensive SBP was associated with higher odds of ADNP (OR, 1.28; P < .5).

Differences by Drug Type

Results differed in accordance with antihypertensive class. ARBs decreased the odds of FTLD by 40% (OR, 0.60; P < .5). Diuretics decreased the odds of AD by 36% (OR, 0.64; P < .001) and of HS by 32% (OR, 0.68; P < .5).

“We see diuretics are a main driver, especially for lower odds of AD and lower odds of HS,” said lead author Hanna L. Nguyen, first-year medical student at the University of California, Irvine.

The results indicate that it is the medications, not blood pressure levels, that account for these associations, she added.

One potential mechanism linking antihypertensives to brain pathology is that with these agents, blood pressure is maintained in the target zone. Blood pressure that’s too high can damage blood vessels, whereas blood pressure that’s too low may result in less than adequate perfusion, said Nguyen.

These medications may also alter pathways leading to degeneration and could, for example, affect the APOE mechanism of AD, she added.

The researchers plan to conduct subset analyses using APOE genetic status and age of death.

Although this is a “massive database,” it has limitations. For example, said Sajjadi, it does not reveal when patients started taking blood pressure medication, how long they had been taking it, or why.

“We don’t know the exact the reason they were taking these medications. Was it just hypertension, or did they also have heart disease, stroke, a kidney problem, or was there another explanation,” he said.

Following the study presentation, session co-moderator Krish Sathian, MBBS, PhD, professor of neurology, neural and behavioral sciences, and psychology and director of the Neuroscience Institute, Penn State University College of Medicine, Hershey, Pennsylvania, called this work “fascinating. It provides a lot of data that really touches on everyday practice,” inasmuch as clinicians often prescribe antihypertensive medications and see patients with these kinds of brain disorders, he said.

The investigators and Sathian report no relevant financial relationships.

ANA 2021: 146th Annual Meeting of the American Neurological Association: Abstract 375. Presented October 18, 2021.

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