Age-related myelin breakdown: a developmental model of cognitive decline and Alzheimer’s disease

Bartzokis, George

doi:10.1016/j.neurobiolaging.2003.03.001

Cited by 968Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeurogenesis and neuroplasticity mechanisms

Age-related myelin breakdown: a developmental model of cognitive decline and Alzheimer’s disease

Bartzokis, George·2004·Neurobiology of Aging

DOI 10.1016/j.neurobiolaging.2003.03.001

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Abstract

A hypothetical model of Alzheimer's disease (AD) as a uniquely human brain disorder rooted in its exceptional process of myelination is presented. Cortical regions with the most protracted development are most vulnerable to AD pathology, and this protracted development is driven by oligodendrocytes, which continue to differentiate into myelin producing cells late into the fifth decade of life. The unique metabolic demands of producing and maintaining their vast myelin sheaths and synthesizing the brain's cholesterol supply make oligodendrocytes especially susceptible to a variety of insults. Their vulnerability increases with increasing age at differentiation as later-differentiating cells myelinate increasing numbers of axonal segments. These vulnerable late-differentiating cells drive the protracted process of intracortical myelination and by increasing local cholesterol and iron levels, progressively increase the toxicity of the intracortical environment forming the basis for the age risk factor for AD. At older ages, the roughly bilaterally symmetrical continuum of oligodendrocyte vulnerability manifests as a progressive pattern of myelin breakdown that recapitulates the developmental process of myelination in reverse. The ensuing homeostatic responses to myelin breakdown further increase intracortical toxicity and results in the relentless progression and non-random anatomical distribution of AD lesions that eventually cause neuronal dysfunction and degeneration. This process causes a slowly progressive disruption of neural impulse transmission that degrades the temporal synchrony of widely distributed neural networks underlying normal brain function. The resulting network "disconnections" first impact functions that are most dependent on large-scale synchronization including higher cognitive functions and formation of new memories. Multiple genetic and environmental risk factors (e.g. amyloid beta-peptide and free radical toxicity, head trauma, anoxia, cholesterol levels, etc.) can contribute to the cognitive deficits observed in aging and AD through their impact on the life-long trajectory of myelin development and breakdown. This development-to-degeneration model is testable through imaging and post mortem methods and highlights the vital role of myelin in impulse transmission and synchronous brain function. The model offers a framework that explains the anatomical distribution and progressive course of AD pathology, some of the failures of promising therapeutic interventions, and suggests further testable hypotheses as well as novel approaches for intervention efforts.

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A role of myelin deterioration in the progression of AD has been previously proposed in light of correlative macroscopic-scale brain imaging studies, but they lacked any evidence of causality.
“A role of myelin deterioration in the progression of AD has been previously proposed in light of correlative macroscopic-scale brain imaging studies54, but they lacked any evidence of causality.”
From Myelin dysfunction drives amyloid-β deposition in models of Alzheimer’s disease (2023) · cites this paper as [54]
Reports exist of hypomyelination and white matter changes in Alzheimer's disease.
“consistent with reports of hypomyelination and white matter changes in AD23,24.”
From APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes (2022) · cites this paper as [24]
Reduced myelin volume and integrity often occur prior to the onset of dementia and are predictive of future cognitive impairment.
“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 [24]
Myelin content in the frontal lobe begins to decline in the fourth decade in the aging brain.
“Functional magnetic resonance imaging (fMRI) studies identified that the myelin content in the frontal lobe begins to decline in the fourth decade in the aging brain (Bartzokis 2004)”
From Apolipoprotein E ε4 disrupts oligodendrocyte differentiation by interfering with astrocyte‐derived lipid transport (2023) · cites this paper as Bartzokis 2004
White matter abnormalities emerge as early findings in the aging brain and sporadic Alzheimer's disease.
“White matter (WM) abnormalities emerge as early findings in the aging brain and sporadic Alzheimer's disease (AD) (Amlien & Fjell 2014;Bartzokis 2004;Medina et al. 2006).”
From Apolipoprotein E ε4 disrupts oligodendrocyte differentiation by interfering with astrocyte‐derived lipid transport (2023) · cites this paper as Bartzokis 2004

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Caspase-3-Mediated Cleavage of Amyloid Precursor Protein and Formation of Amyloid β Peptide in Traumatic Axonal Injury
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Lipids in the Nervous System of Different Species as a Function of Age: Brain, Spinal Cord, Peripheral Nerve, Purified Whole Cell Preparations, and Subcellular Particulates: Regulatory Mechanisms and Membrane Structure
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Regional Brain Changes in Aging Healthy Adults: General Trends, Individual Differences and Modifiers
Raz, N., Lindenberger, U., Rodrigue, K. M., Kennedy, K. M., Head, D., Williamson, A., Dahle, C., Gerstorf, D., & Acker, J. D. (2005) · Cerebral Cortex · doi:10.1093/cercor/bhi044 · Cited by 2,875 · see citing works
Brain development in children and adolescents: Insights from anatomical magnetic resonance imaging
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A single-cell atlas of entorhinal cortex from individuals with Alzheimer’s disease reveals cell-type-specific gene expression regulation
Grubman, A., Chew, G., Ouyang, J. F., Sun, G., Choo, X. Y., McLean, C., Simmons, R. K., Buckberry, S., Vargas-Landin, D. B., Poppe, D., et al. (2019) · Nature Neuroscience · doi:10.1038/s41593-019-0539-4 · Cited by 956 · see citing works
Life-Span Changes of the Human Brain White Matter: Diffusion Tensor Imaging (DTI) and Volumetry
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Age-related myelin degradation burdens the clearance function of microglia during aging
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Normative estimates of cross-sectional and longitudinal brain volume decline in aging and AD
Fotenos, A. F., Snyder, A. Z., Girton, L. E., Morris, J. C., & Buckner, R. L. (2005) · Neurology · doi:10.1212/01.wnl.0000154530.72969.11 · Cited by 579 · see citing works
Alzheimer's disease as homeostatic responses to age-related myelin breakdown
Bartzokis, G. (2011) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2009.08.007 · Cited by 546 · see citing works
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Aging of cerebral white matter: a review of MRI findings
Gunning‐Dixon, F. M., Brickman, A. M., Cheng, J. C., & Alexopoulos, G. S. (2009) · International Journal of Geriatric Psychiatry · doi:10.1002/gps.2087 · Cited by 564 · see citing works
Single-nucleus transcriptome analysis reveals dysregulation of angiogenic endothelial cells and neuroprotective glia in Alzheimer’s disease
Lau, S.-F., Cao, H., Fu, A. K. Y., & Ip, N. Y. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2008762117 · Cited by 476 · see citing works
White matter changes in mild cognitive impairment and AD: a diffusion tensor imaging study
Medina, D., deToledo-Morrell, L., Urresta, F., Gabrieli, J. D. E., Moseley, M., Fleischman, D., Bennett, D. A., Leurgans, S., Turner, D. A., & Stebbins, G. T. (2006) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2005.03.026 · Cited by 492 · see citing works
APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes
Blanchard, J. W., Akay, L. A., Davila-Velderrain, J., von Maydell, D., Mathys, H., Davidson, S. M., Effenberger, A., Chen, C.-Y., Maner-Smith, K., Hajjar, I., et al. (2022) · Nature · doi:10.1038/s41586-022-05439-w · Cited by 493 · see citing works
Divergence of human and mouse brain transcriptome highlights Alzheimer disease pathways
Miller, J. A., Horvath, S., & Geschwind, D. H. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0914257107 · Cited by 480 · see citing works
Myelin dysfunction drives amyloid-β deposition in models of Alzheimer’s disease
Depp, C., Sun, T., Sasmita, A. O., Spieth, L., Berghoff, S. A., Nazarenko, T., Overhoff, K., Steixner-Kumar, A. A., Subramanian, S., Arinrad, S., et al. (2023) · Nature · doi:10.1038/s41586-023-06120-6 · Cited by 476 · see citing works
A Systems Level Analysis of Transcriptional Changes in Alzheimer's Disease and Normal Aging
Miller, J. A., Oldham, M. C., & Geschwind, D. H. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.4098-07.2008 · Cited by 385 · see citing works
A meta-analysis of diffusion tensor imaging in mild cognitive impairment and Alzheimer's disease
Sexton, C. E., Kalu, U. G., Filippini, N., Mackay, C. E., & Ebmeier, K. P. (2011) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2010.05.019 · Cited by 410 · see citing works
Heterogeneous age-related breakdown of white matter structural integrity: Implications for cortical “disconnection” in aging and Alzheimer's disease.
Bartzokis, G., Sultzer, D., Lu, P. H., Nuechterlein, K. H., Mintz, J., & Cummings, J. L. (2004) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2003.09.005 · Cited by 363 · see citing works
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Systemic 5-fluorouracil treatment causes a syndrome of delayed myelin destruction in the central nervous system
Han, R., Yang, Y. M., Dietrich, J., Luebke, A., Mayer-Pröschel, M., & Noble, M. (2008) · Journal of Biology · doi:10.1186/jbiol69 · Cited by 316 · see citing works
Diffusion tensor imaging in preclinical and presymptomatic carriers of familial Alzheimer’s disease mutations
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Parietal cortex matters in Alzheimer's disease: An overview of structural, functional and metabolic findings
Jacobs, H. I. L., Van Boxtel, M. P. J., Jolles, J., Verhey, F. R. J., & Uylings, H. B. M. (2012) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2011.06.009 · Cited by 293 · see citing works
Genes and pathways underlying regional and cell type changes in Alzheimer’s disease
Miller, J. A., Woltjer, R. L., Goodenbour, J. M., Horvath, S., & Geschwind, D. H. (2013) · Genome Medicine · doi:10.1186/gm452 · Cited by 275 · see citing works
NODDI in clinical research
Kamiya, K., Hori, M., & Aoki, S. (2020) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2020.108908 · Cited by 283 · see citing works
“The trends observed by (Cox et al., 2016) and (Slater et al., 2019) agree with the ‘last in, first out’ hypothesis (Bartzokis, 2004), where the tracts that are latest to develop are the most vulnerable to the effects of aging.”
Increased Iron Levels and Decreased Tissue Integrity in Hippocampus of Alzheimer’s Disease Detected in vivo with Magnetic Resonance Imaging
Raven, E. P., Lu, P. H., Tishler, T. A., Heydari, P., & Bartzokis, G. (2013) · Journal of Alzheimer s Disease · doi:10.3233/jad-130209 · Cited by 270 · see citing works
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Multiple DTI index analysis in normal aging, amnestic MCI and AD. Relationship with neuropsychological performance
Bosch, B., Arenaza-Urquijo, E. M., Rami, L., Sala-Llonch, R., Junqué, C., Solé-Padullés, C., Peña-Gómez, C., Bargalló, N., Molinuevo, J. L., & Bartrés-Faz, D. (2012) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2010.02.004 · Cited by 272 · see citing works
Cellular senescence and Alzheimer disease: the egg and the chicken scenario
Saez-Atienzar, S., & Masliah, E. (2020) · Nature Reviews Neuroscience · doi:10.1038/s41583-020-0325-z · Cited by 257 · see citing works
Relationship between white matter fractional anisotropy and other indices of cerebral health in normal aging: tract-based spatial statistics study of aging
Kochunov, P., Thompson, P. M., Lancaster, J. L., Bartzokis, G., Smith, S., Coyle, T., Royall, D. R., Laird, A., & Fox, P. T. (2007) · NeuroImage · doi:10.1016/j.neuroimage.2006.12.021 · Cited by 250 · see citing works
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Memory training impacts short‐term changes in aging white matter: A Longitudinal Diffusion Tensor Imaging Study
Engvig, A., Fjell, A. M., Westlye, L. T., Moberget, T., Sundseth, Ø., Larsen, V. A., & Walhovd, K. B. (2012) · Human Brain Mapping · doi:10.1002/hbm.21370 · Cited by 250 · see citing works
Association of Amyloid Pathology With Myelin Alteration in Preclinical Alzheimer Disease
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., et al. (2017) · JAMA Neurology · doi:10.1001/jamaneurol.2016.3232 · Cited by 252 · see citing works
Myelin breakdown and iron changes in Huntington's disease: pathogenesis and treatment implications
Bartzokis, G., Lu, P. H., Tishler, T. A., Fong, S. M., Oluwadara, B., Finn, J. P., Huang, D., Bordelon, Y., Mintz, J., & Perlman, S. (2007) · Neurochemical Research · doi:10.1007/s11064-007-9352-7 · Cited by 238 · see citing works
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Early Oligodendrocyte/Myelin Pathology in Alzheimer's Disease Mice Constitutes a Novel Therapeutic Target
Desai, M. K., Mastrangelo, M. A., Ryan, D. A., Sudol, K. L., Narrow, W. C., & Bowers, W. J. (2010) · The American Journal of Pathology · doi:10.2353/ajpath.2010.100087 · Cited by 232 · see citing works
Dynamic changes in myelin aberrations and oligodendrocyte generation in chronic amyloidosis in mice and men
Behrendt, G., Baer, K., Buffo, A., Curtis, M. A., Faull, R. L., Rees, M. I., Götz, M., & Dimou, L. (2013) · Glia · doi:10.1002/glia.22432 · Cited by 219 · see citing works
White matter integrity and cognition in childhood and old age
Deary, I. J., Bastin, M. E., Pattie, A., Clayden, J. D., Whalley, L. J., Starr, J. M., & Wardlaw, J. M. (2006) · Neurology · doi:10.1212/01.wnl.0000199954.81900.e2 · Cited by 207 · see citing works
Aging, stress and the hippocampus
Miller, D. B., & O’Callaghan, J. P. (2005) · Ageing Research Reviews · doi:10.1016/j.arr.2005.03.002 · Cited by 206 · see citing works
Functional implications of hippocampal volume and diffusivity in mild cognitive impairment
Müller, M. J., Greverus, D., Dellani, P. R., Weibrich, C., Wille, P. R., Scheurich, A., Stoeter, P., & Fellgiebel, A. (2005) · NeuroImage · doi:10.1016/j.neuroimage.2005.06.029 · Cited by 210 · see citing works
NSAID use and dementia risk in the Cardiovascular Health Study*: Role of <i>APOE</i> and NSAID type
Szekely, C. A., Breitner, J. C. S., Fitzpatrick, A. L., Rea, T. D., Psaty, B. M., Kuller, L. H., & Zandi, P. P. (2008) · Neurology · doi:10.1212/01.wnl.0000284596.95156.48 · Cited by 204 · see citing works
Body mass index and magnetic resonance markers of brain integrity in adults
Gazdzinski, S., Kornak, J., Weiner, M. W., & Meyerhoff, D. J. (2008) · Annals of Neurology · doi:10.1002/ana.21377 · Cited by 191 · see citing works
The role of myelin damage in Alzheimer’s disease pathology
Papuć, E., & Rejdak, K. (2020) · Archives of Medical Science · doi:10.5114/aoms.2018.76863 · Cited by 188 · see citing works
Focal demyelination in Alzheimer’s disease and transgenic mouse models
Mitew, S., Kirkcaldie, M. T. K., Halliday, G. M., Shepherd, C. E., Vickers, J. C., & Dickson, T. C. (2010) · Acta Neuropathologica · doi:10.1007/s00401-010-0657-2 · Cited by 186 · see citing works
Cognitive plasticity in adulthood and old age: Gauging the generality of cognitive intervention effects
Noack, H., Lövdén, M., Schmiedek, F., & Lindenberger, U. (2009) · Restorative Neurology and Neuroscience · doi:10.3233/rnn-2009-0496 · Cited by 180 · see citing works
Relating imaging indices of white matter integrity and volume in healthy older adults
Hugenschmidt, C. E., Peiffer, A. M., Kraft, R. A., Casanova, R., Deibler, A. R., Burdette, J. H., Maldjian, J. A., & Laurienti, P. J. (2008) · Cerebral Cortex · doi:10.1093/cercor/bhm080 · Cited by 166 · see citing works
Regional white matter and neuropsychological functioning across the adult lifespan.
Brickman, A. M., Zimmerman, M. E., Paul, R. H., Grieve, S. M., Tate, D. F., Cohen, R. A., Williams, L. M., Clark, C. R., & Gordon, E. (2006) · Biological Psychiatry · doi:10.1016/j.biopsych.2006.01.011 · Cited by 166 · see citing works
Oligodendroglia and Myelin in Neurodegenerative Diseases: More Than Just Bystanders?
Ettle, B., Schlachetzki, J. C. M., & Winkler, J. (2016) · Molecular Neurobiology · doi:10.1007/s12035-015-9205-3 · Cited by 160 · see citing works
Multimodal magnetic resonance imaging assessment of white matter aging trajectories over the lifespan of healthy individuals
Bartzokis, G., Lu, P. H., Heydari, P., Couvrette, A., Lee, G. J., Kalashyan, G., Freeman, F., Grinstead, J. W., Villablanca, P., Finn, J. P., et al. (2012) · Biological Psychiatry · doi:10.1016/j.biopsych.2012.07.010 · Cited by 152 · see citing works
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White matter integrity declined over 6-months, but dance intervention improved integrity of the fornix of older adults
Burzynska, A. Z., Jiao, Y., Knecht, A. M., Fanning, J., Awick, E. A., Chen, T., Gothe, N., Voss, M. W., McAuley, E., & Kramer, A. F. (2017) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2017.00059 · Cited by 150 · see citing works
Sub-regional hippocampal injury is associated with fornix degeneration in Alzheimer’s disease.
Lee, D. Y., Fletcher, E., Carmichael, O. T., Singh, B., Mungas, D., Reed, B., Martinez, O., Buonocore, M. H., Persianinova, M., & DeCarli, C. (2012) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2012.00001 · Cited by 137 · see citing works
Microstructural white matter changes in cognitively normal individuals at risk of amnestic MCI
Zhuang, L., Sachdev, P. S., Trollor, J. N., Kochan, N. A., Reppermund, S., Brodaty, H., & Wen, W. (2012) · Neurology · doi:10.1212/wnl.0b013e3182661f4d · Cited by 125 · see citing works
Longitudinal, region-specific course of diffusion tensor imaging measures in mild cognitive impairment and Alzheimer’s disease
Nowrangi, M. A., Lyketsos, C. G., Leoutsakos, J. S., Oishi, K., Albert, M., Mori, S., & Mielke, M. M. (2013) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2012.05.2186 · Cited by 120 · see citing works
Is synaptic loss a unique hallmark of Alzheimer’s disease?
Scheff, S. W., Neltner, J. H., & Nelson, P. T. (2014) · Biochemical Pharmacology · doi:10.1016/j.bcp.2013.12.028 · Cited by 118 · see citing works
Multiple indices of diffusion identifies white matter damage in mild cognitive impairment and Alzheimer’s disease
O'Dwyer, L., Lamberton, F., Bokde, A. L. W., Ewers, M., Faluyi, Y. O., Tanner, C., Mazoyer, B., O'Neill, D., Bartley, M., Collins, D. R., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0021745 · Cited by 119 · see citing works
Using support vector machines with multiple indices of diffusion for automated classification of mild cognitive impairment
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Exploratory voxel-based analysis of diffusion indices and hemispheric asymmetry in normal aging
Ardekani, S., Kumar, A., Bartzokis, G., & Sinha, U. (2007) · Magnetic Resonance Imaging · doi:10.1016/j.mri.2006.09.045 · Cited by 115 · see citing works
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Oxidative stress and genetic markers of suboptimal antioxidant defense in the aging brain: A theoretical review
Salminen, L. E., & Paul, R. H. (2014) · Reviews in the Neurosciences · doi:10.1515/revneuro-2014-0046 · Cited by 113 · see citing works
Plasmalogen phospholipids protect internodal myelin from oxidative damage
Luoma, A. M., Kuo, F., Cakici, O., Crowther, M. N., Denninger, A. R., Avila, R. L., Brites, P., & Kirschner, D. A. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.03.012 · Cited by 97 · see citing works
Relationships between brain metabolism decrease in normal aging and changes in structural and functional connectivity
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Authors: Bartzokis, G.
Affiliations: University of California, Los Angeles (US)
Corresponding author: Bartzokis, George
Venue: Neurobiology of Aging
Publisher: Elsevier BV
Published: 2004-01
Volume: 25
Issue: 1
Pages: 5-18
ISSN: 0197-4580 (ISSN-L)
DOI: 10.1016/j.neurobiolaging.2003.03.001
OpenAlex: W1981000616
Cited by: 968
References: 274
Citations by year: 2026: 31 · 2025: 37 · 2024: 49 · 2023: 40 · 2022: 50 · 2021: 46 · 2020: 50 · 2019: 48 · 2018: 40 · 2017: 47 · 2016: 42 · 2015: 48 · 2014: 40 · 2013: 58 · 2012: 43
FWCI: 3.43
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Neurobiology of Aging (publishedVersion)
PubMed (publishedVersion)
Funders: National Institute on Aging (P50AG016570, AG 16570)
National Institute of Mental Health (MH6357-01A1)
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Keywords: Alzheimer's disease, myelination, oligodendrocytes, myelin breakdown, cognitive decline, brain aging, cortical development, cholesterol, iron, neuronal synchronization, memory impairment, amyloid-beta, free radical toxicity, head trauma, anoxia
MeSH terms: Aging, Alzheimer Disease, Animals, Brain, Cognition Disorders, Disease Models, Animal, Humans, Myelin Sheath, Neurons, Oligodendroglia, Risk Factors, Cell Death

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Age-related myelin breakdown: a developmental model of cognitive decline and Alzheimer’s disease

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