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Review
. 2024 Aug 1;16(1):177.
doi: 10.1186/s13195-024-01547-z.

Association between treatment with sacubitril/valsartan and the risk of Alzheimer's disease: a clinical update

Antoine Garnier-Crussard  1   2
Affiliations
Review

Association between treatment with sacubitril/valsartan and the risk of Alzheimer's disease: a clinical update

Antoine Garnier-Crussard. Alzheimers Res Ther. .

Abstract

Since 2014, sacubitril/valsartan (Entresto®) is widely prescribed for heart failure. Despite neprilysin inhibition's benefits in heart failure, concerns about potential amyloid-beta (Aβ) accumulation and Alzheimer's disease (AD) risk have persisted. This narrative review, a decade post-approval, evaluates the risk of amyloid pathology and neurocognitive disorders in long-term sacubitril/valsartan use. Clinical trials, real-world studies, and pharmacovigilance data do not indicate an increased risk of cognitive decline. In patients treated with sacubitril/valsartan blood-based amyloid biomarkers show perturbations, while neuroimaging biomarkers reveal no significant increase in amyloid load. Despite a theoretical risk of amyloid accumulation and AD under treatment with sacubitril/valsartan, current clinical data appears reassuring, and there is no signal indicating an increased risk of cognitive decline, but a perturbation of amyloid blood-based biomarkers, which implies great caution when interpreting biomarkers in this context.

Keywords: Alzheimer; Amyloid; Entresto; LCZ696; Neprilysin; Sacubitril/valsartan.

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Conflict of interest statement

Independent of this work, AGC is an unpaid sub-investigator or principal investigator Alzheimer’s disease clinical trials: NCT04867616 (UCB Pharma), NCT04241068 (Biogen), NCT05310071 (Biogen), NCT03446001 (TauRx Therapeutics), NCT03444870 (Roche), NCT04374253 (Roche), NCT04777396 (Novo Nordisk), NCT04777409 (Novo Nordisk), NCT04770220 (Alzheon), NCT05423522 (Medesis Pharma).

Figures

Fig. 1
Fig. 1
Summary of the effect of sacubitril/valsartan and AD risk. Neprilysin inhibition (sacubitril) may lead to both a potential and theoretical protective pathway (e.g., enhancing neuroprotective neuropeptide Y (NPY), substance P (SP), and glucagon-like peptide 1 (GLP-1), and improving heart function - green text in the figure) and a pathway potentially/theoretically increasing the risk of AD (e.g., reducing Aβ clearance, elevating bradykinin (BK), and natriuretic peptides (NP)… - orange text in the figure) [7]. To date, there is no clinical evidence in humans indicating an elevated risk of cognitive decline or Alzheimer’s disease during treatment, but there are alterations in amyloid blood-based biomarkers (blue text in the figure). Image Heart & Brain generated/drawn by AI (https://www.craiyon.com), and edited by A.G-C.
See this image and copyright information in PMC

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