A gene variant associated with accelerated brain atrophy may represent a promising therapy target for people at greater risk of developing Alzheimer’s disease, a new study from Duke University School of Medicine has found.

About one-fifth of U.S. seniors aged 65 and older show some signs of mild cognitive decline (MCI), a complex of mental issues characterized by forgetfulness and impaired judgment. While the symptoms rarely interfere with a person’s daily life, they can put one at greater risk of developing certain types of dementia. With global Alzheimer’s rates on the rise, knowledge about MCI is rapidly becoming a crucial part of disease control and prevention.

What is Epsilon 4, and Why Does It Matter?

Dr. Jeffrey Petrella, associate professor of radiology and senior author of the current study, said in a press release that new findings show how a certain allele, or gene variant, may speed up the development of Alzheimer’s in people with MCI. This allele, which is a variation of the gene apolipoprotein E (APOE), appears to ensure faster brain atrophy in areas of the brain where you really don’t want atrophy to occur at all. "We all carry two APOE alleles, and most people have at least one copy of the APOE epsilon 3 (ɛ3) variant, which is considered neutral with respect to Alzheimer's risk," Petrella explained. The less common allele epsilon 4, on the other hand, is associated with a higher Alzheimer’s risk, earlier age of onset, and faster disease progression.

For the study, the researchers analyzed data from 237 patients enrolled in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) — a repository of medical records from at-risk patients. The subjects, who had not yet developed Alzheimer’s disease, were around 80 years of age and had previously been diagnosed with MCI. Using magnetic resonance imaging (MRI), the team measured each subject’s brain atrophy rates over a 12- to 48-month period.

Genetic testing later revealed that the rate of atrophy was significantly faster in subjects who carried the epsilon 4 allele. The atrophy was observed in 13 of the 15 brain regions that are damaged by Alzheimer’s disease. “The results showed atrophy in brain regions we know are affected by AD, in a population of patients who do not have AD, but are at risk for it," Petrella explained. "This suggests the possibility of a genotype-specific network of related brain regions that undergo faster atrophy in MCI and potentially underlies the observed cognitive decline."

Reining In Alzheimer’s Disease Rates

Neurodegenerative disorders like Alzheimer’s disease currently affect millions of people worldwide. Recent projections indicate that the amount of cases will triple by 2050. The conditions, which are characterized by a gradual loss of nerve functions, usually result in mental decline and an array of cognitive impairments. In turn, these symptoms often bring with them a number of lifestyle changes as well as an increased risk of injuries.

According to Petrella, the findings have the potential to break new ground in Alzheimer’s intervention, as current pharmaceutical therapies are palliative rather than curative. "Current FDA-approved drugs treat symptoms, but don't modify the underlying cause of the disease," he explained. "We want to make continued inroads toward the goal of developing and testing drugs that modify the disease process itself."

Source: Petrella J, Hostage CA, Choudhury KR, Doraiswamy PM. Mapping the Effect of the Apolipoprotein E Genotype on 4-Year Atrophy Rates in an Alzheimer's Disease-related Brain Network. Radiology. 2014