Common drug for cardiac failure jams a debated blood test for Alzheimer's disease

Alzheimer's disease (AD) is associated with damaging protein aggregates in the brain, with beta-amyloid aggregates called plaques being the key pathology. Entresto (sacubitril/valsartan) is a combined neprilysin inhibitor and angiotensin receptor blocker, approved for the treatment of heart failure.

Concerns were raised by the FDA that this neprilysin inhibition treatment may increase the risk of AD, since neprilysin is one of the main enzymes responsible for degrading Aβ in the brain. The PERSPECTIVE trial (NCT02884206) showed that 3-year neprilysin inhibition treatment was not associated with increased Aβ accumulation, determined by PET, or with cognitive deterioration, which was reassuring.

This study assessed the effect of 52 weeks of treatment with a combination of the neprilysin inhibitor sacubitril and the angiotensin receptor blocker valsartan (sacubitril/valsartan, Entresto) vs. valsartan alone on AD blood biomarkers in a clinical trial (NCT035525575) on 92 patients with cardiac failure. At week 26, and persisting at week 52, both plasma Aβ42 and Aβ40 markedly increased upon neprilysin inhibition.

Importantly, this study highlights that a commonly used treatment in the elderly confounds the plasma Aβ ratio, a debated AD blood test. In fact, sacubitril/valsartan treatment impacted the plasma Aβ42/Aβ40 ratio more than 3-fold (>30% reduction) more than the mean change seen in AD patients (~10% reduction).

Reference: Common drug for cardiac failure jams a debated blood test for Alzheimer’s disease; JAMA Neurology; DOI: 10.1001/jamaneurol.2023.4719