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Colin Birkenbihl1, Hannah M Klinger1, Michael J Properzi2

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Summary
This summary is machine-generated.

Lower medial temporal lobe (MTL) tau and younger age are linked to resistance against neocortical tau spread in Alzheimer's disease (AD). This resistance may involve amyloid-beta (Aβ) and impacts cognitive reserve.

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Area of Science:

  • Neuroscience
  • Alzheimer's Disease Research
  • Biomarker Discovery

Background:

  • Neocortical tau pathology, particularly in individuals with high beta-amyloid (Aβ), is a suspected driver of Alzheimer's disease (AD) neurodegeneration and cognitive decline.
  • Resistance to neocortical tau spread, defined by lower-than-expected tau in the neocortex relative to Aβ burden and demographics, was investigated.
  • Understanding tau resistance may offer insights into AD pathogenesis and individual variability in disease progression.

Purpose of the Study:

  • To examine the associations between resistance to neocortical tau pathology and markers of AD pathology, cognitive performance, and brain reserve.
  • To investigate the role of medial temporal lobe (MTL) tau, neocortical Aβ, and demographic factors in influencing tau resistance.
  • To explore the relationship between brain reserve measures (hippocampal volume, entorhinal cortical thickness) and tau resistance.

Main Methods:

  • Tau resistance was quantified using an inverse learning method, estimating deviation from a model of high neocortical tau burden.
  • Linear regression models analyzed associations between tau resistance and MTL tau-PET, neocortical Aβ-PET, brain reserve measures, and cognitive performance (PACC) in a pooled cohort.
  • Models were adjusted for age, sex, education, cohort, and APOEε4 status.

Main Results:

  • Lower MTL tau, lower Aβ burden, and younger age were significantly associated with higher neocortical tau resistance.
  • Higher cognitive performance (PACC), greater hippocampal volume, and thicker entorhinal cortices were associated with lower tau resistance.
  • An interaction between Aβ and MTL tau burden influenced lower resistance, with only lower PACC and younger age remaining significant in Aβ+ individuals.

Conclusions:

  • Baseline MTL tau levels and age appear to influence resistance to tauopathy spread into neocortical regions, potentially mediated by Aβ in early AD stages.
  • The inverse association with cognition and brain reserve suggests that 'tau resistance' may be more apparent in individuals with greater cognitive impairment and lower reserve.
  • These findings highlight the complex interplay of tau, Aβ, age, and individual reserve in modulating AD neurodegenerative processes.