Alzheimer’s disease(AD)imposes a substantial clinical and societal burden,yet currently approved symptomatic therapies do not modify the underlying disease biology.Recently,three anti-amyloid monoclonal antibodies(ad...Alzheimer’s disease(AD)imposes a substantial clinical and societal burden,yet currently approved symptomatic therapies do not modify the underlying disease biology.Recently,three anti-amyloid monoclonal antibodies(aducanumab,lecanemab,and donanemab)have demonstrated robust amyloid clearance.Their clinical effects are statistically significant but modest,underscoring the need for broader,biologically informed strategies.Guided by the 2024 Alzheimer’s Association ATNIVS biomarker framework,this review synthesizes disease-modifying therapies(DMTs)targeting amyloid(A),tau(T),neurodegeneration(N),inflammation(I),vascular injury(V),andα-synuclein(S).For each domain,we summarize mechanisms of action and pivotal clinical trial results,highlighting safety considerations such as amyloid-related imaging abnormalities(ARIA)with anti-amyloid antibodies.We further outline future directions,including biomarker-based staging for trial enrollment,rational combination regimens(for example,anti-amyloid plus anti-tau),and endpoint selection aligned with minimal clinically important differences(MCID).Applying the ATNIVS framework to AD DMT development may accelerate the implementation of mechanism‑matched interventions.This approach can also facilitate precision therapeutics across diverse patient subgroups.展开更多
基金supported by the National Key Research and Development Program of China(2022YFC3602600)the National Natural Science Foundation of China(82220108009)+1 种基金Beijing Outstanding Young Scientist Program(JWZQ20240101023)STI2030-Major Projects(2021ZD0201801).
文摘Alzheimer’s disease(AD)imposes a substantial clinical and societal burden,yet currently approved symptomatic therapies do not modify the underlying disease biology.Recently,three anti-amyloid monoclonal antibodies(aducanumab,lecanemab,and donanemab)have demonstrated robust amyloid clearance.Their clinical effects are statistically significant but modest,underscoring the need for broader,biologically informed strategies.Guided by the 2024 Alzheimer’s Association ATNIVS biomarker framework,this review synthesizes disease-modifying therapies(DMTs)targeting amyloid(A),tau(T),neurodegeneration(N),inflammation(I),vascular injury(V),andα-synuclein(S).For each domain,we summarize mechanisms of action and pivotal clinical trial results,highlighting safety considerations such as amyloid-related imaging abnormalities(ARIA)with anti-amyloid antibodies.We further outline future directions,including biomarker-based staging for trial enrollment,rational combination regimens(for example,anti-amyloid plus anti-tau),and endpoint selection aligned with minimal clinically important differences(MCID).Applying the ATNIVS framework to AD DMT development may accelerate the implementation of mechanism‑matched interventions.This approach can also facilitate precision therapeutics across diverse patient subgroups.
