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Polygenic risk score may predict Alzheimer's disease risk at younger age

Polygenic risk score may help predict and identify younger populations at higher risk for Alzheimer‘s disease, according to findings from two studies.

In a study published in Molecular Psychiatry, polygenic risk score for Alzheimer’s disease could identify mild cognitive impairment in adults who were in their 50s.

“Current studies of the [Alzheimer’s disease] polygenic risk score typically occurs in adults in their 70s, but the [Alzheimer’s disease] pathological process begins decades before the onset of dementia,” senior author William S. Kremen, PhD, department of psychiatry and Center for Behavior Genetics of Aging, University of California, San Diego, said in a press release. “By focusing on a younger population with cognitive impairment, we may be better able to identify patients for critical early interventions and clinical trials.”

Researchers examined 1,176 white, non-Hispanic community-dwelling men of European ancestry enrolled in the Vietnam Era Twin Study of Aging (VETSA) – 7% of whom had amnestic mild cognitive impairment (MCI) and 4% of whom had non-amnestic MCI. The average age of the participants was 56 years and 89% were younger than 60 years. They analyzed single nucleotide polymorphisms included in the Alzheimer’s disease polygenic risk score.

After controlling for covariates, Kremen and colleagues determined that higher polygenic risk scores correlated significantly with greater odds of having amnestic MCI than having normal cognition (ORs =1.36–1.43 for thresholds P<.2–.5).

Analysis showed that participants with an Alzheimer’s disease polygenic risk score in the upper quartile were up to 3 times more likely to have MCI than those who scored in the lowest quartile, according to the press release. This relationship remained significant after accounting for apolipoprotein E (APOE)-related single nucleotide polymorphisms from the Alzheimer’s disease polygenic risk score or directly genotyped APOE. Notably, diabetes was three times more likely for participants who had non-amnestic MCI (ORs=3.1–3.41 for thresholds P<.05–.5).

“Our research team found that the polygenic score could differentiate individuals with mild cognitive impairment from those who were cognitively normal,” Kremen said in the release. “The Alzheimer‘s Association and others have modeled how the impact of delaying the onset of [Alzheimer’s disease] by five years could reduce the number of cases by nearly 50 percent by 2050. We want to do what we can to make this projection a reality.”

Early life associations

According to research published in The American Journal of Psychiatry, Alzheimer’s polygenic risk score may also affect memory and hippocampal volume during childhood and adolescence, which could help identify those at higher risk for developing Alzheimer’s disease in early life.

“Neuropathological features can appear decades before disease onset. Measures of cognitive function in childhood and early adulthood predict later risk,“ Luiza K. Axelrud, PhD, department of psychiatry and legal medicine, Universidade Federal do Rio Grande do Sul, Hospital de Clínicas de Porto Alegre, Brazil, and colleagues wrote. “Despite these interesting clues, no study has investigated associations among aggregate genetic risk factors for Alzheimer’s disease, cognition measures, and brain volumes in children and adolescents.”

Researchers examined the relationship between Alzheimer’s disease polygenic risk score and cognitive abilities and hippocampal volume among youth in two samples of Brazilian children aged 6 years to 14 years in two Brazilian cities: a discovery sample (n = 364) and replication sample (n = 352). Then, they assessed distinct cognitive tasks and MRI acquisition protocol to determine comparable associations using data from an additional replication sample of 1,029 Canadian teens. Participants completed cognitive and standardized tests, which researchers used to measure memory and executive function and reading and writing abilities.

The results showed that a one-unit increase in z score for Alzheimer’s polygenic risk score predicted a 0.185 point reduction in score for immediate recall and a 0.282 point reduction for delayed recall in the discovery sample (P < .0001). These findings were mirrored among children in the Brazilian replication sample (immediate recall: P = .003; delayed recall: P = .008).

There was no link between Alzheimer’s disease polygenic risk score and reading or writing scores in the Brazilian discovery cohort, nor was there an association between risk score and executive function. However, the researchers observed a positive association between polygenic risk score and right hippocampal volume (P = .045), though it was not replicated in the Brazilian replication sample. The researchers also found that the association between polygenic risk score and hippocampal volumes varied with level of polygenic risk score. The associations were not significant in the Canadian sample.

“Alzheimer’s polygenic risk score may influence developmental processes underlying nondeclarative visuoconstructive memory and hippocampal volume in early life, expanding the understanding of the influences of [single nucleotide polymorphisms] associated with Alzheimer’s disease before the diagnosis of the disease,” Axelrud and colleagues wrote. “Further research is needed to replicate these findings in other samples and to advance our understanding of mechanisms linking genetic risk for Alzheimer’s disease and the development of cognitive functions.” – by Savannah Demko

Disclosures: Kremen reports no relevant financial disclosures. Please see the full study for all other authors’ relevant financial disclosures. Axelrud reports no relevant financial disclosures. Please see the full study for all other authors’ relevant financial disclosures.