APP

About APP

APP on chromosome 21q21.3 encodes amyloid precursor protein, a transmembrane protein highly expressed in neurons. Sequential cutting of APP by beta secretase and gamma secretase produces amyloid beta peptides, which aggregate into the amyloid plaques that are a defining feature of Alzheimer disease. Rare variants in APP cause early onset familial Alzheimer disease, and duplications of the gene have a similar effect. Because APP lies on chromosome 21, people with Down syndrome carry three copies and develop Alzheimer type brain changes at a much younger age than the general population. Conversely, the protective A673T variant, identified in Iceland, reduces amyloid beta production and is associated with lower risk of Alzheimer disease and cognitive decline. Antibodies that clear amyloid plaques, such as lecanemab, are based on the amyloid hypothesis built in large part on APP genetics.