APP and dementia: For instance, individuals carrying autosomal dominant mutations in components of the APP processing pathway (APP, PSEN1 or PSEN2) develop a highly penetrant form of familial AD (‘FAD’), whereas elevated APP gene dosage due duplication of its locus (21q21.3) in Trisomy 21 results in precocious dementia-like symptoms during middle age coupled with AD neuropathological hallmarks (Lott and Head, 2019).