From genetic roots to recent advancements in gene therapy targeting amyloid beta in Alzheimer's disease.

Abstract

Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders. The pathological hallmarks of AD are amyloid-beta (Aβ) plaques and tau protein tangles, which cause neurodegeneration and lead to cognitive decline. The distinguished role of Aβ plaques in the onset of the disease, especially in familial AD, alongside the genetic complexity of AD, underscores the need for precise and targeted genetic interventions targeting Aβ. This review first highlights the amyloidogenic and non-amyloidogenic pathways and inflammatory mechanisms contributing to Aβ accumulation. It also introduces the role of genetic variants such as amyloid precursor protein (APP), presenilin (PSEN1), PSEN2, and Apolipoprotein E (APOE) alongside the molecular and cellular mechanisms involved in Aβ pathology. Then, gene therapy techniques are discussed for their potential to target Aβ either directly by inhibiting its production or enhancing its degradation or indirectly by targeting APOE, inflammatory pathways, and neurotrophic factors. While these approaches show significant preclinical promise, challenges such as timing, safety, and delivery across the blood-brain barrier persist and need further investigation.