Alzheimer's disease paradigm shifts beyond amyloid, demanding sequential combination therapies for systemic drivers

Alzheimer's disease (AD), the leading cause of dementia, is undergoing a profound paradigm shift, moving beyond a simple proteinopathy. The traditional linear amyloid cascade hypothesis has proven insufficient, as evidenced by the marginal clinical gains and severe radiological risks (e.g., Amyloid-Related Imaging Abnormalities (ARIA)) of recent amyloid-clearing disease-modifying therapies (DMTs). This highlights a critical gap: current treatments often fail to address the complex, multisystem nature of AD, including chronic neuroinflammation, endolysosomal failure, and metabolic starvation (often termed "Type 3 Diabetes").

This critical review synthesizes recent mechanistic, translational, and clinical insights to dismantle the traditional linear amyloid cascade hypothesis for Alzheimer's disease. The authors explored the synergistic interplay between amyloid-β (Aβ) and tau propagation, positioning chronic neuroinflammation, endolysosomal failure, and metabolic starvation as fundamental disease drivers. Crucially, they highlighted the emerging biological bridge of CNS-PNS crosstalk, linking central neurodegeneration and peripheral neuropathies via systemic immune activation and microbiota-gut-brain axis dysbiosis. The review systematically evaluated the limitations of monotherapy and proposed a future therapeutic mandate.

The review posits that Alzheimer's disease is a complex, multisystem disorder, not merely a localized proteinopathy. It emphasizes the synergistic interplay between Aβ and tau propagation, identifying chronic neuroinflammation, endolysosomal failure, and metabolic starvation (Type 3 Diabetes) as fundamental drivers. A significant finding is the emerging concept of CNS-PNS crosstalk, where central neurodegeneration and peripheral neuropathies are linked by systemic immune activation and microbiota-gut-brain axis dysbiosis. While recent disease-modifying therapies (DMTs) validate Aβ clearance as a target, their marginal clinical gains and severe radiological risks like ARIA expose the profound limitations of monotherapy. The authors argue that isolated amyloid clearance is merely an induction phase. > The future of AD therapeutics mandates a sequential combination approach—pairing early plaque debulking with lifelong metabolic and neuroimmune maintenance. This strategy is supported by scalable fluid biomarkers like plasma p-tau217 and the expanded ATN(I) framework.