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.