Newly published study connects gene variants to middle-age cognitive decline

By Jack Mazurak

Scientists analyzing a gene linked to obesity and diabetes found that people with certain variants experienced more cognitive decline in middle age.

Mosley

The findings, published Jan. 1 in the journal “Neurology,” add another element to an array that could someday chart risk profiles for each person’s likelihood of developing Alzheimer’s or dementia.

Just as importantly, those gene variants could become targets for drug developers if further research shows a link between mid-life cognitive decline and more serious late-life dementia.

“Ultimately we’d like to know more about risk factors that affect cognition because the time to intervene is earlier rather than later,” said Dr. Thomas Mosley, professor of geriatric medicine and director of the Memory Impairment and Neurodegenerative Dementia (MIND) Research Center.

“You want to identify risk factors earlier in life because then you’re most likely to be able to change the outcome.

“People may be able to make lifestyle changes and, as better interventions develop, we may be able to prevent the onset of more serious cognitive changes.”

For the study, Mosley and collaborators at other institutions sampled 2,083 African-Americans from the Jackson metro area and 8,364 white Americans from North Carolina, Maryland and Minnesota.

The study participants had taken tests in 1990 for memory, processing speed and language skills. Six years later, the same people took the same tests. That gave Mosley and his colleagues a snapshot of each person’s cognitive changes.

All participants, part of a larger study called Atherosclerosis Risk in Communities, or ARIC, were between 45 and 64.

The scientists knew from their earlier research that diabetes is related to cognitive decline, and other studies have linked obesity to cognitive decline. For those reasons, they focused on an obesity- and diabetes-linked gene, FTO.

“So this was a way to link these prior findings back to a promising genetic target,” Mosley said.

In the last couple of years, the researchers looked at four variants of FTO. While everyone has the FTO gene, not everyone has all four of the variants.

The scientists overlaid the cognition-test results with each individual’s FTO analysis. They found white Americans with two of the four gene variants had more change in their cognition than participants without those variants.

“The amount of cognitive decline was statistically significant but not huge,” Mosley said. “We still don’t know whether that modest amount of cognitive change in mid-life translates into increased risks for more clinically significant changes such as dementia in late life. We have an ongoing study to attempt to answer this question.”

African-Americans showed no changes associated with the gene variants. As well, the results didn’t change when analyzed by other risk factors, including age, gender education, diabetes, high blood pressure or body fat.

Mosley said most of the obesity-related findings about FTO also have related to white Americans, not African-Americans.

“It could be those variants operate differently in African-Americans. Or that the effects of FTO are less easily detected in African-Americans, perhaps washed out by the influence of other competing risk factors,” he said.

Dr. Eric Boerwinkle, professor and director of the IMM Center for Human Genetics at the University of Texas Health Science Center at Houston, collaborated with Mosley.

“Our study helps to identify exactly which variants of this gene may be associated with obesity and diabetes, and independently, may play a role in cognitive decline for people in middle age,” Boerwinkle said.

“Although the amount of change was modest, finding the genetic pathways in which these variants are involved and how they contribute to a decline in memory could help scientists develop new treatments for early prevention.”

The National Heart, Lung, and Blood Institute funded for the research.

The researchers now are looking at the 25-year changes in the 12,000-plus members of the ARIC cohort in what’s called the ARIC Neurocognitive Study.