Published October 2, 2024 News and Trends Cholesterol Drug Shows Promise for Preventing Alzheimer’s Disease Little Rock, AR—Could taking ezetimibe, which inhibits the absorption of cholesterol in the intestines, also lower the risk of Alzheimer’s disease and related dementias (ADRD)? A new study suggested that could be the case.The mechanism through which heart disease elevates the risk of ADRD has been investigated intensively. It is known that cardiac aging and myocardial infarction (MI) can increase reactive oxygen species (ROS), implicated in the etiology of chronic inflammation and ADRD.Furthermore, inflammatory serum markers are elevated in AD and neuro-inflammation is a common sequela of MI, according to a recent study.“These features suggest early roles of inflammation in both MI and AD. Age-associated chronic inflammation, even of moderate severity, contributes to protein aggregation in and around neurons, which in turn augments neuro-inflammation, creating a positive-feedback loop or vicious cycle,” the researchers from the University of Arkansas for Medical Sciences in Little Rock wrote.The study team explained in the Aging Biology journal that many factors predispose to progression of cognitive impairment to ADRD. Among those are age, APOE(ε4) alleles, traumatic brain injury, heart disease, hypertension, obesity/diabetes, and Down’s syndrome.Because protein aggregation is diagnostic for neurodegenerative diseases and could be causal through promotion of chronic neuroinflammation, the researchers isolated aggregates from postmortem hippocampi of ADRD patients, heart disease patients, and age-matched controls.The article emphasized that aggregates “characterized by high-resolution proteomics (with or without crosslinking), were significantly elevated in heart-disease and ADRD hippocampi. Hexokinase-1 (HK1) and 14-3-3G/γ proteins, previously implicated in neuronal signaling and neurodegeneration, are especially enriched in ADRD and heart disease aggregates vs. controls (each P <.008), and their interaction was implied by extensive crosslinking in both disease groups.”By screening the HK1::14-3-3G interface with FDA-approved drug structures, the study team found they predicted strong affinity for ezetimibe, a common nonstatin cholesterol-lowering medication.“Diverse cultured human-cell and whole-nematode models of ADRD aggregation showed that this drug potently disrupts HK1::14-3-3G adhesion, reduces disease-associated aggregation, and activates autophagy,” the authors wrote. “Mining clinical databases supports drug reduction of ADRD risk, decreasing it to 0.14 overall (P <.0001; 95% C.I. 0.06-0.34), and <0.12 in high-risk heart-disease subjects (P <.006). These results suggest that drug disruption of the 14-3-3G::HK1 interface blocks an early ‘lynchpin’ adhesion, prospectively reducing aggregate accrual and progression of ADRD.”The content contained in this article is for informational purposes only. The content is not intended to be a substitute for professional advice. Reliance on any information provided in this article is solely at your own risk.