APOEε4: Why Alzheimer's "Prophet" Struggles To Become A Therapeutic "Savior"

While APOEε4 remains the most significant genetic risk factor for late-onset Alzheimer’s Disease (AD), its transition from a predictive biomarker to a viable therapeutic target has been stalled by mechanistic complexity and the "too-late" paradox of clinical intervention. Current drug development is hindered by the challenge of inhibiting the allele’s toxic gain-of-function, including impaired $A\beta$ clearance and neuroinflammation, without disrupting essential lipid transport and blood-brain barrier maintenance.

This article explores the shift toward precision intervention, analyzing emerging strategies such as CRISPR-Cas9 gene reprogramming, AAV-based gene therapies like LX1001, and small-molecule structure correctors designed to stabilize APOEε4 into an ε3-like conformation. We examine how integrating multi-omics with early-stage stratification can capture the "golden window" of preclinical intervention. Read further to learn more about the latest advancements in gene silencing, protein regulation, and pathway integration strategies essential for modern AD drug pipelines.