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Open Access 01-12-2019 | Alzheimer's Disease | Research

Resistance and resilience to Alzheimer’s disease pathology are associated with reduced cortical pTau and absence of limbic-predominant age-related TDP-43 encephalopathy in a community-based cohort

Authors: Caitlin S. Latimer, Bridget T. Burke, Nicole F. Liachko, Heather N. Currey, Mitchell D. Kilgore, Laura E. Gibbons, Jonathan Henriksen, Martin Darvas, Kimiko Domoto-Reilly, Suman Jayadev, Tom J. Grabowski, Paul K. Crane, Eric B. Larson, Brian C. Kraemer, Thomas D. Bird, C. Dirk Keene

Published in: Acta Neuropathologica Communications | Issue 1/2019

Abstract

Alzheimer’s disease neuropathologic change (ADNC) is defined by progressive accumulation of β-amyloid plaques and hyperphosphorylated tau (pTau) neurofibrillary tangles across diverse regions of brain. Non-demented individuals who reach advanced age without significant ADNC are considered to be resistant to AD, while those burdened with ADNC are considered to be resilient. Understanding mechanisms underlying ADNC resistance and resilience may provide important clues to treating and/or preventing AD associated dementia. ADNC criteria for resistance and resilience are not well-defined, so we developed stringent pathologic cutoffs for non-demented subjects to eliminate cases of borderline pathology. We identified 14 resistant (85+ years old, non-demented, Braak stage ≤ III, CERAD absent) and 7 resilient (non-demented, Braak stage VI, CERAD frequent) individuals out of 684 autopsies from the Adult Changes in Thought study, a long-standing community-based cohort. We matched each resistant or resilient subject to a subject with dementia and severe ADNC (Braak stage VI, CERAD frequent) by age, sex, year of death, and post-mortem interval. We expanded the neuropathologic evaluation to include quantitative approaches to assess neuropathology and found that resilient participants had lower neocortical pTau burden despite fulfilling criteria for Braak stage VI. Moreover, limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) was robustly associated with clinical dementia and was more prevalent in cases with high pTau burden, supporting the notion that resilience to ADNC may depend, in part, on resistance to pTDP-43 pathology. To probe for interactions between tau and TDP-43, we developed a C. elegans model of combined human (h) Tau and TDP-43 proteotoxicity, which exhibited a severe degenerative phenotype most compatible with a synergistic, rather than simply additive, interaction between hTau and hTDP-43 neurodegeneration. Pathways that underlie this synergy may present novel therapeutic targets for the prevention and treatment of AD.

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Title: Resistance and resilience to Alzheimer’s disease pathology are associated with reduced cortical pTau and absence of limbic-predominant age-related TDP-43 encephalopathy in a community-based cohort
Authors: Caitlin S. Latimer
Bridget T. Burke
Nicole F. Liachko
Heather N. Currey
Mitchell D. Kilgore
Laura E. Gibbons
Jonathan Henriksen
Martin Darvas
Kimiko Domoto-Reilly
Suman Jayadev
Tom J. Grabowski
Paul K. Crane
Eric B. Larson
Brian C. Kraemer
Thomas D. Bird
C. Dirk Keene
Publication date: 01-12-2019
Publisher: BioMed Central
Keywords: Alzheimer's Disease
Alzheimer's Disease
Dementia
Dementia
Pathology
Encephalopathy
Autopsy
Published in: Acta Neuropathologica Communications / Issue 1/2019
Electronic ISSN: 2051-5960
DOI: https://doi.org/10.1186/s40478-019-0743-1

At a glance: The STEP trials

Springer Medicine

Resistance and resilience to Alzheimer’s disease pathology are associated with reduced cortical pTau and absence of limbic-predominant age-related TDP-43 encephalopathy in a community-based cohort

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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