Mutation in the gene for a protein important in cholesterol metabolism may increase risk for developing Alzheimer disease

Mutation in the gene called CYP46, which produces a protein important in metabolism of excess cholesterol within the brain, may be associated with an increased risk for Alzheimer’s disease, according to an article in the January issue of the Archives of Neurology.

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."

 

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