PT  - JOURNAL ARTICLE
AU  - Imbimbo, Bruno P.
AU  - Lucca, Ugo
AU  - Watling, Mark
TI  - Can Anti–β-amyloid Monoclonal Antibodies Work in Autosomal Dominant Alzheimer Disease?
AID  - 10.1212/NXG.0000000000000535
DP  - 2021 Feb 01
TA  - Neurology Genetics
PG  - e535
VI  - 7
IP  - 1
4099  - http://ng.neurology.org/content/7/1/e535.short
4100  - http://ng.neurology.org/content/7/1/e535.full
SO  - Neurol Genet2021 Feb 01; 7
AB  - 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 (APP) or presenilins (PSENs) 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.AD=Alzheimer disease; ADAD=autosomal dominant AD; AICD=APP intracellular domain; API=Alzheimer Preventive Initiative; APP=amyloid precursor protein; APT=Adaptive Prevention Trial; BACE1=β-site APP cleaving enzyme-1; DIAN-TU=Dominantly Inherited Alzheimer Network Trials Unit; IgG=immunoglobulin G; NfL=neurofilament light; OCIAD1=ovarian carcinoma immunoreactive antigen domain containing 1; OR=odds ratio; SAD=sporadic AD