Possible Targets for the Treatment of Alzheimer’s Disease – A Narrative Review

Abstract

Background: Alzheimer’s disease (AD) accounts for 60–70% of dementia cases worldwide, with over 55 million people currently affected and numbers projected to triple by 2050. Despite extensive research, most therapies remain symptomatic, and the global burden continues to rise. Objective: To narratively synthesize recent evidence on approved and investigational therapies for AD, emphasizing mechanisms, efficacy signals, safety, and clinical implementation challenges. Methods: Literature from PubMed/MEDLINE, ClinicalTrials.gov, and FDA/EMA regulatory documents published between 2019 and 2025 was reviewed. Priority was given to pivotal randomized controlled trials, regulatory labels, and high-quality systematic reviews. Data were extracted on mechanisms of action, clinical outcomes, adverse effects, and monitoring requirements, and narratively synthesized. Results: Acetylcholinesterase inhibitors (donepezil, rivastigmine, galantamine) and the NMDA antagonist memantine consistently improve cognitive scores by 1–3 points on standard scales, with benefits lasting 6–12 months before decline resumes. Combination therapy yields marginally greater effects but is limited by tolerability and cost. Aducanumab demonstrated amyloid reduction but failed to show consistent clinical benefit and was discontinued in 2024. In contrast, lecanemab (CLARITY-AD, n≈1800) slowed cognitive decline by ~27% on the CDR-SB over 18 months and achieved FDA approval in 2023, while donanemab (TRAILBLAZER-ALZ-2, n≈1700) reduced decline by ~35% and gained approval in 2024, though both carry a 20–30% risk of amyloid-related imaging abnormalities (ARIA) requiring MRI monitoring. Tau immunotherapies such as AADvac-1 and bepranemab show robust target engagement but have yet to demonstrate cognitive efficacy. Adjunctive approaches, including masitinib (tyrosine kinase inhibition), intranasal insulin, and albumin/plasma exchange (AMBAR study), report modest signals in exploratory endpoints but remain unconfirmed. Nanoparticle and exosome-based platforms improve blood–brain barrier penetration in preclinical models, though human translation is limited. Conclusion: Symptomatic therapies remain relevant but modest in impact. The approvals of lecanemab and donanemab mark a pivotal shift toward disease-modifying treatment, albeit with safety and implementation challenges. Tau-directed strategies, anti-inflammatory agents, metabolic modulators, and regenerative approaches are promising but unproven. Future progress will depend on integrating biomarker-driven diagnosis, rigorous ARIA management, equitable health-system planning, and development of multimodal therapeutic combinations.