EPIGENETIC THERAPY FOR ALZHEIMER’S DISEASE: CURRENT APPROACHES

Abstract

Alzheimer’s disease remains the leading cause of dementia worldwide, and anti-amyloid antibodies, while a genuine milestone, have not closed the gap for most patients. Attention has therefore turned to a second layer of disease biology. The Alzheimer brain carries a reorganised epigenome: DNA methylation is redistributed across the cortex, repressive histone marks accumulate, acetylation at plasticity genes is lost, regulatory elements erode in a cell-type-specific manner, and the non-coding and epitranscriptomic machinery is perturbed. Because these marks are chemically reversible, they are druggable in a way the genome is not. This review surveys the resulting therapeutic strategies: histone deacetylase inhibitors, from pan-selective compounds to agents directed at HDAC2, HDAC3 and HDAC6; acetyltransferase activators and bromodomain inhibitors; sirtuin modulators and nicotinamide adenine dinucleotide precursors; inhibitors of the H3K9 methyltransferases EHMT1 and EHMT2; one-carbon metabolic interventions; programmable epigenome editors built on catalytically dead Cas9; and oligonucleotide and RNA-modification approaches. For each we weigh the mechanistic rationale against what has happened in patients. A consistent pattern emerges: compounds that rescue memory in transgenic mice have underperformed clinically for reasons that are systematic rather than idiosyncratic — inadequate isoform selectivity, poor blood–brain barrier penetration, dose-limiting toxicity, absent target-engagement biomarkers, and intervention at a disease stage that may be too late. We argue that progress now depends less on identifying new epigenetic targets than on solving these translational problems.