Genetic risk factors

Scientists who study the genetics of Alzheimers distinguish between familial

Alzheimers disease, which runs in families, and sporadic Alzheimers disease,
where no obvious inheritance pattern is seen. True familial Alzheimers disease
accounts for less than 5% of Alzheimers cases. Sporadic Alzheimers is much more
common.

Familial Alzheimers Disease

All Familial Alzheimers disease known so far has an early onset, and as many as 50
percent of the cases are now known to be caused by defects in three genes located
on three different chromosomes, the structures inside cells that house the genetic
code. Some families have mutations in a gene called amyloid precurser protein
(APP), which causes an abnormal form of the amyloid protein to be produced. Other
families have mutations in a gene called presenilin 1, which causes an abnormal
presenilin 1 protein to be produced. Still others have mutations in a very similar
gene called presenilin 2, which causes an abnormal presenilin 2 protein to be
produced.

Even if one of these mutations is present in only one of the two copies of a gene
inherited from a persons parents, the person will inevitably develop that form of
early-onset Alzheimers (this is called autosomal dominant inheritance). However,
the total known number of these cases is small (between 100 and 200 worldwide),
and there is as yet no evidence that any of these mutations play a major role in the
more common, sporadic or non-familial form of late-onset Alzheimers. Scientists
are working to reveal the normal function of APP and presenilins and to determine
how mutations of these genes cause the onset of familial Alzheimers disease.

Sporadic Alzheimers Disease

Although there is no evidence that autosomal dominant inheritance of mutated
genes causes late-onset Alzheimers, genetics does appear to play a role in the
development of this more common form of the disease. Research has found an
increased risk for late-onset Alzheimers in people who inherit one or two copies of a
particular variation of a gene called apolipoprotein E (APOE) the variation known
as APOE e4. Different variations, or alleles, of particular genes produce variations in
inherited characteristics, such as eye color or blood type. In this case, the variations
are in the APOE gene that directs the manufacture of apolipoprotein E, a protein

that helps carry blood cholesterol throughout the body, among other functions. It is
found in neurons and other supportive brain cells (called glia) of healthy brains, but
it is also associated in excess amounts with the plaques found in the brains of
people with Alzheimers.

Researchers are particularly interested in three common alleles of the APOE gene:
e2, e3 and e4. The finding that increased risk is linked with inheritance of the APOE
e4 allele has helped explain some of the variations in age of onset of Alzheimers
disease based on whether people have inherited zero, one, or two copies of the
APOE e4 allele from their parents. The more APOE e4 alleles one inherits, the lower
the age of disease onset. The relatively rare APOE e2 allele may protect some
people against the disease: It seems to be associated with a lower risk for
Alzheimers and a later age of onset if the disease does develop. APOE e3 is the
most common version found in the general population and may play a neutral role
in Alzheimers risk.

Does everyone who carries the APOE gene develop Alzheimers disease?
The inheritance of one or two APOE e4 alleles does not predict Alzheimers with
certainty. That means that, unlike early-onset familial Alzheimers disease, a person
can have one or two APOE e4 alleles and still not get the disease, and a person who
develops the disease may not have any APOE e4 alleles. APOE e4 increases the risk
of developing Alzheimers, but it does not cause the disease. The ways in which
APOE e4 increases the likelihood of developing Alzheimers are not known with
certainty, but one possible mechanism is that it facilitates beta amyloid buildup in
plaques and this contributes to lowering the age of onset of the disease. Other
theories involve interactions with cholesterol levels and effects on nerve cell death
that are independent of its effects on plaque buildup.