Hiding in Plain Sight: FDA-Approved Cholesterol Drug Ezetimibe as a Treatment for Alzheimer’s

Age is the most prominent nongenetic risk factor for Alzheimer's disease (AD), with incidence doubling every 5 years beyond age 65.Protein aggregation is one of the most consistent features of age-progressive diseases, as well as normal aging.Many age-associated diseases add disease-specific aggregates on top of those observed in the healthy aged-including essentially all neurodegenerative diseases, diverse myopathies, lung disease, and chronic kidney disease.Such data are consistent with, but do not prove, the hypothesis that aggregation may be a common mechanism driving both aging and the numerous pathologies that accompany it.A new study by Ganne et al. 1 reports that ezetimibe, a drug they had selected for its disruption of aggregates in silico and in diverse preclinical models of age-and Alzheimer'sassociated pathology, reduced the prospective risk of Alzheimer's Disease and Related Dementias (ADRD) by sevenfold in the general population and eightfold among heartdisease patients for whom the risk of subsequent ADRD was roughly doubled.Ezetimibe was approved by the FDA in 2002 for reduction of circulating cholesterol levels.The authors note that, while the controls (nearly 1 million subjects not taking ezetimibe) were well matched to ezetimibe recipients for age, gender, and established ADRD risk factors such as hypertension, diabetes, and kidney disease, the groups were not matched for cholesterol levels.It would not be unreasonable to assume that the patients prescribed ezetimibe had initiated it due to relatively high serum cholesterol levels, so these researchers point out that double-blind randomized trials of newly enrolled patients would have to be conducted to establish a causal connection.There is ample evidence that high LDL-cholesterol increases AD risk 2,3 , suggesting that statins could achieve the greatest risk reduction among such patients.