Neocortical‐type Lewy bodies and limbic‐predominant age‐related TDP‐43 encephalopathy neuropathologic change in community‐dwelling older persons

Background Lewy bodies are common in aging and often co‐occur with Alzheimer's disease (AD). There is recent and expanding recognition of another common proteinopathy, limbic predominant age‐related TDP‐43 neuropathologic change (LATE‐NC), in the aging brain and all 3 proteinopathies are associated with the APOEε4 genotype. Most studies have focused on the association of LATE‐NC and AD, but there are few studies that specifically focus on LATE‐NC and Lewy body disease. The objective of this study was to test the hypothesis that neocortical Lewy bodies are independently associated with LATE‐NC. Method Participants without dementia from three longitudinal clinical‐pathologic studies, the Rush Memory and Aging Project, the Religious Orders Study, and the Minority Aging Research Study were included. Uniform neuropathologic examinations provided measures of LATE‐NC, neocortical Lewy bodies, and AD. LATE‐NC pathology was defined as the distribution of TDP‐43 in the brain by using a staging system: stage 0, no TDP‐43 deposition; stage 1, TDP‐43 deposition localized to the amygdala; stage 2, extension to the hippocampus and/or entorhinal cortex; stage 3, further extension to the neocortex. Lewy bodies were assessed in the neocortical regions by immunohistochemistry. Ordinal logistic regression models were used to examine the association of neocortical Lewy bodies with the odds of having more severe LATE‐NC after controlling for demographics, global AD pathology score, and APOEε4. Result 1564 participants [mean age‐at‐death= 89.5 years (SD= 6.7); mean education=16.2 years (SD= 3.6); 68% women; 26% APOEε4] were included in the analyses. Neocortical Lewy bodies were present in 214 (13.7%) of descendants. 136 (63.5%) subjects with neocortical Lewy bodies had LATE‐NC pathology [stage 1 (n=40), stage 2 (n=32), and stage 3 (n=64)]. Neocortical Lewy bodies were associated with a higher odds of more advanced LATE‐NC stages (Odds Ratio = 1.55; 95% Confidence Interval = 1.17–2.04) after controlling for demographics and AD pathology. These results persisted after adjusting for presence of APOEε4. Conclusion These findings suggest that neocortical Lewy bodies are independently associated with LATE‐NC in the older brain. Future research is needed on the diagnosis, prognosis, and pathogenesis of mixed neocortical Lewy body disease and LATE‐NC and related neurodegeneration in aging brain.