Neprilysin Inhibition Using Sacubitril and Valsartan Increases Alzheimer Biomarker Levels of Aß42, Aß40

Author(s):

Over a year period on the combination agent, patients showed significantly amplified Aß42 and Aß40 levels with no significant differences in other biomarkers of ptau, GFAP, or neurofilament light.

Wagner S. Brum

A recently published post-hoc exploratory analysis showed that long-term treatment with sacubitril/valsartan, a neprilysin inhibitor and angiotensin receptor blocker used for heart failure, resulted in increases in plasma amyloid-ß(Aß)42 and Aß40 pathology. The investigators wrote that these changes should not alarm clinicians and that the study highlights the agent’s potential to confound plasma Aß42/Aß40 tests for Alzheimer disease (AD).¹

Published in JAMA Neurology, the post-hoc analysis featured 92 patients from the RECOVER-LV trial (NCT03552575), a double-blind trial that compared sacubitril/valsartan vs valsartan in patients with coronary heart disease. Led by Wagner S. Brum, an MD/PhD student at the University of Gothenberg, the new findings showed significant increases in plasma Aß42 and Aß40 in the sacubitril/valsartan compared with the valsartan group at 26 weeks that persisted up to the 52-week time point (Aß42, 30.7% [95% CI, 23.7-38.0]; P <.001; Aß40, 93.0% [95% CI, 81.3-105.5; P <.001).

Additional findings showed a decrease in Aß42/Aß40 ratio at 26 weeks that persisted at the 52-week final time point (–31.7%; 95% CI, –34.1% to –29.1%; P <.001). "This pattern of Aβ42/Aβ40 reduction (increases in both peptides) differs from AD, wherein Aβ42/Aβ40 is reduced, reflecting pathologic decreases of Aβ42 and unchanged Aβ40 levels,” Brum et al wrote.¹ "Our findings align with a pharmacokinetic study showing that sacubitril/valsartan did not alter cerebrospinal fluid Aβ42 or Aβ40 levels in healthy volunteers but consistently increased plasma Aβ40 levels with a less sensitive immunoassay."

The cohort was largely comprised of men (91.3%); however, it was noted that 3 female participants randomized to sacubitril/valsartan also experienced reductions in plasma Aß42/Aß40. Additionally, other biomarkers such as phosphorylated tau 217 and 181, glial fibrillary acidic protein, and neurofilament light, were not significantly changed through treatment, which the study authors wrote was “reassuring.”

"Given the frequent co-occurrence of heart disease and cognitive impairment and increasing clinical availability of plasma Aβ42/Aβ40 tests, results for patients receiving sacubitril/valsartan should be interpreted cautiously; treatment-related Aβ42/Aβ40 reductions may lead to false-positive results and misclassification of Aβ positivity as being AD,” the study authors added.¹ "This drug interaction contraindication for an AD blood test underscores the importance of considering potential confounders, especially in patients with comorbidities, such as for p-tau and kidney disease, and suggests that a multibiomarker assessment may better control for factors affecting individual biomarker classes.”

Sacubitril/valsartan is among a new class of drugs called angiotensin receptor neprilysin inhibitors. The medication is FDA-approved to treat patients with chronic heart failure with reduced ejection fraction with NYHA class 2, 3, or 4. Its typically used in place of an ACEI or angiotensin II receptor blocker and in conjunction with other standard heart-failure treatments such as beta-blockers and aldosterone antagonist.

RECOVER-LV, a prospective, double-blind, active comparator trial conducted from July 2018 to June 2019, compared sacubitril/valsartan 97/103 mg twice daily with valsartan 160 mg twice daily. The primary outcome, change in LV end-systolic volume index, showed no significant between-group difference (–1.9 mL/m2; 95% CI, –4.8 to 1.0; P = .19). Additional findings demonstrated no significant between-group differences in NT-proBNP, high-sensitivity cardiac troponin I, LV end-diastolic volume index, left atrial volume index, LV ejection fraction, LV mass index, or patient global assessment of change.²

REFERENCES
1. Brum WS, Dochety KF, Ashton NJ, et al. Effect of neprilysin inhibition on Alzheimer disease plasma biomarkers: a secondary analysis of a randomized clinical trial. JAMA Neurol. Published online December 18, 2023. doi:10.1001/jamaneurol.2023.4719
2. Docherty KF, Campbell RT, Brooksbank KJM, et al. Effect of neprilysin inhibition on left ventricular remodeling in patients with asymptomatic left ventricular systolic dysfunction late after myocardial infarction. Circulation. 2021;144:199-209. doi:10.1161/CIRCULATIONAHA.121.054892