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Association of Amyloid Pathology With Myelin Alteration in Preclinical Alzheimer Disease
Open accessAbstract
IMPORTANCE: The accumulation of aggregated β-amyloid and tau proteins into plaques and tangles is a central feature of Alzheimer disease (AD). While plaque and tangle accumulation likely contributes to neuron and synapse loss, disease-related changes to oligodendrocytes and myelin are also suspected of playing a role in development of AD dementia. Still, to our knowledge, little is known about AD-related myelin changes, and even when present, they are often regarded as secondary to concomitant arteriosclerosis or related to aging. OBJECTIVE: To assess associations between hallmark AD pathology and novel quantitative neuroimaging markers while being sensitive to white matter myelin content. DESIGN, SETTING, AND PARTICIPANTS: Magnetic resonance imaging was performed at an academic research neuroimaging center on a cohort of 71 cognitively asymptomatic adults enriched for AD risk. Lumbar punctures were performed and assayed for cerebrospinal fluid (CSF) biomarkers of AD pathology, including β-amyloid 42, total tau protein, phosphorylated tau 181, and soluble amyloid precursor protein. We measured whole-brain longitudinal and transverse relaxation rates as well as the myelin water fraction from each of these individuals. MAIN OUTCOMES AND MEASURES: Automated brain mapping algorithms and statistical models were used to evaluate the relationships between age, CSF biomarkers of AD pathology, and quantitative magnetic resonance imaging relaxometry measures, including the longitudinal and transverse relaxation rates and the myelin water fraction. RESULTS: The mean (SD) age for the 19 male participants and 52 female participants in the study was 61.6 (6.4) years. Widespread age-related changes to myelin were observed across the brain, particularly in late myelinating brain regions such as frontal white matter and the genu of the corpus callosum. Quantitative relaxometry measures were negatively associated with levels of CSF biomarkers across brain white matter and in areas preferentially affected in AD. Furthermore, significant age-by-biomarker interactions were observed between myelin water fraction and phosphorylated tau 181/β-amyloid 42, suggesting that phosphorylated tau 181/β-amyloid 42 levels modulate age-related changes in myelin water fraction. CONCLUSIONS AND RELEVANCE: These findings suggest amyloid pathologies significantly influence white matter and that these abnormalities may signify an early feature of the disease process. We expect that clarifying the nature of myelin damage in preclinical AD may be informative on the disease's course and lead to new markers of efficacy for prevention and treatment trials.
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“Reduced myelin volume and integrity often occur prior to the onset of dementia and are predictive of future cognitive impairment23,24,33,36.”
From APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes (2022) · cites this paper as [33]
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“Dysfunction of oligodendrocytes and myelin breakdown may be early events in AD72–75.”
From Integrated multimodal cell atlas of Alzheimer’s disease (2024) · cites this paper as [74]
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Metadata
- Authors
- Dean, D. C., Hurley, S. A., Kecskemeti, S. R., O’Grady, J. P., Canda, C., Davenport-Sis, N. J., Carlsson, C. M., Zetterberg, H., Blennow, K., Asthana, S., Sager, M. A., Johnson, S. C., Alexander, A. L., & Bendlin, B. B.
- Affiliations
- University of Wisconsin–Madison (US)
- University of Oxford (GB)
- Alzheimer Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison4Wisconsin Alzheimer Institute, University of Wisconsin School of Medicine and Public Health, Madison
- UCL Queen Square Institute of Neurology (GB)
- University of Gothenburg (SE)
- Corresponding author
- Dean, Douglas C.
- ORCID
- Venue
- JAMA Neurology
- Publisher
- American Medical Association (AMA)
- Published
- 2017-01-01
- Volume
- 74
- Issue
- 1
- Pages
- 41
- ISSN
- 2168-6149 (ISSN-L)
- PMC
- PMC5195903
- OpenAlex
- W2554389950
- Cited by
- 252
- References
- 44
- Citations by year
- 2026: 26 · 2025: 40 · 2024: 33 · 2023: 36 · 2022: 34 · 2021: 17 · 2020: 19 · 2019: 16 · 2018: 17 · 2017: 13
- FWCI
- 13.62
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- JAMA Neurology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- National Institutes of Health (UL1TR000427)
- National Institute on Aging (R01AG037639, P50AG033514, R01AG021155, R01AG027161, R56AG037639)
- National Center for Research Resources (UL1RR025011)
- National Center for Advancing Translational Sciences
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R21HD078119, P30HD003352, T32HD007489)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced Neuroimaging Techniques and Applications
- Keywords
- preclinical Alzheimer's disease, amyloid pathology, white matter, myelin water fraction, relaxometry, cerebrospinal fluid biomarkers, phosphorylated tau 181, amyloid-beta 42, tau protein, corpus callosum, neuroimaging biomarkers
- MeSH terms
- Age Factors, Aged, Alzheimer Disease, Apolipoproteins E, Female, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Middle Aged, Myelin Sheath, Peptide Fragments, Phosphorylation, Statistics as Topic, Water, Cohort Studies, Biomarkers, Amyloid beta-Peptides, tau Proteins, Disease Progression, Plaque, Amyloid
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