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Background Information
Recognition of two main types of Alzheimer Disease was an important first step
in the search for genetic causes. Early-onset Alzheimer Disease is more rare,
usually affecting people aged 30 to 60. The more common type is late-onset
Alzheimer's disease which occurs in those 60-65 and older. Researchers working
on Alzheimer Disease realized that in some families many family members had
early-onset Alzheimer Disease. They used linkage analysis, an approach in which
DNA samples from many members of such families are examined to see whether they
shared an abnormal gene. Abnormalities (mutations) in three genes that can cause
early onset familial Alzheimer Disease were discovered. On chromosome 21, the
mutation causes an abnormal amyloid precursor protein (APP) to be produced. On
chromosome 14, the mutation causes an abnormal protein called presenilin 1 to be
produced. On chromosome 1, the mutation causes yet another abnormal protein to
be produced. This protein, called presenilin 2, is very similar to presenilin 1.
These genetic mutations were highly penetrant, meaning that an individual who
inherited only one of these mutated genes will almost inevitably develop
early-onset Alzheimer Disease. However, because early onset familial Alzheimer
Disease is rare, these genetic abnormalities account for only a very small
fraction of all Alzheimer Disease
Relatively less is known about the genetic causes of the more common late onset
Alzheimer Disease. The only gene definitely shown to contribute to the risk an
individual will develop late onset Alzheimer Disease is the e4 version of the
Apolipoprotein E gene (APOE e4). Unlike the mutations in APP and the presenilins,
having an APOE e4 gene does not definitely lead to Alzheimer Disease. Instead it
acts as a risk factor, increasing the chances of developing Alzheimer Disease,
and causing it to develop several years sooner. In order to identify more genes
that contribute to late onset Alzheimer Disease, several approaches are ongoing.
One approach is to see whether late onset Alzheimer Disease may itself be
divided into subgroups (similar to early versus late onset). We have been
examining whether the presence of delusions or hallucinations (psychosis) during
the course of Alzheimer Disease identifies a subgroup in which new Alzheimer
Disease genes can be found. Because psychosis is not unique to Alzheimer
Disease, occurring in other mental illnesses such as schizophrenia and
depression, and in neurologic illnesses such as Huntington Disease, it is
possible that the search for psychosis genes in Alzheimer Disease will also lead
to finding genes that can contribute to psychosis and cognitive disturbance in
these other disorders.
There are several ways in which genes might contribute to psychosis in Alzheimer
Disease (AD+P) and other disorders, shown in the Figure.
In Pathway A1, modifier genes lead to AD+P after onset of AD, which is due to
distinct genetic and environmental influences. Some of these disease-modifying
genes could also modify the course of other neurodegenerative (Pathway A2) or
neurodevelopmental (Pathway A3) illnesses, contributing to psychosis risk in
these conditions. In pathway B, genes that increase the liability to onset
of AD would also increase the risk for AD+P. In pathway C, genes contributing
major risk for idiopathic psychoses such as schizophrenia would be seen to also
contribute to AD+P risk. See
Psychotic symptoms in Alzheimer disease: Evidence for a
distinct phenotype
for
additional details regarding existing data supporting or contradicting the
proposed pathways.
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