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Clinical Manifestations.

Colin Birkenbihl1, Hannah M Klinger1, Michael J Properzi2

  • 1Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Alzheimer'S & Dementia : the Journal of the Alzheimer'S Association
|December 25, 2025
PubMed
Summary
This summary is machine-generated.

Resistance to neocortical tau spread is associated with lower medial temporal lobe tau and younger age. This suggests tau resistance may be linked to greater cognitive impairment and lower brain reserve in Alzheimer's disease research.

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Area of Science:

  • Neuroscience
  • Alzheimer's Disease Research
  • Biomarkers

Background:

  • Neocortical tau pathology, particularly in individuals with high beta-amyloid (Aβ), is implicated as a primary driver of Alzheimer's disease (AD) neurodegeneration and cognitive decline.
  • Resistance to tau pathology spread from medial temporal lobe (MTL) regions is defined by lower-than-expected neocortical tau levels relative to individual factors like Aβ burden.
  • Understanding tau resistance mechanisms is crucial for elucidating AD progression and identifying potential therapeutic targets.

Purpose of the Study:

  • To investigate the associations between resistance to neocortical tau pathology and key markers of AD.
  • To examine the relationship between tau resistance, Alzheimer's disease biomarkers (Aβ and tau), cognitive performance, and brain reserve.
  • To explore the role of MTL tau and Aβ in modulating neocortical 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, brain reserve (hippocampal volume, entorhinal cortical thickness), and neocortical Aβ-PET.
  • Cognitive performance (PACC), MTL tau, Aβ-PET, and their interaction were assessed, adjusting for demographic and genetic factors (age, sex, education, cohort, APOEε4).

Main Results:

  • Lower MTL tau, lower Aβ burden, and younger age were significantly associated with increased neocortical tau resistance.
  • Higher cognitive performance (PACC), greater hippocampal volume, and thicker entorhinal cortices were linked to lower tau resistance.
  • An interaction between Aβ and MTL tau burden significantly influenced tau resistance, with specific findings in Aβ-positive individuals.

Conclusions:

  • Baseline MTL tau levels and age are significant factors in resisting tauopathy progression into neocortical regions, potentially mediated by Aβ in early AD stages.
  • The inverse relationship between tau resistance and cognitive/brain reserve markers suggests tau resistance is more pronounced in individuals with greater cognitive impairment and lower reserve.
  • These findings highlight the complex interplay of tau, Aβ, and individual factors in AD pathogenesis and resistance mechanisms.