Alzheimer’s Disease in the Era of Geroscience: Mechanisms, Biomarkers, and Therapeutic Prospects

Abstract

Alzheimer’s disease (AD) is the leading cause of dementia and a heterogeneous neurodegenerative disorder characterized by amyloid-β (Aβ) and tau pathology, impaired proteostasis, neurovascular dysfunction, maladaptive glial and immune responses, and synaptic dysfunction. Human genetic evidence supports an upstream role for Aβ. Anti-Aβ monoclonal antibodies substantially reduce amyloid burden and modestly slow clinical decline in early symptomatic AD. Continued decline despite plaque removal is consistent with ongoing downstream tau pathology, glial responses, and neuronal injury. This narrative review examines AD mechanisms, biomarkers, and therapeutic prospects from a geroscience perspective and applies the eight hallmarks of neurodegenerative diseases as an analytical framework. Advances in blood-based biomarkers, particularly plasma phosphorylated tau 217, may improve biological detection, but their clinical value depends on assay performance, intended use, and patient context. Gut dysbiosis and gut–brain communication are considered separately as candidate systemic modifiers because causal evidence in humans remains insufficient. The hallmarks are overlapping analytical categories, not independent primary causes, and their therapeutic relevance depends on disease stage and pathway activity. Future studies should establish which preventive strategies and biomarker-guided, stage-matched combination therapies improve clinically meaningful outcomes and identify the patients most likely to benefit.