Medical Health Cluster

24 agosto, 2022

In Alzheimer’s Disease, Myelin May Protect Against Tau Pathology

The study covered in this summary was published in as a preprint and has not yet been peer reviewed.

Key Takeaways

  • Tau protein levels are lower in more highly myelinated cortical regions.
  • Tau spreading is reduced between cortical regions that are connected by more highly myelinated fiber tracts.
  • Myelin may offer protection against tau accumulation associated with Alzheimer’s disease (AD).

Why This Matters

  • Tau protein deposition and spreading are clinically relevant hallmarks of AD.
  • Autopsy studies have suggested that tau protein accumulation favors brain regions with less myelin.
  • The spreading of tau protein among brain regions appears to favor regions that are functionally connected.
  • Quantitative correlation of myelin level with tau protein accumulation would help physicians to offer patient-specific prognoses.
  • Identification of myelin as a protective factor would implicate it as a possible therapeutic target for AD.

Study Design

  • The 612-member study population comprised select, biomarker-characterized patients (with dementia and without dementia) from the Alzheimer’s Disease Neuroimaging Initiative (ANDI) and the BioFINDER-1 study.
  • Data from cross-sectional tau-PET assessments and MRI-based myelin mapping were used to correlate region-specific levels of myelin and tau protein in the cerebral cortex.
  • Data from longitudinal tau-PET assessments, MRI-based myelin mapping, and MRI-based structural and functional connectivity mapping were used to correlate tau protein changes in functionally paired regions with the myelin level of their connecting fiber tracts over 1 to 4 years.

Key Results

  • Regions of interest with higher myelin water fractions had significantly lower tau-PET scores (rho = -0.267, P < .001 for the ANDI cohort; and rho = -0.175, P = .013 for the BioFINDER-1 cohort).
  • Linear regression analysis, testing the association of functional connectivity, fiber tract myelination, and covariance of tau-PET scores between linked brain regions, demonstrated a significant association (β = -0.185 and β = -0.166 for the respective cohorts; P < .001 for both cohorts), with more myelinated tracts showing a lesser association with tau covariance.
  • Among cognitively normal patients who lacked AD biomarkers, there was no significant correlation between regional myelin and tau-PET levels (rho = -0.13, P = .067; and rho = 0.027, P = .7 for the respective cohorts) or among fiber tract connectivity, fiber tract myelination, and tau covariance (β = 0.027, P = .39; and β = -0.026, P = .43 for the respective cohorts).
  • Sensitivity analyses that incorporated amyloid-PET assessments showed that the study results remained significant when amyloid-PET scores were controlled (P ≥ .005) and were therefore independent of amyloid beta levels.
  • Limitations

    • Although MRI-based measurement of myelin can be confounded by iron content, myelin water imaging (used in this study) is demonstrably superior to other MRI measures in accurately assessing myelin levels.
    • An imaging template derived from healthy persons protected the MRI analysis from pathologic alterations in iron that could otherwise obfuscate the data.
    • This study did not track myelin changes over time, although in previous studies, demyelination has been associated with tau fibrils, and it is hypothesized that this association is causal.
    • Next steps include exploration of myelin’s mechanism of protection, including the possibility that in less-myelinated regions, which are prone to myelin damage, remyelination activity initiates tau pathology.
    • Understanding of the mechanism of protection would support the development of myelin-targeted therapies.


    • The study was funded by the German Center for Neurodegenerative Diseases and by a grant from the Deutsche Forschungsgemeinschaft.
    • The ANDI is funded by the National Institute on Aging and by the National Institute of Biomedical Imaging and Bioengineering; participation in this study was supported by grants from the National Institutes of Health and the Department of Defense.
    • The ANDI receives funding from the Canadian Institutes of Health Research to support clinical sites in Canada.
    • The ANDI is also supported by contributions from the following, facilitated by the Foundation for the National Institutes of Health: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc; Cogstate; Eisai Inc; Elan Pharmaceuticals, Inc; Eli Lilly and Company; Eurolmmun; F. Hoffman-La Roche Ltd and its affiliated company Genentech, Inc; Fujirebio; GE Healthcare; IXICO Ltd; Janssen Alzheimer Immunotherapy Research & Development, LLC; Johnson & Johnson Pharmaceutical Research & Development LLC; Lumosity; Lundbeck; Merck & Co, Inc; Meso Scale Diagnostics, LLC; NeuroRX Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics.

    Créditos: Comité científico Covid

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