Genetic studies were exceptionally important, pointing to increased dose of the gene for the amyloid precursor protein (APP) in Down syndrome (DS) and a familial AD (FAD) due to duplication of APP and to mutations in APP and in the genes for Presenilin 1 and 2 (<i>PSEN1, 2</i>), which encode the γ-secretase enzyme that processes APP (Dorszewska et al., 2016).
These results reveal a potential regulatory link between Dyrk1A and PS1 in the Aβ pathway of DS and AD brains, suggesting that up-regulated Dyrk1A may accelerate AD pathogenesis through PS1 phosphorylation.
A genetic association between a polymorphism in intron 8 of the PS-1 gene and AD has been described in some series, and an increased risk of AD has been reported in mothers of DS probands.
We conclude that unlike the general population, neither PS-1 nor ACT polymorphisms appear to have a similar detrimental effect on dementia in DS.Am.J. Med.Genet.(Neuropsychiatr.Genet.)88:616-620, 1999.
The neuropathology of 2 subjects with this PS1 mutation (ages at death: 35 and 37 years) was compared to four Down syndrome (DS) patients (mean age at death: 62 years) and 4 sporadic AD patients (mean age at death: 79 years with a mean duration of disease of 18 years).
Therefore, (one of) the effects of the mutations in the presenilin 1:PS-1 (S182) gene may be to cause or at least promote an early and excessive deposition of Abeta42(43) within the brain, a property shared with other inherited forms of AD, such as those due to amyloid precursor protein mutations, and Down's syndrome (trisomy 21).