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Acta Neuropathol Commun. 2019 Jun 7;7(1):9. doi: 10.1186/s40478-019-0743-1.

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.

Author information

1
Division of Neuropathology, Department of Pathology, University of Washington, Seattle, WA, 98104, USA. caitlinl@uw.edu.
2
Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
3
Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA.
4
Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, WA, USA.
5
Division of Neuropathology, Department of Pathology, University of Washington, Seattle, WA, 98104, USA.
6
Department of Medicine, University of Washington, Seattle, WA, USA.
7
Department of Neurology, University of Washington, Seattle, Washington, USA.
8
Deparment of Radiology, University of Washington, Seattle, Washington, USA.
9
Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA.
10
Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA.

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.

KEYWORDS:

Alzheimer’s disease neuropathologic change; C. elegans; Dementia; Hyperphosphorylated tau; Resilience; Resistance; TDP-43

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