According to background information given
in the article, lower cholesterol levels in the brain reduce the
concentration of beta-amyloid proteins, which contribute to the
development of the disorder. Because of the importance between lower
cholesterol levels and a potentially lower risk for dementia, the
researchers looked at the relation between CYP46 and beta-amyloid,
as well as other biological traits associated with Alzheimer’s disease.
Andreas Papassotiropoulos, M.D., and his Swiss
colleagues looked at traits including the concentrations of the
proteins beta-amyloid and tau in the brains and spinal fluid of
patients with and without the disorder. They collected brain tissue
samples from 55 deceased elderly patients without dementia, 38 samples
of spinal fluid from patients living with Alzheimer’s disease, and
25 samples from living patients without the disorder. The researchers
also looked at the association between mutation of CPY46 and Alzheimer’s
disease in 201 patients with the disorder and 248 patients without
it.
The researchers found that mutations in CYP46
were associated with increases in the concentration of beta-amyloid
in the brain and spinal fluid. Tau protein levels were also higher
in the spinal fluid of patients with mutations in CYP46. Furthermore,
researchers found that patients in 2 independent populations with
mutated CYP46 alleles had more than 2 times the risk of developing
late-onset sporadic Alzheimer’s disease. Patients with mutated CYP46
alleles who also had one or two apolipoprotein E alleles (APOE4
mutations linked to a higher incidence of the disorder), had almost
10 times the risk of patients carrying no mutations in either CYP46
or APOE4.
"We observed that brain beta-amyloid
load in subjects with the CYP46*TT genotype [a mutated allele] was
significantly higher than in CYP46*TT-negative [the normal allele]
subjects. Moreover, the genetic combination of APOE4 and CYP46*TT
was associated with the highest levels of brain beta-amyloid load.
In addition, CYP46*TT resulted in elevated levels of cerebrospinal
fluid beta-amyloid in patients with Alzheimer’s disease," wrote
the authors. "These observations underscore a possible relationship
between cholesterol and brain amyloid formation."
In an accompanying editorial, Benjamin Wolozin,
M.D., Ph.D., wrote, "Lipid metabolism, and cholesterol metabolism
in particular, is perhaps the greatest factor affecting health in
the United States. We are a nation of increasingly obese people,
and factors related to cholesterol metabolism have already been
shown to be a major determinant of disease in the cardiovascular
system. How the body handles cholesterol is clearly a major challenge
for the body as we age. There is increasing interest in understanding
how the cholesterol in the central nervous system might affect disease."
"The first genetic risk factor identified for late-onset Alzheimer
disease was APOE4, a cholesterol transport protein," wrote
Wolozin. "The discovery of a strong link between polymorphisms
[mutations] in CYP46 and late-onset Alzheimer disease now points
to a second genetic risk factor related to cholesterol metabolism.
A third risk factor, alpha2-microglobulin, has a tenuous genetic
link to late-onset Alzheimer disease but also participates in cholesterol
metabolism. Together, these results suggest the possibility that
late-onset Alzheimer disease, the most common degenerative disease
of the brain, is a general end point for abnormalities that increase
the amount of cholesterol in the central nervous system. If so,
inhibiting cholesterol metabolism in the brain might represent a
viable treatment for late-onset Alzheimer disease."