The DOI matches its Crossref record; 274 of the 274 references it cites were found in a registry or an index.
Age-related myelin breakdown: a developmental model of cognitive decline and Alzheimer’s disease
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 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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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
In the citing paper
“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
In the citing paper
“The trends observed by (Cox et al., 2016) and (Slater et al., 2019) agree with the 'last in, first out' hypothesis (Bartzokis, 2004)”
From NODDI in clinical research (2020) · cites this paper as Bartzokis, 2004
In the citing paper
“In animal models, demyelination can be triggered by the accumulation of amyloid-beta peptides, phosphorylated Tau, or proinflammatory cytokines (35–37).”
From Single-nucleus transcriptome analysis reveals dysregulation of angiogenic endothelial cells and neuroprotective glia in Alzheimer’s disease (2020) · cites this paper as [35]
In the citing paper
“Indeed, aging-related myelin loss is associated with cognitive impairment in AD (35).”
From Single-nucleus transcriptome analysis reveals dysregulation of angiogenic endothelial cells and neuroprotective glia in Alzheimer’s disease (2020) · cites this paper as [35]
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Cited by
Sorted by citations
Regional Brain Changes in Aging Healthy Adults: General Trends, Individual Differences and Modifiers
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Metadata
- 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)
- 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
- Locations
- Neurobiology of Aging (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (P50AG016570, AG 16570)
- National Institute of Mental Health (MH6357-01A1)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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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