Can Anti-β-amyloid Monoclonal Antibodies Work in Autosomal Dominant Alzheimer Disease?

Neurol Genet

Department of Research & Development (B.P.I.), Chiesi Farmaceutici, Parma, Italy; Laboratory of Geriatric Neuropsychiatry (U.L.), Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy; and CNS & Pain Department (M.W.), TranScrip Partners, Reading, United Kingdom.

Published: February 2021

The dominant theory of Alzheimer disease (AD) has been that amyloid-β (Aβ) accumulation in the brain is the initial cause of the degeneration leading to cognitive and functional deficits. Autosomal dominant Alzheimer disease (ADAD), in which pathologic mutations of the amyloid precursor protein () or presenilins () genes are known to cause abnormalities of Aβ metabolism, should thus offer perhaps the best opportunity to test anti-Aβ drugs. Two long-term preventive studies (Dominantly Inherited Alzheimer Network Trials Unit Adaptive Prevention Trial [DIAN-TU-APT] and Alzheimer Preventive Initiative-ADAD) were set up to evaluate the efficacy of monoclonal anti-Aβ antibodies (solanezumab, gantenerumab, and crenezumab) in carriers of ADAD, but the results of the DIAN-TU-APT study have shown that neither solanezumab nor gantenerumab slowed cognitive decline in 144 subjects with ADAD followed for 4 years, despite one of the drugs (gantenerumab) significantly affected biomarkers relevant to their intended mechanism of action. Surprisingly, solanezumab significantly accelerated cognitive decline of both asymptomatic and symptomatic subjects. These failures further undermine the Aβ hypothesis and could support the suggestion that ADAD is triggered by accumulation of other APP metabolites, rather than Aβ.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862085PMC
http://dx.doi.org/10.1212/NXG.0000000000000535DOI Listing

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