Mechanism Behind Alzheimer’s Greatest Genetic Risk Factor Possibly Discovered

Buck Institute and UCLA researchers have discovered a new role for a specific genetic form (allele) of a certain gene, which might explain its status as the most important genetic risk factor for the development of Alzheimer’s disease. The research paper, “Direct Transcriptional Effects of Apolipoprotein E,” was published in The Journal of Neuroscience.

Individuals carry two copies of the apolipoprotein E (ApoE) gene, which codes for the apolipoprotein E, a lipid-binding protein. There are three types of the ApoE gene (alleles): e2, e3, and e4, which can be carried in different combinations, constituting the person’s ApoE genotype. The e2 allele, the rarest form of the gene, has been associated with a low risk of developing Alzheimer’s disease, even if the individual carries just one copy. The ApoE3, the most common form, appears to have no influence on Alzheimer’s risk.

However, the e4 allele, present in about 20 percent of the population, according to the Alzheimer’s Drug Discovery Foundation, not only increases the risk for Alzheimer’s disease but it is also known as the greatest genetic risk factor for late-onset Alzheimer’s. But the mechanism which allows this allele to play such a pivotal role in the onset of Alzheimer’s has been one of the big unanswered questions in medicine and neurobiology.

Researchers may have found a possible explanation. Using neural cell lines, skin fibroblasts from Alzheimer’s patients, and ApoE-targeted replacement mouse brains, the team studied the protein’s behavior, and observed that ApoE4 also functions as a transcription factor that controls gene expression, entering the nucleus and binding DNA with high affinity. ApoE4 was found to bind the promoter regions of 1,700 different genes, primarily those associated with aging, insulin resistance, inflammation, oxidative damage, accumulation of amyloid plaques and tau protein aggregation, all processes that have been implicated in Alzheimer’s pathogenesis.

“Our group hopes this work will lead to a new type of screen for Alzheimer’s prevention and treatment,” co-senior author Dr. Rammohan Rao, associate research professor at the Buck Institute, said in a press release. “We are also designing and engineering novel drug candidates that target not one, but several of the ApoE4 mediated pathways simultaneously.

“Ultimately we want to develop a drug that can be given to ApoE4 carriers that would prevent the development of Alzheimer’s disease, and these results provide a mechanism and screen to do that,” Rao said.