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.
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.
['Latimer|Caitlin S|CS|0000-0003-3727-4278', 'Burke|Bridget T|BT|', 'Liachko|Nicole F|NF|', 'Currey|Heather N|HN|', 'Kilgore|Mitchell D|MD|', 'Gibbons|Laura E|LE|', 'Henriksen|Jonathan|J|', 'Darvas|Martin|M|', 'Domoto-Reilly|Kimiko|K|', 'Jayadev|Suman|S|', 'Grabowski|Tom J|TJ|', 'Crane|Paul K|PK|', 'Larson|Eric B|EB|', 'Kraemer|Brian C|BC|', 'Bird|Thomas D|TD|', 'Keene|C Dirk|CD|']
D000367:Age Factors D000368:Aged D000369:Aged, 80 and over D000544:Alzheimer Disease D000818:Animals D017173:Caenorhabditis elegans D015331:Cohort Studies D004268:DNA-Binding Proteins D005260:Female D006801:Humans D057187:Independent Living D008032:Limbic System D008297:Male D000073216:Mental Status and Dementia Tests D019579:Neocortex D011446:Prospective Studies D055500:Resilience, Psychological D016875:tau Proteins
Resistance Resilience TDP-43 Hyperphosphorylated tau Dementia C. elegans Alzheimer’s disease neuropathologic change