Pathologic Features of Asymptomatic Limbic‐Predominant Age‐Related TDP‐43 Encephalopathy Neuropathologic Change (LATE‐NC).

Background: LATE‐NC is a newly‐defined TDP‐43 proteinopathy that is common in older adults and associated with amnestic dementia syndrome. To our knowledge, no prior study has studied individuals resilient to LATE‐NC (participants with Stage 2 or 3 LATE‐NC but no cognitive impairment at autopsy). The extensive autopsy dataset at the National Alzheimer's Coordinator Center (NACC) uniquely positions us to examine these rare individuals. To determine if asymptomatic participants have lower levels of other neuropathologic diseases, we compared neuropathologic features against participants with clinical dementia. Method: We included autopsied participants from NACC's Uniform Data Set whose last visit was within two years of death or had clinical dementia at their last visit. Participants were excluded if they had rare neuropathologic diseases or were not evaluated for each neuropathologic feature. For asymptomatic (normal cognition, 75+ years old, stage 2 or 3 LATE‐NC) individuals, we calculated the odds of having non‐LATE pathologic features against a control group (stage 2 or 3 LATE‐NC, clinical dementia), adjusting for age at death, sex, education, and presence of APOE e4 allele(s). Features included Alzheimer's pathology (amyloid plaques and neurofibrillary tangles) vascular pathology (number of infarcts and microinfarcts; severity of arteriosclerosis, atherosclerosis, and cerebral amyloid angiopathy), and Lewy body disease (LBD) staging. Result: Of participants who met inclusion criteria, 20 were asymptomatic and 505 were controls. In unadjusted analyses, asymptomatic participants had lower severity of amyloid plaques, tau tangles, LBD, microinfarcts, and arteriosclerosis, and were less likely to have an APOE e4 allele. In adjusted logistic regression analysis, associations remained only for tau tangles, LBD, and APOE. Interestingly, we found no association of asymptomatic LATE‐NC with amyloid plaques (Thal phase or CERAD score). Conclusion: Resilience to LATE‐NC is associated with lower odds of other neuropathologic disease, including neurofibrillary tangles and Lewy bodies. This supports prior research indicating an interactive effect of multiple neuropathologic diseases on risk of dementia. Severity of amyloid plaques was not associated with risk of dementia in participants with LATE‐NC, indicating that amyloid‐reducing therapies may not be an effective way to prevent LATE symptoms. [ABSTRACT FROM AUTHOR]