Lewy body dementia, including both Parkinson’s disease dementia and dementia with Lewy bodies, is defined by underlying Lewy body pathology and cognitive decline that impacts daily life. Although Lewy body dementia is the second most common type of neurodegenerative dementia following Alzheimer’s, research continues to be substantially scarce in this dementia compared to Alzheimer’s. While sex differences consistently get reported in Alzheimer’s, sex differences in Lewy body dementia are still not clearly understood and needs more investigations.

Autopsy studies so far showed females are not as likely as males to have pure Lewy body pathology, and have a higher likelihood for other pathologies accompanying Lewy body pathology (e.g., Alzheimer’s pathology). Having additional pathologies with Lewy body pathology lowers the likelihood of having a Lewy body dementia phenotype. However, our previous work showed that even when females have pure Lewy body pathology, they continue to be less likely to have a Lewy body dementia phenotype. Adding Alzheimer’s pathology to the mix showed that females continue to be less likely than males to have a Lewy body dementia phenotype when comparing females and males with similar levels of Lewy body and Alzheimer’s pathology. So, building up on these previous studies we performed using the National Alzheimer’s Coordinating Center data, we wanted to look into the clinical correlates of substantia nigra neuron loss, the third pathology feature mentioned in the Lewy body dementia diagnosis.

Nigral loss has been associated with parkinsonism in people with Lewy body dementia. Although not every person with Lewy body dementia has nigral loss, it increases the likelihood of someone having a Lewy body dementia phenotype when it occurs given associations with parkinsonism. Females are less likely than males to have parkinsonism in Lewy body dementia. Thus, we wondered if nigral loss contributes to this sex difference.

We included 159 females and 263 males with brainstem, limbic, or neocortical Lewy body pathology from the National Alzheimer’s Coordinating Center database. We identified whether people had clinician report of Lewy body dementia core features (cognitive fluctuations, visual hallucinations, rapid eye movement sleep behavior disorder, parkinsonism) during follow-up. We used generalized linear models adjusting for age and Alzheimer’s pathology staging for the association between nigral loss and (1) Lewy body pathology staging, (2) presence of Lewy body dementia core features. We also assessed whether any of the core clinical features can predict underlying nigral loss using the clinical profile at the first visit with dementia.

Similar to our previous papers, we noted that females died older and had higher levels of Braak tau staging. However, Lewy body pathology staging and nigral loss levels were similar for females and males. Females were less likely than males to have a Lewy body dementia phenotype. We found that more advanced Lewy body pathology staging was associated with more severe nigral loss, more so for males. In terms of nigral loss association with clinical features, more nigral loss was associated with a higher likelihood of parkinsonism and Lewy body dementia phenotype, more so for males. We did not identify any core features associated with nigral loss at the first visit with dementia in a subgroup of 40 females and 58 males who developed dementia during follow-up.

These findings build up on our previous reports in the National Alzheimer’s Coordinating Center data for people with pathologically-defined Lewy body dementia. Similar to Lewy body and Alzheimer’s pathology correlates differing by sex, nigral loss correlates also differ by sex. Females with Lewy body pathology have a higher risk of underdiagnosis compared to males, even when they have lower levels of Alzheimer’s pathology and higher levels for nigral loss. Furthermore, as we utilize DaTScan, which correlates with nigral loss, as a supportive biomarker for Lewy body dementia, the utility of this biomarker likely differs by sex. Understanding why females may not develop dementia or other symptoms despite having as much pathology as males, can help with therapeutic efforts.