Resistance and resilience to Alzheimer\u2019s disease pathology are associated with reduced cortical pTau and absence of limbic-predominant age-related TDP-43 encephalopathy in a community-based cohort

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

doi:10.1186/s40478-019-0743-1

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.

Highlights

Alzheimer’s disease neuropathologic change (ADNC) is defined by the presence of extracellular amyloid (A) β plaques with varying levels of intracellular neurofibrillary tangles of hyperphosphorylated tau present in well-characterized, stereotypical patterns throughout the brain
We evaluated for each cohort the range of Cognitive Abilities Screening Instrument (CASI) latencies prior to death, with the assumption that a shorter latency provides a higher degree of confidence in the cognitive assessment
We found that the resistant group as a whole had a mean CASI latency of 1.04 years, with a range from 92 days to 1.8 years, and half having a CASI latency of less than one year

Summary

Introduction

Alzheimer’s disease neuropathologic change (ADNC) is defined by the presence of extracellular amyloid (A) β plaques with varying levels of intracellular neurofibrillary tangles of hyperphosphorylated tau (pTau) present in well-characterized, stereotypical patterns throughout the brain. The more extensively the brain is involved by Aβ and pTau pathology, the greater the likelihood an individual was cognitively impaired or demented as a result of the clinical manifestations of Alzheimer’s disease (AD). These clinical-neuropathologic correlations have been described in diverse autopsy cohort studies and are summarized in the 2012 NIA-AA guidelines for the neuropathological evaluation of AD [55]. While the vast majority of individuals over the age of 85 at death have some degree of AD neuropathology, those who have at least an intermediate degree of ADNC as defined by the NIA-AA guidelines are considered to have sufficient pathologic burden to explain dementia prior to death. Resilient and resistant individuals are relatively few in number in autopsy cohorts and represent the extremes of the population, understanding mechanisms that underlie their resilience or resistance to ADNC, which are likely to be distinct, may provide important clues to develop preventive and therapeutic strategies for AD

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