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Mounting evidence suggests that this impairment results from both the intrinsic dysfunction of neural stem cells (NSCs)\u2014such as transcriptional alterations in quiescent states\u2014and extrinsic niche disruptions, including the dysregulation of the Reelin signaling pathway and heightened neuroinflammation. Notably, AHN deficits may precede classical amyloid-\u03b2 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\u2014including BDNF-targeted nanocarriers, NSC-derived extracellular vesicles, and multimodal lifestyle interventions\u2014highlight the translational promise of enhancing neurogenesis in models of familial AD. We further propose the Neurogenesis Impairment Index (NII)\u2014a 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\u2014such as interspecies differences in neurogenesis rates and the limitations of stem cell-based therapies\u2014this integrative perspective offers a promising avenue to bridge mechanistic insights with clinical innovation in the development of next-generation AD treatments.<\/jats:p>","DOI":"10.3390\/ijms26136105","type":"journal-article","created":{"date-parts":[[2025,6,26]],"date-time":"2025-06-26T06:55:13Z","timestamp":1750920913000},"page":"6105","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Hippocampal Neurogenesis in Alzheimer\u2019s Disease: Multimodal Therapeutics and the Neurogenic Impairment Index Framework"],"prefix":"10.3390","volume":"26","author":[{"given":"Li","family":"Ma","sequence":"first","affiliation":[{"name":"Research Center for Natural Peptide Drugs, Shaanxi Engineering & Technological Research Centre for Conservation & Utilization of Regional Biological Resources, Yanan University, Yanan 716000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Wei","sequence":"additional","affiliation":[{"name":"Research Center for Natural Peptide Drugs, Shaanxi Engineering & Technological Research Centre for Conservation & Utilization of Regional Biological Resources, Yanan University, Yanan 716000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5220-0800","authenticated-orcid":false,"given":"Ming","family":"Jiang","sequence":"additional","affiliation":[{"name":"Research Center for Natural Peptide Drugs, Shaanxi Engineering & Technological Research Centre for Conservation & Utilization of Regional Biological Resources, Yanan University, Yanan 716000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanyan","family":"Wu","sequence":"additional","affiliation":[{"name":"Research Center for Natural Peptide Drugs, Shaanxi Engineering & Technological Research Centre for Conservation & Utilization of Regional Biological Resources, Yanan University, Yanan 716000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xia","family":"Liu","sequence":"additional","affiliation":[{"name":"Research Center for Natural Peptide Drugs, Shaanxi Engineering & Technological Research Centre for Conservation & Utilization of Regional Biological Resources, Yanan University, Yanan 716000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8456-4476","authenticated-orcid":false,"given":"Qinghu","family":"Yang","sequence":"additional","affiliation":[{"name":"Research Center for Natural Peptide Drugs, Shaanxi Engineering & Technological Research Centre for Conservation & Utilization of Regional Biological Resources, Yanan University, Yanan 716000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhantao","family":"Bai","sequence":"additional","affiliation":[{"name":"Research Center for Natural Peptide Drugs, Shaanxi Engineering & Technological Research Centre for Conservation & Utilization of Regional Biological Resources, Yanan University, Yanan 716000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6653-4812","authenticated-orcid":false,"given":"Liang","family":"Yang","sequence":"additional","affiliation":[{"name":"Research Center for Natural Peptide Drugs, Shaanxi Engineering & Technological Research Centre for Conservation & Utilization of Regional Biological Resources, Yanan University, Yanan 716000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1016\/S0140-6736(20)32205-4","article-title":"Alzheimer\u2019s Disease","volume":"397","author":"Scheltens","year":"2021","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.stem.2023.01.002","article-title":"Adult Hippocampal Neurogenesis in Alzheimer\u2019s Disease: A Roadmap to Clinical Relevance","volume":"30","author":"Salta","year":"2023","journal-title":"Cell Stem Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1038\/s41591-019-0375-9","article-title":"Adult Hippocampal Neurogenesis Is Abundant in Neurologically Healthy Subjects and Drops Sharply in Patients with Alzheimer\u2019s Disease","volume":"25","author":"Cafini","year":"2019","journal-title":"Nat. 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