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

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.

Unified AI framework to uncover deep interrelationships between gene expression and Alzheimer’s disease neuropathologies

“…cognitive or neurological decline (consistent with previous literature, e.g. Latimer et al (2019)). To annotate each node in the consensus embedding, we display their correlations with various phenotypes and covariates, as well as their enrichment for REACTOME pathways.…”

Concomitant LATE‐NC in Alzheimer's disease is not associated with increased tau or amyloid‐β pathological burden

“…Complex protein interactions within shared common pathways are implicated in both ageing and AD that can result in the pathologic phosphorylation, misfolding and aggregation of various proteins inclusive of TDP-43 and tau. Findings from in vitro models [46], human neuropathological studies [4,25,47] and transgenic C. elegans models [47] indicate a possible synergistic relationship between TDP-43 and tau. Therefore, we might expect to see differences in the pathological tau burden between AD/LATE-NC and AD cases, and an association between pathological tau load and LATE-NC stage.…”

TDP-43: From Alzheimer’s Disease to Limbic-Predominant Age-Related TDP-43 Encephalopathy

“…Moreover, LATE exhibits a different neuroanatomical distribution of FTLD, and is relatively more restricted than FTLD (Kadokura et al, 2009). Autopsy showed that at least 25% of identifiable cognitive dysfunctions were associated with LATE-NC, and many subjects with LATE-NC had Aβ plaques, tauopathy, and a higher p-tau burden (Latimer et al, 2019;Nelson et al, 2019). Diagnostic and staging guidelines for LATE-NC were proposed for use during routine autopsies.…”