Objective: To assess sex differences in regional Lewy body pathology densities and their clinical correlations in cases with Lewy body (LB) pathology at autopsy.

Background: Lewy body diseases (LBD) have known sex differences with lower prevalence, higher rates of clinical underdiagnosis and Alzheimer disease (AD) co-pathology in females compared to males. Pathological differences between sexes have been associated with clinical correlates and recent work suggests existing sex differences at the regional pathology level. Hence, sex differences in regional pathology along the LBD spectrum and its clinical correlations may help understand phenotypic differences between sexes.

Method: Cases with postmortem LB pathology from the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND) were selected and grouped as LBD including cases with dementia with Lewy bodies (DLB; n=181) and Parkinson’s disease (PD) with neocortical LB (n=131) that may have AD co-pathology, AD with LB (ADLB; not meeting criteria for DLB) (n=400), PD (not reaching neocortical LB) (n=147) and incidental Lewy body disease (ILBD) (n=103). Alpha-synucleinopathy (aSyn) density scores (0–4) were assessed in the olfactory bulb, brainstem regions of the medulla (IX-X), the locus coeruleus (LC) and substantia nigra (SN), limbic regions of the amygdala (AMY), transentorhinal (TRANS) and anterior cingulate cortex (ACC), and in temporal (MTG), frontal (MFG) and parietal (IPG) neocortical regions.

Results: Of 871 cases, 533 (61%) were males. Females were older at death and had a lower MMSE score (18.2 vs. 16.1). When corrected for age, disease duration and MMSE; higher aSyn densities were found in females in MTG and IPG in LBD while higher densities were found in males in the SN in the PD group and in all 3 brainstem regions and AAC in ADLB. No differences were found in ILBD. UPDRS and MMSE predicts MTG and IPG aSyn in LBD, REM sleep behavior disorder (RBD) and UPDRS predicts SN aSyn in PD while MMSE, RBD and UPDRS predicts LB pathology in all 3 brainstem regions in ADLB in both sexes.

Conclusion: These results suggest that female with LBD and males with PD and ADLB might be more vulnerable to LB pathology in neocortex and brainstem regions respectively. While clinical correlates of these differences still need to be further delineated, these results highlight that sex specific expression of symptoms may be driven by differential distribution of LB pathology by brain regions.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/sex-differences-in-regional-densities-of-lewy-body-pathology/