Genetic basis of motoric cognitive risk syndrome in the Health and Retirement Study

Objective: To examine polygenic inheritance of motoric cognitive risk syndrome (MCR), a predementia syndrome characterized by the presence of subjective cognitive complaints and slow gait.

Methods: We analyzed 4,915 individuals, age 65 years and above, with European ancestry (mean age 75.0 ± 6.8 years, 56.6% women) in the Health and Retirement Study. Polygenic scores (PGS) were calculated as weighted sums of the effect of single nucleotide polymorphisms, with effect sizes derived from genome-wide association studies. The association between PGSs of 9 phenotypes (general cognition, body mass index [BMI], mean arterial pressure, education, Alzheimer disease [AD], neuroticism, well-being, waist circumference, and depressive symptoms) and MCR as well as its key components (cognitive complaints and slow gait) were examined by logistic regression, adjusting for age, sex, education, and genetic ancestry, and reported as odds ratios (ORs) with 95% confidence intervals (CIs).

Results: There were 260 prevalent MCR cases, 529 with slow gait, and 1,928 with subjective cognitive complaints. Higher PGSs for BMI (OR 1.22, 95% CI 1.07-1.39) and waist circumference (OR 1.23, 95% CI 1.07-1.40) were associated with MCR, and PGS of AD showed a suggestive association (OR 1.16, 95% CI 1.02-1.32). Higher PGS for neuroticism (OR 1.10, 95% CI 1.03-1.18) was associated with cognitive complaints, whereas higher well-being PGS (OR 0.92, 95% CI 0.87-0.98) was protective. PGS for BMI (OR 1.16, 95% CI 1.06-1.28), waist circumference (OR 1.19, 95% CI 1.08-1.31), and AD (OR 1.13, 95% CI 1.03-1.24) was associated with slow gait.

Conclusion: Obesity-related genetic traits increase risk of MCR syndrome; further investigation is required to identify potential therapeutic targets.