Familial Alzheimer's disease: genetic influences on the disease process (Review)

Alzheimer's disease (AD) has both genetic and environmental etiologies. Genetic causes include presenilin (PS) mutations on chromosomes 1 and 14, and amyloid precursor protein (APP) mutations on chromosome 21. At least two susceptibility genes also exist. In this review phenotypic differences in AD groups are described and possible differences in the mechanism(s) by which AD mutations lead to dementia are reviewed. Clinical, pathological and biochemical phenotypes distinguish AD cases with different etiologies. For example, age-at-onset and age-at-death between PS-1, PS-2, APP and sporadic AD groups differ. Also, some forms of AD are associated with more Abeta deposition others, and some AD groups have morphologically distinct Abeta deposits or other unique histopathologic features. APP-related AD mutations always occur within the Abeta portion of the APP gene, adjacent to sites where alpha-, beta- and gamma-secretase breakdown pathways operate in the expressed protein. These mutations alter APP metabolism leading to increased Abeta production. It is unknown if other AD groups are subject to identical changes in APP metabolism. Activation of apoptosis pathways, more general defects in protein transport or metabolism, differential regulation of tau kinases or other factors may also be important. Overall, data support the notion that differences occur in the disease process in etiologically distinct AD groups.