A narrative review of aging-targeted mechanisms and interventions in Alzheimer’s disease

Abstract

Background & Objective: The biggest risk factor for Alzheimer’s disease (AD) is aging, contributing to impaired clearance of tau and amyloid-beta (Aβ) proteins, microglial senescence, endoplasmic reticulum (ER) stress, lipid dysregulation, and excitotoxicity. This review investigates how aging speeds up the pathophysiology of AD and evaluates emerging geroscience-based interventions targeting biological aging mechanisms to delay or prevent cognitive decline.

Methods: A narrative review of the literature from 2015 to 2025 was conducted, integrating longitudinal studies, meta-analyses, and preclinical models that examine the aging-AD interface. The MEDLINE, Embase, Cochrane, Google Scholar, and PubMed databases were searched using specifically related keywords, such as ageing, AD, AD pathology, anti-aging strategies, and AD therapies.

Results: An initial search identified 320 publications. After screening for relevance and removing duplicates, 220 studies were excluded and 30 duplicates removed, leaving 72 eligible studies for synthesis in this narrative review. These included preclinical, clinical, and meta-analytic data examining aging mechanisms and geroscience-based interventions in Alzheimer’s disease. Most of these studies discussed aging-related mechanisms—glymphatic dysfunction, APOE ε4-associated lipid transport impairment, BDNF depletion, and glutamate excitotoxicity—, and anti-ageing strategies such as lifestyle interventions (e.g., physical activity, sleep optimization, cognitive engagement) and medical and biological therapies for AD.

Conclusion: Targeting aging mechanisms offers a paradigm shift in AD prevention and treatment; however, multidisciplinary collaboration is essential to translate geroscience into clinical practice. The integration of lifestyle and pharmacological strategies may yield synergistic neuroprotective benefits. Future research should focus on integrated, multimodal interventions that combine lifestyle modification with pharmacological and biological therapies. Tailored approaches—based on genetic risk profiles (e.g., APOE status), comorbidities, and individual aging trajectories—may optimize clinical outcomes. To evaluate the long-term safety and effectiveness of innovative treatments like senolytics, epigenetic modulators, and stem cell-based therapies in older populations, extensive, longitudinal clinical trials are also required. Developments in biological age biomarkers, machine learning, and systems biology have the potential to improve risk assessment and therapy customization.