Genetic score can identify Alzheimer’s risk much earlier


New research reveals that a polygenic risk score for Alzheimer’s disease can correctly identify adults who have mild cognitive impairment while they are in their 50s.

The researchers hope that their results will help to identify those at risk of Alzheimer’s disease long before symptoms emerge, and thereby further efforts to better treat or slow its progression.

A polygenic risk score can assess the genetic liability for a specific disease by studying the genomes of large numbers of people that have the disease. It takes into account the effects of many small variations in DNA that are linked to the disease.

The international study, which is published in the journal Molecular Psychiatry, is the first to use an Alzheimer’s disease polygenic risk score to identify mild cognitive impairment (MCI) — which often precedes Alzheimer’s — in a younger population of adults.

“Current studies of the [Alzheimer’s disease] polygenic risk score,” says senior study author William S. Kremen, who is a professor of psychiatry in the School of Medicine at the University of California, San Diego, “typically occur in adults in their 70s, but the [Alzheimer’s disease] pathological process begins decades before the onset of dementia.”

MCI and Alzheimer’s disease

People with MCI have “slight but noticeable” problems with memory, thinking, and other cognitive abilities, but these are not sufficiently severe to interfere with their daily lives or capacity to live independently.

Having MCI — the sort that affects memory, in particular — means that there is a greater chance of developing Alzheimer’s disease or another dementia. But not everyone with MCI will go on to develop dementia. In some cases, MCI can remain stable or even reverse.

There were 5 million adults living with Alzheimer’s disease in the United States in 2013, and this number is expected to rise to 14 million by 2050.

Prof. Kremen explains that some models have shown that delaying the onset of Alzheimer’s disease by just 5 years could “reduce the number of cases by nearly 50 percent by 2050.”

He also suggests that, by looking for MCI in younger groups of adults, “we may be better able to identify patients for critical early interventions and clinical trials.”

Polygenic score correctly identified MCI

For their new study, Prof. Kremen and team analyzed data on 1,329 men who were participants in a genetic behavioral study called the VETSA: Vietnam Era Twin Study of Aging. The average age of the men was 56 years, and 89 percent of them were under 60.

When they ranked the VETSA participants according to their Alzheimer’s disease polygenic risk scores, the researchers found that those in the top 25 percent had a two and a half to three times higher chance of having MCI than those in the lowest 25 percent.

The polygenic risk score that they used came from Alzheimer’s disease genome-wide association studies. These studies have identified variations in DNA building blocks called single nucleotide polymorphisms (SNPs) that are present in people with Alzheimer’s and not present in people without the disease.

Thus, a person’s Alzheimer’s disease polygenic risk score is a sum of the disease-related genetic variations, or SNPs, in their genome, weighted according to the estimated impact of each one.

The use of polygenic risk scores to assess genetic liability to disease is a relatively new field and is based on the idea that the genetic basis of disease, especially complex diseases, arises from the “small effects of hundreds or even thousands of variants,” as opposed to just one or two genes.

Our research team found that the polygenic score could differentiate individuals with mild cognitive impairment from those who were cognitively normal.”

Prof. William S. Kremen


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