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Alzheimer's Disease Markers Linked to Polygenic Risk Score

NEW YORK (GenomeWeb) – A team led by Harvard Medical School researchers has developed polygenic risk scores that could be used to detect Alzheimer's disease before clinical symptoms appear.

Alzheimer's disease is highly heritable, and some risk loci like APOE gene variants are known. There are also other genes that have been implicated in disease development. As the Harvard-led team reported in Neurology yesterday, it developed polygenic risk scores based on genome-wide association study findings and applied it to an older cohort of more than 160 people with dementia and 1,000 without dementia to find that a high risk score is linked with worse memory, smaller hippocampi, and cognitive decline, even in people without dementia. Over time, a higher risk score was also associated with clinical progression.

Likewise, when they applied their scores to a cohort of some 1,300 people under the age of 35, the researchers found that younger people with a high risk score also had smaller hippocampi.

"The stage of Alzheimer's before symptoms show up is thought to last over a decade," corresponding author Elizabeth Mormino from Massachusetts General Hospital said in a statement. "Given that current clinical trials are testing whether therapies can slow memory and thinking decline among people at risk for the disease, it is critical to understand the influence of risk factors before symptoms are present."

She and her colleagues based their polygenic risk scores on the results of a meta-analysis of Alzheimer's disease conducted by the International Genomics of Alzheimer's Project. That meta-analysis unearthed 11 loci linked to the onset of Alzheimer's disease.

To test their polygenic risk scores, the researchers drew on patients with mild cognitive impairment, patients with Alzheimer's disease-related dementia, and a set of controls from the Alzheimer's Disease Neuroimaging Initiative (ANDI) Study for whom genotyping data was available. They examined whether various iterations of their risk scores were associated with disease-related markers like memory decline, disease progression, and hippocampus volume.

Among the ANDI research participants — whose median age was early 70s — the researchers reported that higher polygenic risk scores were associated with Alzheimer's markers like worse memory, lower hippocampal volume, and disease-like levels of amyloid at baseline, even among the participants without dementia. Within three years of follow up, higher polygenic risk scores were also associated with disease progression, both from mild cognitive impairment to Alzheimer's disease and from clinically normal to mild cognitive impairment. According to the researchers, this link to decline even in people without dementia highlights the influence of genetic risk on longitudinal trajectories.

They also noted an association between polygenic risk scores and amyloid beta in participants without dementia.

Mormino and her colleagues then examined the relationship between these polygenic risk scores and markers of disease in a cohort of 1,322 people between the ages of 18 and 35 without disease. In this group, too, they noted a link between a higher risk score and hippocampal volume.

This, they said, indicates that the effect of genetic risk isn't limited to later life stages and suggests that genetic risk of Alzheimer's disease has effects that can be caught prior to the onset of clinical dementia symptoms, even in young adults.

Mormino and her colleagues did note that their study was limited by its size. "Our study was small and larger numbers of participants will need to be studied to confirm our findings," she added.