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

Article type: Research Article

Authors: Carlos, Arenn F.^a | Machulda, Mary M.^b | Rutledge, Matthew H.^a | Nguyen, Aivi T.^c | Reichard, R. Ross^c | Baker, Matthew C.^d | Rademakers, Rosa^{d; e; f} | Dickson, Dennis W.^d | Petersen, Ronald C.^a | Josephs, Keith A.^{a; *}

Affiliations: [a] Department of Neurology, Mayo Clinic, Rochester, MN, USA | [b] Department of Psychology and Psychiatry, Mayo Clinic, Rochester, MN, USA | [c] Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA | [d] Department of Neuroscience (Neuropathology), Mayo Clinic, Jacksonville, FL, USA | [e] VIB Center for Molecular Neurology, VIB, Antwerp, Belgium | [f] Department of Biomedical Sciences, University of Antwerp, Antwerp, Flanders, Belgium

Correspondence: [*] Correspondence to: Keith A. Josephs, MD., MST, MSc, Professor of Neuroscience and Neurology, Ani Professor of Alzheimer’s Disease Research, Department of Neurology, Mayo Clinic, 200 1st St S.W., Rochester, MN 55905, USA. Tel.: +1 507 538 1038; Fax: +1 507 538 6012; E-mail: [email protected].

Abstract: 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, ∼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 ~ 10–15%. There was evidence for association of APOE ɛ4 allele with limbic AD-TDP and of TMEM106B rs3173615 C allele with diffuse AD-TDP. Pathologically, widespread amyloid-β 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.

Keywords: Alzheimer’s disease, neuropathology, neuropsychology, TDP-43 proteinopathy

DOI: 10.3233/JAD-221094

Journal: Journal of Alzheimer's Disease, vol. 93, no. 4, pp. 1521-1535, 2023