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Tau molecular diversity contributes to clinical heterogeneity in Alzheimer's disease.

ABSTRACT: Alzheimer's disease (AD) causes unrelenting, progressive cognitive impairments, but its course is heterogeneous, with a broad range of rates of cognitive decline¹. The spread of tau aggregates (neurofibrillary tangles) across the cerebral cortex parallels symptom severity^2,3. We hypothesized that the kinetics of tau spread may vary if the properties of the propagating tau proteins vary across individuals. We carried out biochemical, biophysical, MS and both cell- and animal-based-bioactivity assays to characterize tau in 32 patients with AD. We found striking patient-to-patient heterogeneity in the hyperphosphorylated species of soluble, oligomeric, seed-competent tau. Tau seeding activity correlates with the aggressiveness of the clinical disease, and some post-translational modification (PTM) sites appear to be associated with both enhanced seeding activity and worse clinical outcomes, whereas others are not. These data suggest that different individuals with 'typical' AD may have distinct biochemical features of tau. These data are consistent with the possibility that individuals with AD, much like people with cancer, may have multiple molecular drivers of an otherwise common phenotype, and emphasize the potential for personalized therapeutic approaches for slowing clinical progression of AD.

SUBMITTER: Dujardin S

PROVIDER: S-EPMC7603860 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Tau molecular diversity contributes to clinical heterogeneity in Alzheimer's disease.

Dujardin Simon S Commins Caitlin C Lathuiliere Aurelien A Beerepoot Pieter P Fernandes Analiese R AR Kamath Tarun V TV De Los Santos Mark B MB Klickstein Naomi N Corjuc Diana L DL Corjuc Bianca T BT Dooley Patrick M PM Viode Arthur A Oakley Derek H DH Moore Benjamin D BD Mullin Kristina K Jean-Gilles Dinorah D Clark Ryan R Atchison Kevin K Moore Renee R Chibnik Lori B LB Tanzi Rudolph E RE Frosch Matthew P MP Serrano-Pozo Alberto A Elwood Fiona F Steen Judith A JA Kennedy Matthew E ME Hyman Bradley T BT

Nature medicine 20200622 8

Alzheimer's disease (AD) causes unrelenting, progressive cognitive impairments, but its course is heterogeneous, with a broad range of rates of cognitive decline<sup>1</sup>. The spread of tau aggregates (neurofibrillary tangles) across the cerebral cortex parallels symptom severity<sup>2,3</sup>. We hypothesized that the kinetics of tau spread may vary if the properties of the propagating tau proteins vary across individuals. We carried out biochemical, biophysical, MS and both cell- and animal ...[more]

PMID: 32572268

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Project description:SEE SARAZIN ET AL DOI101093/BRAIN/AWW041 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: The advent of the positron emission tomography tracer (18)F-AV1451 provides the unique opportunity to visualize the regional distribution of tau pathology in the living human brain. In this study, we tested the hypothesis that tau pathology is closely linked to symptomatology and patterns of glucose hypometabolism in Alzheimer's disease, in contrast to the more diffuse distribution of amyloid-β pathology. We included 20 patients meeting criteria for probable Alzheimer's disease dementia or mild cognitive impairment due to Alzheimer's disease, presenting with a variety of clinical phenotypes, and 15 amyloid-β-negative cognitively normal individuals, who underwent (18)F-AV1451 (tau), (11)C-PiB (amyloid-β) and (18)F-FDG (glucose metabolism) positron emission tomography, apolipoprotein E (APOE) genotyping and neuropsychological testing. Voxel-wise contrasts against controls (at P < 0.05 family-wise error corrected) showed that (18)F-AV1451 and (18)F-FDG patterns in patients with posterior cortical atrophy ('visual variant of Alzheimer's disease', n = 7) specifically targeted the clinically affected posterior brain regions, while (11)C-PiB bound diffusely throughout the neocortex. Patients with an amnestic-predominant presentation (n = 5) showed highest (18)F-AV1451 retention in medial temporal and lateral temporoparietal regions. Patients with logopenic variant primary progressive aphasia ('language variant of Alzheimer's disease', n = 5) demonstrated asymmetric left greater than right hemisphere (18)F-AV1451 uptake in three of five patients. Across 30 FreeSurfer-defined regions of interest in 16 Alzheimer's disease patients with all three positron emission tomography scans available, there was a strong negative association between (18)F-AV1451 and (18)F-FDG uptake (Pearson's r = -0.49 ± 0.07, P < 0.001) and less pronounced positive associations between (11)C-PiB and (18)F-FDG (Pearson's r = 0.16 ± 0.09, P < 0.001) and (18)F-AV1451 and (11)C-PiB (Pearson's r = 0.18 ± 0.09, P < 0.001). Voxel-wise linear regressions thresholded at P < 0.05 (uncorrected) showed that, across all patients, younger age was associated with greater (18)F-AV1451 uptake in wide regions of the neocortex, while older age was associated with increased (18)F-AV1451 in the medial temporal lobe. APOE ϵ4 carriers showed greater temporal and parietal (18)F-AV1451 uptake than non-carriers. Finally, worse performance on domain-specific neuropsychological tests was associated with greater (18)F-AV1451 uptake in key regions implicated in memory (medial temporal lobes), visuospatial function (occipital, right temporoparietal cortex) and language (left > right temporoparietal cortex). In conclusion, tau imaging-contrary to amyloid-β imaging-shows a strong regional association with clinical and anatomical heterogeneity in Alzheimer's disease. Although preliminary, these results are consistent with and expand upon findings from post-mortem, animal and cerebrospinal fluid studies, and suggest that the pathological aggregation of tau is closely linked to patterns of neurodegeneration and clinical manifestations of Alzheimer's disease.

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Tau molecular diversity contributes to clinical heterogeneity in Alzheimer's disease.

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Tau molecular diversity contributes to clinical heterogeneity in Alzheimer's disease.

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