28 Dec 2023

Anyone on the heart failure drug Entresto who tests positive for Alzheimer’s disease based on blood Aβ42/40 might not want to panic. That’s because the drug can lower the amyloid ratio three times more than does brain amyloidosis. This is according to scientists led by Kaj Blennow of the University of Gothenburg, Sweden, and John McMurray at the University of Glasgow in the U.K. Alzforum covered these results when Blennow presented them at the Clinical Trials on Alzheimer’s Disease conference last year (Dec 2022 conference news). The paper appeared December 18 in JAMA Neurology.

Entresto combines valsartan, an anti-hypertensive drug, and sacubitril, an inhibitor of neprilysin. The latter degrades Aβ. Might long-term use of Entresto raise the risk of AD? No, according to a Phase 3 trial, which showed that older adults taking Entresto for three years had normal cognition and as much amyloid on PET scans as people taking just valsartan.

But what of peripheral Aβ? Would the drug limit its degradation? To find out, first author Wagner Brum analyzed blood samples from 92 people enrolled in a Phase 3 study of systolic dysfunction after a heart attack. Eighty-four participants were men, and almost all were Caucasian. Half took Entresto; half took valsartan. Brum measured plasma Aβ40 and Aβ42, as well as the other AD biomarkers, including phosphotau-181, p-tau217, glial acidic fibrillary protein (GFAP), and neurofilament light (NfL).

Aβ Up, Ratio Down. In people taking Entresto (green), plasma levels of Aβ42 (left) and Aβ40 (middle) rose while the ratio of Aβ42/40 dropped (right). There was little to no change in either marker in people taking valsartan alone (blue line). [Courtesy of Kaj Blennow, University of Gothenburg.]

Entresto did not change the plasma levels of p-tau181, p-tau217, GFAP, or NfL. However, after taking the drug for 26 weeks, plasma Aβ40 and Aβ42 increased from baseline and remained high after a year on the drug. Aβ40 jumped 93 percent, while Aβ42 rose 32 percent, corresponding to a 32 percent reduction in Aβ42/40 (image above).

This ratio drops only 8 to 14 percent in people with brain amyloid, meaning Entresto could confound blood tests for screening or diagnosis of AD. These data come on the heels of the first direct-to-consumer plasma Aβ42/40 AD test, which hit the market in August (Aug 2023 news). Other blood tests, such as PrecivityAD^TM, are only available at dementia clinics (Dec 2022 conference news).

“Providers of these types of tests may, therefore, interpret and report the results in patients receiving Entresto with caution since a reduction in the Aβ42/40 ratio could lead to misclassification of these patients as Aβ plaque-positive, and thus having AD,” wrote Blennow. He also suggests possibly re-evaluating published papers on plasma Aβ tests to remove people on Entresto and adjust results as needed.—Chelsea Weidman Burke

Comments

1. • Takaomi Saido
     RIKEN Center for Brain Science
   • Posted: 12 Jan 2024

   Nobuhisa Iwata, a former member of my laboratory and currently professor of Nagasaki University, quantified plasma Aβ40 and 42 in wild-type and neprilysin knockout mice. Aβ40 and 42 were 1.6 and 1.7 times higher in the knockout mice, respectively, and the difference was statistically significant. The difference in the Aβ42/40 ratio did not reach statistical significance, presumably due to the deviation of data although the sample size was relatively large (n = 6). Shirotani and colleagues are writing a brief report on this finding.

   In any case, these data indicate that neprilysin inhibition in the cardiovascular system likely affects plasma Aβ levels, and that use of Aβ quantification for diagnosis of preclinical and clinical AD needs to be carefully interpreted.

   View all comments by Takaomi Saido

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References

News Citations

1. Blood Amyloid Test May Help Diagnose Alzheimer’s, but Questions Remain 29 Dec 2022
2. Direct-to-Consumer Alzheimer’s Blood Test Opens Pandora’s Box 31 Aug 2023

External Citations

1. Phase 3 trial
2. Phase 3 study

Further Reading

No Available Further Reading