LITTLE ROCK, AR — The mechanism through which heart disease elevates the risk of Alzheimer’s disease and related dementia (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,” wrote researchers from the University of Arkansas for Medical Sciences and the Central Arkansas Veterans Healthcare System in Little Rock.
The study team explained in the Aging Biology journal that many factors predispose to progression of cognitive impairment to Alzheimer’s disease and related dementias (ADRD). Among those are age, APOE(ε4) alleles, traumatic brain injury, heart disease, hypertension, obesity/diabetes and Down syndrome.1
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 articles 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<0.008), and their interaction was implied by extensive crosslinking in both disease groups.”
By screening the hexokinase-1::14-3-3G interface with Food and Drug Administration-approved drug structures, the study team found they predicted strong affinity for ezetimibe, a common non-statin 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<0.0001; 95% C.I. 0.06-0.34), and <0.12 in high-risk heart-disease subjects (P<0.006). 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.”
- Ganne A, Mainali N, Balasubramaniam M, Atluri R, et. Al. Ezetimibe Lowers Risk of Alzheimer’s and Related Dementias over Sevenfold, Reducing Aggregation in Model Systems by Inhibiting 14-3-3G::Hexokinase Interaction. Aging Biol. 2024;2:20240028. doi: 10.59368/agingbio.20240028. Epub 2024 Jun 26. PMID: 39263528; PMCID: PMC11389752.