Linkage analyses have implicated several genes as causes or risk factors for Alzheimer's disease in different families: the amyloid precursor protein gene, the apolipoprotein-E gene (E4 subtype) on chromosome 19, the S182 gene on chromosome 14 and the STM2 gene on chromosome 1.
Presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid precursor protein (APP) genes account for the majority of autosomal dominant Alzheimer's disease (AD), with PSEN1 being the most common.
A significant member of early-onset familial type of Alzheimer's disease cases has been shown to be caused by dominant mutations in either of the two genes encoding presenilin 1 (PS1) and presenilin 2 (PS2).
Although the mechanism(s) whereby the PS-1 and PS-2 gene mutations operate remains unclear, it seems from the present study that the effect of the PS-2 gene mutation on the brain is much less severe, at least as far as Abeta deposition is concerned, than that of the PS-1 mutation, which seems to confer a much earlier and a much more aggressive development of AD.
Rare familial cases may be caused by mutations in one of three genes-amyloid precursor protein, presenilin-1 and presenilin-2; however, the molecular basis of >99% of AD cases is unknown.
Interestingly, in the latter series, we found five new non-synonymous changes in all three genes and a presenilin 2 variant (R62H) that has been previously related to AD.
Eleven early-onset dementia families, all with affected individuals who have either presented clinical symptoms of early onset familial Alzheimer's disease (EOFAD) or have been confirmed to have EOFAD by autopsy, and two early onset cases with biopsy-confirmed AD pathology, were screened for missense mutations in the entire coding region of presenilin-1 (PS-1) and -2 (PS-2) genes.
This hypothesis in turn is derived largely from the characterization of rare disease-causing mutations in three genes, which code for the amyloid precursor protein (APP), presenilin 1 (PS-1) and presenilin 2 (PS-2) and account for most cases of early-onset autosomal dominant familial AD.
The PSEN2 (p.Val214Leu, c.640G>T; p.Lys82Arg, c.245A>G) mutations were identified in 2 early-onset AD patients and 1 early-onset AD patient, respectively.
Autosomal dominant Alzheimer's disease (AD) is caused by mutations in amyloid precursor protein, presenilin 1 (PSEN1), and presenilin 2 genes and is mostly associated with early-onset form of AD (EOAD), whereas very few mutations were also found in late-onset AD (LOAD) cases.
Approximately 1% of all cases of Alzheimer's disease are inherited autosomal dominantly, and to date, three causative genes have been found, the Presenilin 1 (PSEN1) gene, the Presenilin 2 (PSEN2) gene and the Amyloid precursor protein (APP) gene.