Alzheimer's Disease: From Molecular Pathogenesis to Disease-Modifying Therapies and Clinical Implementation in Aging...

Alzheimer's disease (AD) is the leading cause of dementia worldwide, disproportionately affecting individuals over 65 years of age and imposing a rapidly escalating burden on healthcare systems and caregivers globally. For decades, management relied on symptomatic agents-cholinesterase inhibitors and memantine-that provide modest cognitive benefits without altering disease progression. The recent approvals of the anti-amyloid monoclonal antibodies lecanemab (2023) and donanemab (2024) represent a paradigm shift, offering the first therapies that modestly but significantly slow clinical decline by targeting the underlying amyloid-β pathology. However, these advances are accompanied by important safety concerns, particularly amyloid-related imaging abnormalities, substantial costs, and unresolved questions regarding long-term clinical meaningfulness and equitable access. This comprehensive review synthesizes current knowledge across the full spectrum of AD, encompassing molecular pathophysiology (amyloid cascade, tau hyperphosphorylation, and neuroinflammation), genetic architecture (familial mutations and APOE-mediated risk), evolving biomarker-based diagnostic frameworks, established symptomatic treatments, and newly approved disease-modifying agents. We further examine emerging therapeutic strategies, including tau-targeted therapies, neuroinflammation-directed approaches, multi-target and combination strategies, drug delivery innovations, and prevention trials in preclinical populations. Throughout, we critically evaluate the evidence, acknowledging controversies and limitations while identifying promising future directions. Importantly, integrating these diagnostic and genetic advances into geriatric care settings presents unique implementation challenges, as aging populations often face comorbidities, polypharmacy, and limited access to specialized diagnostic infrastructure. As AD therapeutics enter a new era, integrating pharmacological interventions with biomarker-guided patient selection, rigorous safety monitoring, and modifiable risk factor management will be essential for optimizing outcomes in aging populations.