Objective: To identify which common genetic variants that confer risk for Alzheimer’s disease (AD) also predict the development of concomitant AD pathology in patients with a primary clinicopathological diagnosis of Lewy body disease (LBD).

Background: Growing evidence suggests synergy between AD and Parkinson’s disease (PD) pathophysiology. 50-80% of autopsy cases with a primary clinicopathological diagnosis of Lewy body disease – most commonly manifesting during life as PD – have concomitant amyloid beta (AB) and tau pathology, the defining pathologies of AD [5]. At autopsy, up to 40% of PD patients exhibit enough AB and tau pathology to qualify for a secondary diagnosis of AD [1]. These findings suggest that LBD patients may be an at-risk/enriched group for subsequently developing AD.

Method: 208 autopsy cases of LBD were assessed for AD neuropathological change (ADNC) and genotyped at 20 single nucleotide polymorphisms (SNPs) found by genomewide association study (GWAS) to associate with risk for AD [2-4]. In a training set of 127 individuals, we developed a logistic regression model predicting the presence of ADNC, using backward stepwise regression for model selection (by AIC) and 10-fold cross-validation (100 iterations) to estimate performance. We then assessed model performance in a separate test set of 81 individuals.

Results: The best fit model generated a risk score for ADNC (ADNC-RS) based on age at disease onset and genotype at 3 SNPs (at the APOE, BIN1, and SORL1 loci). In the training set, the area under the receiver operating curve (AUC) for this model was 0.751. In the test set, the AUC was 0.781. Importantly, individuals with ADNC-RS in the top quintile had four-fold enrichment for the presence of AD pathology at autopsy compared with individuals with ADNC-RS in the lowest two quintiles.

Conclusion: In patients with primary LBD, common AD genetic risk variants identified by GWAS predict risk for concomitant AD pathology. A simple model incorporating only 3 AD risk SNPs and age at disease onset substantially enriches for the subset of LBD patients with concomitant ADNC at autopsy. Our findings have implications for identifying LBD patients in which targeting of amyloid-beta or tau may be a promising therapeutic strategy.To be presented at Advances in Alzheimer’s and Parkinson’s Therapies: An AAT-AD/PD Focus Meeting on April 3, 2020.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-adnpc-rs-a-risk-score-that-identifies-lewy-body-disease-individuals-at-risk-for-developing-concomitant-alzheimers-pathology/