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Chronic traumatic encephalopathy (CTE) is a tauopathy associated with repetitive mild head impacts characterized by perivascular hyperphosphorylated tau (p-tau) in neurofibrillary tangles (NFTs) and neurites in the depths of the neocortical sulci. In moderate to advanced CTE, NFTs accumulate in the hippocampus, potentially overlapping neuroanatomically with primary age-related tauopathy (PART), an age-related tauopathy characterized by Alzheimer disease-like tau pathology in the hippocampus devoid of amyloid plaques. We measured p-tau burden using positive-pixel counts on immunohistochemically stained and neuroanatomically segmented hippocampal tissue. Subjects with CTE had a higher total p-tau burden than PART subjects in all sectors (p = 0.005). Within groups, PART had significantly higher total p-tau burden in CA1/subiculum compared to CA3 (p = 0.02) and CA4 (p = 0.01) and total p-tau burden in CA2 trended higher than CA4 (p = 0.06). In CTE, total p-tau burden in CA1/subiculum was significantly higher than in the dentate gyrus; and CA2 also trended higher than dentate gyrus (p = 0.01, p = 0.06). When controlling for p-tau burden across the entire hippocampus, CA3 and CA4 had significantly higher p-tau burden in CTE than PART (p

Primary age-related tauopathy (PART) is a neurodegenerative pathology with features distinct from but also overlapping with Alzheimer disease (AD). While both exhibit Alzheimer-type temporal lobe neurofibrillary degeneration alongside amnestic cognitive impairment, PART develops independently of amyloid-β (Aβ) plaques. The pathogenesis of PART is not known, but evidence suggests an association with genes that promote tau pathology and others that protect from Aβ toxicity. Here, we performed a genetic association study in an autopsy cohort of individuals with PART (n = 647) using Braak neurofibrillary tangle stage as a quantitative trait. We found some significant associations with candidate loci associated with AD (SLC24A4, MS4A6A, HS3ST1) and progressive supranuclear palsy (MAPT and EIF2AK3). Genome-wide association analysis revealed a novel significant association with a single nucleotide polymorphism on chromosome 4 (rs56405341) in a locus containing three genes, including JADE1 which was significantly upregulated in tangle-bearing neurons by single-soma RNA-seq. Immunohistochemical studies using antisera targeting JADE1 protein revealed localization within tau aggregates in autopsy brains with four microtubule-binding domain repeats (4R) isoforms and mixed 3R/4R, but not with 3R exclusively. Co-immunoprecipitation in post-mortem human PART brain tissue revealed a specific binding of JADE1 protein to four repeat tau lacking N-terminal inserts (0N4R). Finally, knockdown of the Drosophila JADE1 homolog rhinoceros (rno) enhanced tau-induced toxicity and apoptosis in vivo in a humanized 0N4R mutant tau knock-in model, as quantified by rough eye phenotype and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) in the fly brain. Together, these findings indicate that PART has a genetic architecture that partially overlaps with AD and other tauopathies and suggests a novel role for JADE1 as a modifier of neurofibrillary degeneration.

AbstractPrimary age-related tauopathy (PART) is a neurodegenerative tauopathy with features distinct from but also overlapping with Alzheimer disease (AD). While both exhibit Alzheimer-type temporal lobe neurofibrillary degeneration alongside amnestic cognitive impairment, PART develops independently of amyloid-β (Aβ) deposition in plaques. The pathogenesis of PART is unknown, but evidence suggests it is associated with genes that promote tau pathology as well as others that protect from Aβ toxicity. Here, we performed a genetic association study in an autopsy cohort of individuals with PART (n=647) using Braak neurofibrillary tangle stage as a quantitative trait adjusting for sex, age, genotyping platform, and principal components. We found significant associations with some candidate loci associated with AD and progressive supranuclear palsy, a primary tauopathy (SLC24A4, MS4A6A, HS3ST1, MAPT and EIF2AK3). Genome-wide association analysis revealed a novel significant association with a single nucleotide polymorphism on chromosome 4 (rs56405341) in a locus containing three genes, including JADE1 which was significantly upregulated in tangle-bearing neurons by single-soma RNA-seq. Immunohistochemical studies using antisera targeting JADE1 protein revealed localization within tau aggregates in autopsy brain from tauopathies containing isoforms with four microtubule-binding domain repeats (4R) and mixed 3R/4R, but not with 3R exclusively. Co-immunoprecipitation revealed a direct and specific binding of JADE1 protein to tau containing four (4R) and no N-terminal inserts (0N4R) in post-mortem human PART brain tissue. Finally, knockdown of the Drosophila JADE1 homolog rhinoceros (rno) enhanced tau-induced toxicity and apoptosis in vivo in a humanized 0N4R mutant tau knock-in model as quantified by rough eye phenotype and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) in the fly brain. Together, these findings indicate that PART has a genetic architecture that partially overlaps with AD and other tauopathies and suggests a novel role for JADE1 as a mediator of neurofibrillary degeneration.

Introduction: Neurofibrillary degeneration in Alzheimer's disease (AD) typically involves the entorhinal cortex and CA1 subregion of the hippocampus early in the disease process, whereas in primary age‐related tauopathy (PART), there is an early selective vulnerability of the CA2 subregion. Methods: Image analysis‐based quantitative pixel assessments were used to objectively evaluate amyloid beta (Aβ) burden in the medial temporal lobe in relation to the distribution of hyperphosphorylated‐tau (p‐tau) in 142 cases of PART and AD. Results: Entorhinal, CA1, CA3, and CA4 p‐tau deposition levels are significantly correlated with Aβ burden, while CA2 p‐tau is not. Furthermore, the CA2/CA1 p‐tau ratio is inversely correlated with Aβ burden and distribution. In addition, cognitive impairment is correlated with overall p‐tau burden. Discussion: These data indicate that the presence and extent of medial temporal lobe Aβ may determine the distribution and spread of neurofibrillary degeneration. The resulting p‐tau distribution patterns may discriminate between PART and AD. Highlights: Subregional hyperphosphorylated‐tau (p‐tau) distribution is influenced by hippocampal amyloid beta burden.Higher CA2/CA1 p‐tau ratio is predictive of primary age‐related tauopathy–like neuropathology.Cognitive function is correlated with the overall hippocampal p‐tau burden. [ABSTRACT FROM AUTHOR]

Background: Age‐related cognitive impairment is complex and multifactorial, with numerous underlying and frequently co‐morbid pathological correlates. Given that conventional measures are imperfect predictors of cognitive impairment, improved approaches are urgently needed to identify correlated histopathological changes in an unbiased way. Methods: We used a weakly supervised deep learning algorithm, clustering‐constrained‐attention multiple‐instance learning (CLAM), on digitized whole slide images of human brain tissue sections from a group of elderly individuals without significant amyloid‐beta deposition to predict the presence or absence of cognitive impairment. The brain tissue sections were from the hippocampus and frontal cortex and were either morphologically stained with LH&E or immunohistochemically stained for hyper‐phosphorylated tau. We used attention analysis to pinpoint the underlying architectural and cellular features that the top‐performing models used for the predictions. Results: Despite noisy labels of cognition, our trained models were able to predict the presence of cognitive impairment with an accuracy that significantly beat chance, in both the morphologically stained and immunohistochemically stained whole slide images. Attention‐based analysis of the features most associated with cognitive impairment in both types of whole slide images analyzed suggests that the models identified white matter alterations in donors with cognitive impairment. Conclusions: The deep learning method for the prediction of cognitive impairment that we present, which appears to be minimally influenced by the human‐identified visually salient aspects of whole slide images, may help to discover unexpected aspects of the pathophysiology associated with cognitive impairment in the elderly. [ABSTRACT FROM AUTHOR]

Introduction: Neurofibrillary degeneration in Alzheimer's disease (AD) typically involves the entorhinal cortex and CA1 subregion of the hippocampus early in the disease process, whereas in primary age-related tauopathy (PART), there is an early selective vulnerability of the CA2 subregion., Methods: Image analysis-based quantitative pixel assessments were used to objectively evaluate amyloid beta (Aβ) burden in the medial temporal lobe in relation to the distribution of hyperphosphorylated-tau (p-tau) in 142 cases of PART and AD., Results: Entorhinal, CA1, CA3, and CA4 p-tau deposition levels are significantly correlated with Aβ burden, while CA2 p-tau is not. Furthermore, the CA2/CA1 p-tau ratio is inversely correlated with Aβ burden and distribution. In addition, cognitive impairment is correlated with overall p-tau burden., Discussion: These data indicate that the presence and extent of medial temporal lobe Aβ may determine the distribution and spread of neurofibrillary degeneration. The resulting p-tau distribution patterns may discriminate between PART and AD., Highlights: Subregional hyperphosphorylated-tau (p-tau) distribution is influenced by hippocampal amyloid beta burden. Higher CA2/CA1 p-tau ratio is predictive of primary age-related tauopathy-like neuropathology. Cognitive function is correlated with the overall hippocampal p-tau burden., (© 2023 the Alzheimer's Association.)