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Objective: To evaluate whether APOE [epsilon]4 is associated with severity of Lewy body (LB) pathology, independently of Alzheimer disease (AD) pathology.

Methods: Six hundred fifty-two autopsy-confirmed LB disease (LBD) cases and 660 clinical controls were genotyped for APOE. In case-control analysis, LBD cases were classified into 9 different groups according to severity of both LB pathology (brainstem, transitional, diffuse) and AD pathology (low, moderate, high) to assess associations between APOE [epsilon]4 and risk of different neuropathologically defined LBD subgroups in comparison to controls. In LBD cases only, we also measured LB counts from 5 cortical regions and evaluated associations with [epsilon]4 according to severity of AD pathology.

Results: As expected, APOE [epsilon]4 was associated with an increased risk of transitional and diffuse LBD in cases with moderate or high AD pathology (all odds ratios >=3.42, all p <= 0.004). Of note, [epsilon]4 was also associated with an increased risk of diffuse LBD with low AD pathology (odds ratio = 3.46, p = 0.001). In the low AD pathology LBD subgroup, [epsilon]4 was associated with significantly more LB counts in the 5 cortical regions, independently of Braak stage and Thal phase (all p <= 0.002).

Conclusions: Our results indicate that APOE [epsilon]4 is independently associated with a greater severity of LB pathology. These findings increase our understanding of the mechanism behind reported associations of [epsilon]4 with risk of dementia with Lewy bodies and Parkinson disease with dementia, and suggest that [epsilon]4 may function as a modifier of processes that favor LB spread rather than acting directly to initiate LB pathology.

(C) 2018 American Academy of Neurology