Hippocampal Neurogenesis in Alzheimer’s Disease: Multimodal Therapeutics and the Neurogenic Impairment Index Framework

Abstract

Alzheimer’s disease (AD) is characterized by progressive cognitive decline strongly associated with impaired adult hippocampal neurogenesis (AHN). Mounting evidence suggests that this impairment results from both the intrinsic dysfunction of neural stem cells (NSCs)—such as transcriptional alterations in quiescent states—and extrinsic niche disruptions, including the dysregulation of the Reelin signaling pathway and heightened neuroinflammation. Notably, AHN deficits may precede classical amyloid-β and Tau pathology, supporting their potential as early biomarkers of disease progression. In this review, we synthesize recent advances in therapeutic strategies aimed at restoring AHN, encompassing pharmacological agents, natural products, and non-pharmacological interventions such as environmental enrichment and dietary modulation. Emerging approaches—including BDNF-targeted nanocarriers, NSC-derived extracellular vesicles, and multimodal lifestyle interventions—highlight the translational promise of enhancing neurogenesis in models of familial AD. We further propose the Neurogenesis Impairment Index (NII)—a novel composite metric that quantifies hippocampal neurogenic capacity relative to amyloid burden, while adjusting for demographic and cognitive variables. By integrating neurogenic potential, cognitive performance, and pathological load, NII provides a framework for stratifying disease severity and guiding personalized therapeutic approaches. Despite ongoing challenges—such as interspecies differences in neurogenesis rates and the limitations of stem cell-based therapies—this integrative perspective offers a promising avenue to bridge mechanistic insights with clinical innovation in the development of next-generation AD treatments.