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Spatiotemporal relationship between subthreshold amyloid accumulation and aerobic glycolysis in the human brain.

ABSTRACT: In Alzheimer's disease, brain amyloid deposition has a distinct topography that correlates with aerobic glycolysis (AG), that is, the use of glucose beyond that predicted by oxygen consumption. The causes for this relationship remain unclear but might provide crucialinsight into how amyloid deposition begins. Here we develop methods to study the earliest topography of amyloid deposition based on amyloid imaging and investigate its spatiotemporal evolution with respect to the topography of AG in adults. We find that the spatiotemporal dynamics of amyloid deposition are largely explained by 1 factor, defined here as the amyloid topography dissimilarity index (ATDI). ATDI is bimodal, more highly dynamic during early amyloid accumulation, and predicts which individuals will cross a conservative quantitative threshold at least 3-5 years in advance. Using ATDI, we demonstrate that subthreshold amyloid accumulates primarily in regions that have high AG during early adulthood. Our findings suggest that early on-target subthreshold amyloid deposition mirrors its later regional pattern, which best corresponds to the topography of young adult brain AG.

SUBMITTER: Goyal MS

PROVIDER: S-EPMC7894981 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Different tau biomarkers become abnormal at different stages of Alzheimer's disease, with CSF phospho-tau typically becoming elevated at subthreshold levels of tau-PET binding. To capitalize on the temporal order of tau biomarker-abnormality and capture the earliest changes of tau accumulation, we implemented an observational study design to examine longitudinal changes in tau-PET, cortical thickness and cognitive decline in amyloid-β-positive individuals with elevated CSF p-tau levels (P+) but subthreshold Tau-PET retention (T-). To this end, individuals without dementia (i.e. cognitively unimpaired or mild cognitive impairment, n = 231) were selected from the BioFINDER-2 study. Amyloid-β-positive (A+) individuals were categorized into biomarker groups based on cut-offs for abnormal CSF p-tau217 and 18F-RO948 (Tau) PET, yielding groups of tau-concordant-negative (A+P-T-; n = 30), tau-discordant (i.e. A+P+T-; n = 48) and tau-concordant-positive (A+P+T+; n = 18) individuals. In addition, 135 amyloid-β-negative, tau-negative, cognitively unimpaired individuals served as controls. Differences in annual change in regional tau-PET, cortical thickness and cognition between the groups were assessed using general linear models, adjusted for age, sex, clinical diagnosis and (for cognitive measures only) education. Mean follow-up time was ∼2 years. Longitudinal increase in tau-PET was faster in the A+P+T- group than in the control and A+P-T- groups across medial temporal and neocortical regions, with the highest accumulation rates in the medial temporal lobe. The A+P+T- group showed a slower rate of increase in tau-PET compared to the A+P+T+ group, primarily in neocortical regions. We did not detect differences in yearly change in cortical thickness or in cognitive decline between the A+P+T- and A+P-T- groups. The A+P+T+ group, however, showed faster cognitive decline compared to all other groups. Altogether, these findings suggest that the A+P+T- biomarker profile in persons without dementia is associated with an isolated effect on increased tau-PET accumulation rates but not on cortical thinning and cognitive decline. While this suggests that the tau-discordant biomarker profile is not strongly associated with short-term clinical decline, this group does represent an interesting population for monitoring the effects of interventions with disease-modifying agents on tau accumulation in early Alzheimer's disease, and for examining the emergence of tau aggregates in Alzheimer's disease. Further, we suggest updating the AT(N) criteria for Alzheimer's disease biomarker classification to APT(N).

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Spatiotemporal relationship between subthreshold amyloid accumulation and aerobic glycolysis in the human brain.

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