Objective: To investigate whether variants from a large Alzheimer’s disease (AD) genome-wide association study (GWAS; Bellenguez et al. 2022) in Europeans – including 85,934 clinically diagnosed/proxy AD cases, and 401,577 controls, are associated with PD dementia (PDD) and cognitive impairment (PDCI).

Background: Dementia is the primary clinical manifestation of AD and a common non-motor complication of PD. PDCI and AD share pathological features, yet the contribution of AD-associated genetic risk variants to PDCI remains incompletely understood.

Method: We analyzed imputed genotyping data from 3,188 PD patients of European ancestry with cognitive measures from GP2 release 11. We extracted 82 AD-associated variants reported by Bellenguez et al., along with all common (MAF ≥ 1%) variants within 79 loci. APOE was included as a positive control. Associations were tested using linear and logistic regression adjusted for sex, age and genetic principal components. Cognitive outcomes included continuous MoCA and MMSE baseline scores, as well as binary outcomes using established cut-offs. For binary, stringent models, PDD was defined as MoCA <19 and MMSE <20; for lenient models, PDCI was defined as MoCA ≤23 and MMSE ≤24. Bonferroni correction was applied per locus. Polygenic Risk Scores (PRS) based on Bellenguez et al. were also tested using PRSice-2 and the Bayesian method SBayesRC, adjusting for sex, age, genetic principal components and APOE ε4 status.

Results: We validated the association of APOE ε4 (β=-0.87, adjusted p=0.047, MoCA) with PDD. None of the 82 AD risk variants reached statistical significance after correction. However, 22 non-coding (20 intronic, 1 nuclear intronic, 1 intergenic) and 1 exonic variant across 12 loci showed significant associations with cognitive impairment, including ANKH and COX7C (MoCA), JAZF1, MAF, MYO15A, PLCG2, SNX1, WDR81 (MMSE), and TSPOAP1 p.Ala585Gly (stringent MMSE model). AD-derived PRS were not significantly associated with PDD.

Conclusion: Our findings suggest limited genetic overlap between established AD risk variants and cognitive impairment in PD. Further studies are needed to determine whether shared biological pathways contribute to dementia across disorders.

References: Bellenguez, Céline, Fahri Küçükali, Iris E. Jansen, et al. 2022. “New Insights into the Genetic Etiology of Alzheimer’s Disease and Related Dementias.” Nature Genetics 54 (4): 412–436.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/investigating-the-link-between-alzheimers-disease-genetic-risk-variants-and-parkinsons-disease-cognitive-impairment-an-exploration-of-genetic-overlap/