Alzheimer's disease (AD) continues to be an unprecedented global challenge as populations age, severely impacting cognitive function and quality of life. While the recent approvals of monoclonal antibodies like lecanemab and donanemab have provided hope by slowing cognitive decline, they have yet to achieve the goal of reversing the disease or fully restoring neurological function.
In a comprehensive review published in Science China Life Sciences by Professor Yan-Jiang Wang and his collaborators examines why single-factor interventions have proven insufficient. The authors argue that the complexity of AD—driven by a multifaceted interplay of amyloid-beta (Aβ) deposition, Tau tangles, genetic predispositions, biological aging, and systemic health—requires a more integrated therapeutic approach.
The Multifaceted Architecture of AD
The review dissects critical areas of AD research:
- Beyond Aβ: While Aβ remains central, its incomplete clinical outcomes highlight the limitations of targeting it alone. Emerging therapies now focus on Tau hyperphosphorylation, which leads to neurofibrillary tangles and neuronal loss.
- The Genetic Landscape: Genetics account for a vast majority of AD variance. Beyond the well-known APOE ε4 risk factor, researchers are now exploring ancestry-specific loci and genome editing (CRISPR/Cas9) as potential one-time interventions.
- Aging as a Driver: Aging is the primary risk factor for AD, involving mitochondrial dysfunction, cellular senescence, and DNA damage. The review highlights "senolytic" therapies that eliminate aged glial cells to improve brain function.
- Systemic Health: Conditions like insulin resistance, hypertension, and even gut dysbiosis significantly exacerbate AD pathology. Repurposing diabetes drugs and targeting the gut-brain axis represent promising systemic avenues.
Future Directions
The authors call for a transition from "reductionist" approaches to "integrated strategies". This includes developing multi-target therapies, utilizing advanced human iPSC-derived organoids for drug validation, and implementing precision medicine based on early biomarkers like plasma pTau217.
"Success in defeating Alzheimer's hinges on interdisciplinary collaboration and holistic innovation," the authors conclude. This review serves as a roadmap for shifting AD from an incurable burden to a manageable or even preventable condition.
