A clinical study has shown that sacubitril/valsartan (Entresto), a drug commonly used for heart failure, significantly alters the plasma Aβ ratio used in Alzheimer’s disease blood tests, potentially leading to false positive diagnoses in patients.

Alzheimer’s disease is associated with damaging protein aggregates in the brain, with Aβ aggregates called plaques being the key pathology. Entresto is a combined neprilysin inhibitor and angiotensin receptor blocker, approved for the treatment of heart failure. Concerns were raised by the US Food and Drug Administration (FDA) that this neprilysin inhibition treatment may increase the risk of Alzheimer’s disease since neprilysin is one of the main enzymes responsible for degrading Aβ in the brain. 

The PERSPECTIVE trial showed that three-year neprilysin inhibition treatment was not associated with increased Aβ accumulation, determined by PET, or with cognitive deterioration, which was reassuring.

The initiation of disease-modifying treatments (anti-amyloid immunotherapies) warrants exact diagnostic tests to verify the presence of brain amyloidosis. While FDA-approved cerebrospinal fluid (CSF) and PET methods are available, less invasive and more accessible screening tests would simplify the diagnostic work-up and patient management. 

A blood test called plasma Aβ ratio has in research studies been found to have a high performance to detect brain amyloidosis, and this test is today offered for clinical use in patients with cognitive impairment in the US. However, the “fold change” (difference in plasma Aβ values between Alzheimer’s disease patients and healthy elderly) is very minor, with only around 10-12% reduction in Alzheimer’s disease. 

This is likely due to that Aβ in blood largely comes from peripheral tissues, which blurs the brain signal. The small fold change indicates poor clinical robustness of this test, which has led to a debate on whether it is suitable for clinical use or not.

This study, published in JAMA Neurology, 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) versus valsartan alone on Alzheimer’s disease 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. 

However, the increase was more pronounced for Aβ40 than for Aβ42 resulting in a 32-34% reduction in the plasma Aβ ratio, ie, making sacubitril/valsartan-treated patients falsely positive on the plasma Aβ test. This marked change was found in all patients on Entresto. No changes were found in other Alzheimer’s disease blood biomarkers (pTau217, pTau181, GFAP or NFL).

Importantly, this study highlights that a commonly used treatment in the elderly confounds the plasma Aβ ratio, a debated Alzheimer’s disease 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 Alzheimer’s disease patients (~10% reduction). There are more than 5 million people in the US with Alzheimer’s disease and around the same number with heart failure. Importantly, about 40% of patients with heart failure also present cognitive impairment, making them potentially eligible for taking the Aβ blood test.

Plasma Aβ42/Aβ40 tests are available clinically in the US. The authors therefore recommend caution when interpreting the results in patients receiving sacubitril/valsartan, as the observed reduction in the ratio could lead to misclassification of patients as Aβ plaque-positive (and thus having Alzheimer’s disease). Further, from a scientific perspective, these findings call for a re-evaluation of published papers on plasma Aβ tests, to adjust results after removal of potential false positives (patients on Entresto). 

From a clinical perspective and for ethical reasons, these findings also suggest that patients who have had a plasma Aβ test in clinical routine should be contacted to clarify whether they were on Entresto treatment at the time of blood sampling and thus may have had a false positive test result.

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