Comparison of Clinical, Genetic, and Pathologic Features of Limbic and Diffuse Transactive Response DNA-Binding Protein 43 Pathology in Alzheimer's Disease Neuropathologic Spectrum

Background: Increasing evidence suggests that TAR DNA-binding protein 43 (TDP-43) pathology in Alzheimer's disease (AD), or AD-TDP, can be diffuse or limbic-predominant. Understanding whether diffuse AD-TDP has genetic, clinical, and pathological features that differ from limbic AD-TDP could have clinical and research implications. Objective: To better characterize the clinical and pathologic features of diffuse AD-TDP and differentiate it from limbic AD-TDP. Methods: 363 participants from the Mayo Clinic Study of Aging, Alzheimer's Disease Research Center, and Neurodegenerative Research Group with autopsy confirmed AD and TDP-43 pathology were included. All underwent genetic, clinical, neuropsychologic, and neuropathologic evaluations. AD-TDP pathology distribution was assessed using the Josephs 6-stage scale. Stages 1-3 were classified as Limbic, those 4-6 as Diffuse. Multivariable logistic regression was used to identify clinicopathologic features that independently predicted diffuse pathology. Results: The cohort was 61% female and old at onset (median: 76 years [IQR:70-82]) and death (median: 88 years [IQR:82-92]). Fifty-four percent were Limbic and 46% Diffuse. Clinically,similar to 10-20% increases in odds of being Diffuse associated with 5-year increments in age at onset (p = 0.04), 1-year longer disease duration (p = 0.02), and higher Neuropsychiatric Inventory scores (p = 0.03), while 15-second longer Trailmaking Test-B times (p = 0.02) and higher Block Design Test scores (p = 0.02) independently decreased the odds by similar to 10-15%. There was evidence for association of APOE epsilon 4 allele with limbic AD-TDP and of TMEM106B rs3173615 C allele with diffuse AD-TDP. Pathologically, widespread amyloid-beta plaques (Thal phases: 3-5) decreased the odds of diffuse TDP-43 pathology by 80-90%, while hippocampal sclerosis increased it sixfold (p < 0.001). Conclusion: Diffuse AD-TDP shows clinicopathologic and genetic features different from limbic AD-TDP.