For those patients that need Rx therapy of a high LDL-cholesterol after lifestyle changes have been followed, our approach at the Kahn Center is a very low dose statin along with ezetimibe (Zetia) along with CoQ10. In many cardiology practices, ezetimibe is an infrequent Rx but at the Kahn Center, 1000s of patients are followed on this Rx.
New data suggests there are important benefits in reducing the risk of Alzheimer's Disease and related dementias (ADRD).
Numerous factors predispose to progression of cognitive impairment to ADRD, most notably age, APOE(ε4) alleles, traumatic brain injury, heart disease, hypertension, obesity/diabetes, and Down's syndrome. Protein aggregation is diagnostic for neurodegenerative diseases, and may be causal through promotion of chronic neuroinflammation.
The authors isolated aggregates from postmortem hippocampi of ADRD patients, heart-disease patients, and age-matched controls. 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.
Screening the hexokinase-1::14-3-3G interface with FDA-approved drug structures predicted strong affinity for ezetimibe, a benign 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.
Mining clinical databases supports drug reduction of ADRD risk, decreasing it by 86% overall and 88% lower in high-risk heart-disease subjects.
These results suggest that drug disruption of the 14-3-3G::HK1 interface with the "benign" cholesterol inhibition Rx ezetimibe blocks an early "lynchpin" adhesion, prospectively reducing aggregate accrual and progression of ADRD.
Ezetimibe is a safe and inexpensive approach to lower LDL-C in those that need Rx therapy. When added to a statin or other cholesterol lowering medication, it provides a proven path to excellent lab values and low risk.
Now, these new data, make ezetimibe even more attractive as a first line approach.
