Genetics of Alzheimer's disease

Alzheimer's disease (AD) provides an example of many gene-mapping techniques:

• AD-type pathology in trisomy 21 (Down's syndrome) suggested that an AD gene could be situated on chromosome 21

• The gene for amyloid precursor protein (APP) was mapped to chromosome 21 ("forward genetics")

• Linkage detected in some presenile AD families to C21 markers close to APP ("reverse genetics")

• Screening of APP detected mutations in some presenile AD families

• Weak linkage and association in cases of senile AD to markers on chromosome 19 near apoliprotein E

• Senile AD positively associated with ApoE e4, and negatively with ApoE e2

• Linkage of other presenile families to chromosome 14 markers led to the identification of a mutated gene, named presenilin 1 (PS1)

• The search for genes with sequence-homology to PS1 rapidly led to the discovery of a new gene on chromosome 1 which was mutated in other presenile AD families, name presenilin 2 (PS2)

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