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 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 [33]
The Conclusions (page not provided) suggest that myelin alterations may be among the earliest features of Alzheimer disease, and the study examined asymptomatic adults. But the Discussion’s Limitations describe the analyses as cross-sectional and call for longitudinal studies; this paper does not show that reduced myelin predicts future cognitive impairment. It also does not establish how often the alterations occur before dementia. (LLM, conf=0.88)
Experimental — accuracy not yet measuredDysfunction of oligodendrocytes and myelin breakdown may be early events in AD.
“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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“Evidence for myelin defects can be found in disorders that present during development and adolescence such as schizophrenia, bipolar disorder, and autism [82,83] in addition to diseases associated with adulthood and aging such as Alzheimer’s disease [84,85] and amyotrophic lateral sclerosis [86,87].”
BackgroundWang, N., Wang, M., Jeevaratnam, S., Rosenberg, C., Ikezu, T. C., Shue, F., Doss, S. V., Alnobani, A., Martens, Y. A., Wren, M., et al. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00577-1 · Cited by 82 · see citing works
Early Life Stress and Epigenetics in Late-onset Alzheimer’s Dementia: A Systematic Review
Lemche, E. (2018) · Current Genomics · doi:10.2174/1389202919666171229145156 · Cited by 82 · see citing works
“Abeta42 reduces neuron-specific endophilin-B1 (SH3GLB1 1q22), a protein involved in beclin-2 mediated apoptosis, autophagy and mitochondrial function, which in turn enhances Abeta42 accumulation and neuronal vulnerability to stress [194].”
BackgroundInfluentialQuintela-López, T., Ortiz-Sanz, C., Serrano-Regal, M. P., Gaminde-Blasco, A., Valero, J., Baleriola, J., Sánchez-Gómez, M. V., Matute, C., & Alberdi, E. (2019) · Cell Death & Disease · doi:10.1038/s41419-019-1636-8 · Cited by 80 · see citing works
Dual role of nitric oxide in Alzheimer's disease
Azargoonjahromi, A. (2023) · Nitric Oxide · doi:10.1016/j.niox.2023.03.003 · Cited by 83 · see citing works
Khattar, N., Triebswetter, C., Kiely, M., Ferrucci, L., Resnick, S. M., Spencer, R. G. S., & Bouhrara, M. (2021) · NeuroImage · doi:10.1016/j.neuroimage.2021.118267 · Cited by 73 · see citing works
“characterize cerebral demyelinating diseases and neurodevelopment (47, 59-74).”
An emerging role of dysfunctional axon-oligodendrocyte coupling in neurodegenerative diseases
Mot, A. I., Depp, C., & Nave, K. (2018) · Dialogues in Clinical Neuroscience · doi:10.31887/dcns.2018.20.4/amot · Cited by 70 · see citing works
Dietary Polyphenols as Therapeutic Intervention for Alzheimer’s Disease: A Mechanistic Insight
Bukhari, S. N. A. (2022) · Antioxidants · doi:10.3390/antiox11030554 · Cited by 70 · see citing works
Myelin in Alzheimer’s disease: culprit or bystander?
Maitre, M., Jeltsch-David, H., Okechukwu, N. G., Klein, C., Patte-Mensah, C., & Mensah-Nyagan, A.-G. (2023) · Acta Neuropathologica Communications · doi:10.1186/s40478-023-01554-5 · Cited by 66 · see citing works
Adult brain aging investigated using BMC-mcDESPOT–based myelin water fraction imaging
Bouhrara, M., Rejimon, A. C., Cortina, L. E., Khattar, N., Bergeron, C. M., Ferrucci, L., Resnick, S. M., & Spencer, R. G. S. (2019) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2019.10.003 · Cited by 68 · see citing works
Dissecting the complexities of Alzheimer disease with in vitro models of the human brain
Blanchard, J., Victor, M. B., & Tsai, L. (2021) · Nature Reviews Neurology · doi:10.1038/s41582-021-00578-6 · Cited by 65 · see citing works
Microbiota impacts on chronic inflammation and metabolic syndrome - related cognitive dysfunction
Arnoriaga‐Rodríguez, M., & Fernández‐Real, J. M. (2019) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-019-09537-5 · Cited by 67 · see citing works
“On the other hand, alterations of myelin described in early and clinical stages of AD in mice [32] and humans [33] are linked to insulin resistance [34].”
BackgroundAlisch, J. S. R., Khattar, N., Kim, R. W., Cortina, L. E., Rejimon, A. C., Qian, W., Ferrucci, L., Resnick, S. M., Spencer, R. G. S., & Bouhrara, M. (2021) · Aging · doi:10.18632/aging.202673 · Cited by 64 · see citing works
“Moreover, as conventional [4], we assumed constant longitudinal and transverse relaxation times for all participants, although these parameters follow complex patterns with aging [30, 62, 63].”
BackgroundXie, Y., Pan, T., Xu, D.-E., Huang, X., Tang, Y., Huang, W., Chen, R., Li, L., Chi, H., & Ma, Q. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.733945 · Cited by 62 · see citing works
Role of Neuron and Glia in Alzheimer’s Disease and Associated Vascular Dysfunction
Bandyopadhyay, S. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.653334 · Cited by 62 · see citing works
T cell-mediated microglial activation triggers myelin pathology in a mouse model of amyloidosis
Kedia, S., Ji, H., Feng, R., Androvic, P., Spieth, L., Liu, L., Franz, J., Zdiarstek, H., Anderson, K. P., Kaboglu, C., et al. (2024) · Nature Neuroscience · doi:10.1038/s41593-024-01682-8 · Cited by 63 · see citing works
Ma, Y., Jang, H., Jerban, S., Chang, E. Y., Chung, C. B., Bydder, G. M., & Du, J. (2022) · Applied Physics Reviews · doi:10.1063/5.0086459 · Cited by 59 · see citing works
Functions and dysfunctions of oligodendrocytes in neurodegenerative diseases
Han, S.-W., Gim, Y., Jang, E., & Hur, E. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.1083159 · Cited by 60 · see citing works
“, 2018), and a number of studies have shown that the extent of myelin loss correlates with Aβ burden (Grimmer et al., 2012; Brickman et al., 2015a; Dean et al., 2017).”
BackgroundInsights into human cerebral white matter maturation and degeneration across the adult lifespan
Kiely, M., Triebswetter, C., Cortina, L. E., Gong, Z., Alsameen, M. H., Spencer, R. G. S., & Bouhrara, M. (2021) · NeuroImage · doi:10.1016/j.neuroimage.2021.118727 · Cited by 56 · see citing works
“Advanced relaxometry-based methods have been introduced to improve specificity of MR-based myelination studies through quantification of the myelin water fraction (MWF) (2, 27-50), and have been applied extensively to study the myelination patterns in diseases and neurodevelopment (1, 4, 31, 50-54).”
MethodNeurodegeneration cell per cell
Balusu, S., Praschberger, R., Lauwers, E., Strooper, B. D., & Verstreken, P. (2023) · Neuron · doi:10.1016/j.neuron.2023.01.016 · Cited by 51 · see citing works
“155 156–161 Aβ oligomers in vitro are sufficient to inhibit myelin formation and induce oligodendrocyte cell death via ROS.”
The presymptomatic phase of amyotrophic lateral sclerosis: are we merely scratching the surface?
Chipika, R. H., Siah, W. F., McKenna, M. C., Shing, S. L. H., Hardiman, O. M., & Bede, P. (2020) · Journal of Neurology · doi:10.1007/s00415-020-10289-5 · Cited by 53 · see citing works
White matter hyperintensities are associated with subthreshold amyloid accumulation
Moscoso, A., Rey-Bretal, D., Silva-Rodríguez, J., Aldrey, J. M., Cortés, J., Pías-Peleteiro, J., Ruibal, Á., & Aguiar, P. (2020) · NeuroImage · doi:10.1016/j.neuroimage.2020.116944 · Cited by 49 · see citing works
Axonal and myelinic pathology in 5xFAD Alzheimer’s mouse spinal cord
Chu, T., Cummins, K., Sparling, J. S., Tsutsui, S., Brideau, C., Nilsson, K. P. R., Joseph, J. T., & Stys, P. K. (2017) · PLoS ONE · doi:10.1371/journal.pone.0188218 · Cited by 51 · see citing works
Konar, A., Gupta, R., Shukla, R. K., Maloney, B., Khanna, V. K., Wadhwa, R., Lahiri, D. K., & Thakur, M. K. (2019) · Scientific Reports · doi:10.1038/s41598-019-48238-6 · Cited by 53 · see citing works
Caballero, M. Á. A., Song, Z., Rubinski, A., Duering, M., Dichgans, M., Park, D. C., & Ewers, M. (2020) · Alzheimer s & Dementia · doi:10.1002/alz.12062 · Cited by 51 · see citing works
Schirge, P. M., Perneczky, R., Taoka, T., Ruiz‐Rizzo, A. L., Ersoezlue, E., Forbrig, R., Guersel, S., Kurz, C., Brendel, M., Hellmann‐Regen, J., et al. (2025) · Alzheimer s Research & Therapy · doi:10.1186/s13195-025-01707-9 · Cited by 50 · see citing works
“Recent studies have also reported associations between white matter changes and both Aβ [24] and tau pathology [25].”
Modeling white matter tract integrity in aging with diffusional kurtosis imaging
Benitez, A. M., Jensen, J. H., Falangola, M. F., Nietert, P. J., & Helpern, J. A. (2018) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2018.07.006 · Cited by 47 · see citing works
“Studies on the early detection of Alzheimer’s disease using complementary MRI techniques report changes in late-myelinating brain regions in particular (Dean et al., 2017; Stricker et al., 2016).”
Yao, F., Hong, X., Li, S., Zhang, Y., Zhao, Q., Du, W., Wang, Y., & Ni, J. (2018) · Journal of Alzheimer’s Disease · doi:10.3233/jad-180261 · Cited by 52 · see citing works
<i>Tlr7</i> drives sex differences in age- and Alzheimer’s disease–related demyelination
Lopez-Lee, C., Kodama, L., Fan, L., Zhu, D., Zhu, J., Wong, M. Y., Ye, P., Norman, K., Foxe, N. R., Ijaz, L., et al. (2024) · Science · doi:10.1126/science.adk7844 · Cited by 49 · see citing works
Kavroulakis, E., Simos, P. G., Kalaitzakis, G., Maris, T. G., Karageorgou, D., Zaganas, I. V., Panagiotakis, S., Basta, M., Vgontzas, A. N., & Papadaki, E. Z. (2017) · Journal of Magnetic Resonance Imaging · doi:10.1002/jmri.25849 · Cited by 49 · see citing works
“It is well known that amyloid-b42 and hyperphosphorylated-tau (HP-tau) accumulation is the causative event of AD, leading to formation of amyloid plaques and neurofibrillary tangles with functional and morphological synaptic changes, glial activation, and neuronal death.(2,3) However, oligodendrocytes and myelin may b…”
BackgroundAPOE genotype determines cell-type-specific pathological landscape of Alzheimer’s disease
Li, Z., Martens, Y. A., Ren, Y., Jin, Y., Sekiya, H., Doss, S. V., Kouri, N., Castanedes-Casey, M., Christensen, T. A., Miller Nevalainen, L. B., et al. (2025) · Neuron · doi:10.1016/j.neuron.2025.02.017 · Cited by 39 · see citing works
Endocannabinoid signaling in brain diseases: Emerging relevance of glial cells
Bernal‐Chico, A., Tepavčević, V., Manterola, A., Utrilla, C. L., Matute, C., & Mato, S. (2022) · Glia · doi:10.1002/glia.24172 · Cited by 48 · see citing works
“before the onset of clinical symptoms (Dean et al., 2017).”
BackgroundCSF β-amyloid and white matter damage: a new perspective on Alzheimer’s disease
Pietroboni, A. M., Scarioni, M., Carandini, T., Basilico, P., Cadioli, M., Giulietti, G., Arighi, A., Caprioli, M., Serra, L., Sina, C., et al. (2017) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp-2017-316603 · Cited by 47 · see citing works
“In any case, our findings confirm, along with previously published data,9 11 12 19 20 that WMHs should be regarded as a crucial feature of AD.”
BackgroundInfluentialNoninvasive Gamma Sensory Stimulation May Reduce White Matter and Myelin Loss in Alzheimer’s Disease
Da, X., Hempel, E., Ou, Y., Rowe, O., Malchano, Z., Hajós, M., Kern, R. Z., Megerian, J. T., & Cimenser, A. (2023) · Journal of Alzheimer s Disease · doi:10.3233/jad-230506 · Cited by 47 · see citing works
Qian, W., Khattar, N., Cortina, L. E., Spencer, R. G. S., & Bouhrara, M. (2020) · NeuroImage · doi:10.1016/j.neuroimage.2020.117369 · Cited by 43 · see citing works
Astrocyte and oligodendrocyte pathology in Alzheimer's disease
Ziar, R., Tesar, P. J., & Clayton, B. L. L. (2025) · Neurotherapeutics · doi:10.1016/j.neurot.2025.e00540 · Cited by 47 · see citing works
“Importantly, many studies have shown that myelin damage occurs in the preclinical phase of AD [74,75].”
Dai, X., Hadjipantelis, P. Z., Wang, J., Deoni, S., & Müller, H. (2019) · Human Brain Mapping · doi:10.1002/hbm.24690 · Cited by 41 · see citing works
“…mcDESPOT has also been used to investigate myelin change in known white matter demyelinating and dysmyelinating disorders, for example, multiple sclerosis (Kitzler et al., 2012; Kolind et al., 2012; Kolind et al., 2013), Alzheimer's disease (Dean et al., 2017), and dementia (Bouhrara et al., 2018).”
BackgroundMethodMercer, J., Erickson‐Owens, D. A., Deoni, S., Dean, D., Tucker, R. J., Parker, A. B., Joelson, S., Mercer, E. N., Collins, J. A., & Padbury, J. F. (2020) · American Journal of Perinatology · doi:10.1055/s-0040-1714258 · Cited by 43 · see citing works
Self-citationOperto, G., Molinuevo, J. L., Cacciaglia, R., Falcon, C., Brugulat-Serrat, A., Suárez-Calvet, M., Grau-Rivera, O., Bargalló, N., Morán, S., Esteller, M., et al. (2019) · NeuroImage: Clinical · doi:10.1016/j.nicl.2019.101983 · Cited by 40 · see citing works
“Dean et al. (2017) in a recent study report widespread age-related changes especially in late-myelinating brain regions and negative associations between relaxometry measures across WM and levels of CSF biomarkers in cognitively asymptomatic participants.”
BackgroundMyelin injury in the central nervous system and Alzheimer's disease.
Wang, S.-S., Zhang, Z., Zhu, T., Chu, S.-F., He, W.-B., & Chen, N.-H. (2018) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2018.05.003 · Cited by 40 · see citing works
Park, M., Moon, Y., Han, S., Kim, H. K., & Moon, W. (2018) · European Radiology · doi:10.1007/s00330-018-5836-x · Cited by 42 · see citing works
Glial Perturbation in Metal Neurotoxicity: Implications for Brain Disorders
Ijomone, O. K., Inelo, U. I., Aneke, V. O., Olajide, T. S., Inyang, H. O., Omotosho, O. I., Oyerinde, T. O., Anadu, V. E., Gbayisomore, T. J., Okeowo, O. M., et al. (2025) · Neuroglia · doi:10.3390/neuroglia6010004 · Cited by 40 · see citing works
Bouhrara, M., Cortina, L. E., Rejimon, A. C., Khattar, N., Bergeron, C. M., Bergeron, J., Melvin, D. L., Zukley, L. M., & Spencer, R. G. S. (2019) · NeuroImage · doi:10.1016/j.neuroimage.2019.116307 · Cited by 40 · see citing works
Myelin repair in Alzheimer’s disease: a review of biological pathways and potential therapeutics
Hirschfeld, L. R., Risacher, S. L., Nho, K. T., & Saykin, A. J. (2022) · Translational Neurodegeneration · doi:10.1186/s40035-022-00321-1 · Cited by 39 · see citing works
“In cognitively normal older adults at risk for AD, evidence supports the association of MWF with cerebrospinal fluid biomarkers of AD such as phosphorylated tau 181, total tau, and Aβ [6].”
BackgroundFaulkner, M. E., Gong, Z., Guo, A., Laporte, J. P., Bae, J., & Bouhrara, M. (2024) · Journal of Neurochemistry · doi:10.1111/jnc.16170 · Cited by 38 · see citing works
MR approaches in neurodegenerative disorders
Blamire, A. M. (2018) · Progress in Nuclear Magnetic Resonance Spectroscopy · doi:10.1016/j.pnmrs.2018.11.001 · Cited by 37 · see citing works
O’Grady, J. P., Dean, D., Yang, K. L., Canda, C., Hoscheidt, S. M., Starks, E. J., Merluzzi, A. P., Hurley, S. A., Davenport, N. J., Okonkwo, O. C., et al. (2019) · Obesity · doi:10.1002/oby.22558 · Cited by 37 · see citing works
“We and others have also shown frontal and temporal white matter regions to exhibit extensive white matter alterations in aging populations (9-11); however, less is known about how myelinated fibers of these regions, particularly within the cortex, are affected by insulin and IR.”
BackgroundMethodInfluentialSelf-citationTardif, C. L., Devenyi, G. A., Amaral, R. S. C., Pelleïeux, S., Poirier, J., Rosa‐Neto, P., Breitner, J. C. S., & Chakravarty, M. M. (2017) · Human Brain Mapping · doi:10.1002/hbm.23897 · Cited by 36 · see citing works
“…elevated concentration of CSF biomarkers have recently been associated with decreased myelin water fraction, measured using MRI, in several brain regions preferentially affected in AD (Dean et al., 2017), providing strong support for the early role of myelin in preclinical AD (Bartzokis, 2011).”
BackgroundAge and Alzheimer’s Disease-Related Oligodendrocyte Changes in Hippocampal Subregions
DeFlitch, L., González‐Fernández, E., Crawley, I., & Kang, S. H. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.847097 · Cited by 32 · see citing works
Rubinski, A., Franzmeier, N., Dewenter, A., Luan, Y., Smith, R. A., Strandberg, O. T., Ossenkoppele, R., Dichgans, M., Hansson, O., Ewers, M., et al. (2022) · Alzheimer s Research & Therapy · doi:10.1186/s13195-022-01074-9 · Cited by 38 · see citing works
“While the use of a template reflects more accurately pre-morbid inter-regional differences in myelination, demyelination has been observed in aging [73], small vessel disease [74], and AD [75] in association with amyloid plaques [48] and fibrillar tau [46].”
Background18F-florbetapir PET as a marker of myelin integrity across the Alzheimer’s disease spectrum
Moscoso, A., Silva‐Rodríguez, J., Aldrey, J. M., Cortés, J., Peleteiro, J. M. P., Ruibal, Á., Aguiar, P., & Initiative, A. D. N. (2021) · European Journal of Nuclear Medicine and Molecular Imaging · doi:10.1007/s00259-021-05493-y · Cited by 33 · see citing works
Zhang, J., Wu, N., Wang, S., Yao, Z., Xiao, F., Lu, J., & Chen, B. (2021) · Aging Cell · doi:10.1111/acel.13380 · Cited by 33 · see citing works
“While some researchers reported that Aβ deposits were correlated well with losses of axons or the myelin sheath (Dean et al., 2017; Kaya et al., 2020; Marin et al., 2016; van Westen et al., 2016), other studies indicated that Aβ deposits were not correlated with the loss of axons or the myelin…”
BackgroundRole of Demyelination in the Persistence of Neurological and Mental Impairments after COVID-19
Khodanovich, M. Y., Kamaeva, D. A., & Naumova, A. V. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231911291 · Cited by 31 · see citing works
“This is in good agreement with changes recently observed in healthy aging [84,85].”
ResultSIRT2 as a potential new therapeutic target for Alzheimer’s disease
Sola-Sevilla, N., & Puerta, E. (2023) · Neural Regeneration Research · doi:10.4103/1673-5374.375315 · Cited by 33 · see citing works
“Myelin impairment is another characteristic of AD brains (Desai et al., 2009; Dean et al., 2017), but it is unclear if this process is a primary or a secondary injury in AD.”
Liu, Z., Chao, J., Wang, C., Sun, G., Roeth, D., Liu, W., Chen, X., Li, L., Tian, E., Feng, L., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112841 · Cited by 29 · see citing works
“15 29–32 Although there is a strong association of the C allele of the rs11136000 SNP with increased risk for AD, mechanisms underlying the risk effect of this CLU SNP remain to be determined.”
InfluentialPietroboni, A. M., Colombi, A., Carandini, T., Scarpini, E. A., Galimberti, D., & Bozzali, M. (2020) · Journal of Alzheimer s Disease · doi:10.3233/jad-200868 · Cited by 30 · see citing works
White Matter and Neuroprotection in Alzheimer’s Dementia
Lorenzini, L., Fernández, M., Baldassarro, V. A., Bighinati, A., Giuliani, A., Calzà, L., & Giardino, L. (2020) · Molecules · doi:10.3390/molecules25030503 · Cited by 29 · see citing works
“Notably, these degenerative changes have not been associated with a high amyloid plaque burden [26,27], while other studies correlates WM pathology in preclinical AD with biomarkers in the cerebrospinal fluid [28].”
BackgroundFujita, S., Buonincontri, G., Cencini, M., Fukunaga, I., Takei, N., Schulte, R. F., Hagiwara, A., Uchida, W., Hori, M., Kamagata, K., et al. (2020) · Human Brain Mapping · doi:10.1002/hbm.25232 · Cited by 28 · see citing works
“Individual and specific regional cortical thickness defined in the Desikan–Killiany Atlas (Desikan et al., 2006), was obtained using FreeSurfer (Version 6.0) (Dale, Fischl, & Sereno, 1999; Fischl, 2012) with the default recon-all command.”
MethodInfluentialQuantitative Analysis of Synthetic Magnetic Resonance Imaging in Alzheimer’s Disease
Lou, B., Jiang, Y., Li, C., Wu, P., Li, S., Qin, B., Chen, H., Wang, R., Wu, B., & Chen, M. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.638731 · Cited by 29 · see citing works
“Specifically, quantitative relaxometry can potentially reflect the changes in tissue characteristics (Deoni, 2010; Callaghan et al., 2014; Knight et al., 2016; Blamire, 2018).”
BackgroundZhou, W., Xia, S., Wang, C., Yang, Q., Verkhratsky, A., & Niu, J. (2025) · Cell Death and Disease · doi:10.1038/s41419-025-07893-6 · Cited by 28 · see citing works
“Recent studies demonstrated abnormal oligodendroglia and myelin in the brains of patients with AD [152 – 155], suggesting that myelin degeneration may be a key pathophysiological aspect of AD, potentially occurring before the onset of amyloid pathology and cognitive decline [156, 157].”
MRI and fluid biomarkers reveal determinants of myelin and axonal loss with aging
Walker, K. A., Duggan, M. R., Gong, Z., Dark, H. E., Laporte, J. P., Faulkner, M. E., An, Y., Lewis, A., Moghekar, A., Resnick, S. M., et al. (2023) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.51730 · Cited by 25 · see citing works
Cai, Y., Pinheiro‐de‐Sousa, I., Slobodyanyuk, M., Chen, F., Huynh, T., Kanyo, J. E., Tang, P., Fuentes, L. A., Braker, A., Welch, R., et al. (2025) · Nature Neuroscience · doi:10.1038/s41593-025-01973-8 · Cited by 32 · see citing works
“The patchy myelin density and altered white matter magnetic resonance imaging signals reported in AD 27–30, Paranodal and juxtaparanodal vulnerability likely arise from two factors.”
Zheng, M., Liu, Z., Mana, L., Qin, G., Huang, S., Gong, Z., Tian, M., He, Y., & Wang, P. (2021) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2021.114264 · Cited by 25 · see citing works
Greater Diffusion Restriction in White Matter in Preclinical Alzheimer Disease
Benitez, A. M., Jensen, J. H., Thorn, K. E., Dhiman, S., Fountain‐Zaragoza, S., Rieter, W. J., Spampinato, M. V., Hamlett, E. D., Nietert, P. J., Falangola, M. F., et al. (2022) · Annals of Neurology · doi:10.1002/ana.26353 · Cited by 27 · see citing works
Zhao, J., Wang, D.-X., Ma, X.-R., Dong, Z.-J., Wu, J., Wang, F., & Wu, Y. (2022) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2022.102205 · Cited by 24 · see citing works
Alanko, V., Gaminde‐Blasco, A., Quintela‐López, T., Loera‐Valencia, R., Solomon, A., Björkhem, I., Cedazo-Mı́nguez, Á., Maioli, S., Tabacaru, G., Latorre‐Leal, M., et al. (2023) · Glia · doi:10.1002/glia.24348 · Cited by 24 · see citing works
“For instance, in studies conducted on asymptomatic subjects with an increased risk of developing AD, a decline in white matter integrity has been associated with pathological AD biomarker levels (Dean et al., 2017).”
BackgroundHe, Y., Li, Q., Fu, Z., Zeng, D., Han, Y., & Li, S. (2023) · Cerebral Cortex · doi:10.1093/cercor/bhad328 · Cited by 23 · see citing works
Use of the NESMA Filter to Improve Myelin Water Fraction Mapping with Brain MRI
Bouhrara, M., Reiter, D. A., Maring, M. C., Bonny, J.-M., & Spencer, R. G. S. (2018) · Journal of Neuroimaging · doi:10.1111/jon.12537 · Cited by 23 · see citing works
“45,67 .”
Fronza, M. G., Baldinotti, R., Sacramento, M., Gutierres, J. M., Carvalho, F. B., Fernandes, M. D. C., Sousa, F. S. S., Seixas, F. K., Collares, T. V., Alves, D. A. C., et al. (2020) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.0c00615 · Cited by 23 · see citing works
Myelin Lipid Alterations in Neurodegenerative Diseases: Landscape and Pathogenic Implications
Xu, Z., He, S., Begum, M. M., & Han, X. (2024) · Antioxidants and Redox Signaling · doi:10.1089/ars.2024.0676 · Cited by 22 · see citing works
“Advanced imaging techniques, such as magnetic resonance imaging (MRI), have also been used to detect myelin loss in patients with AD (Dean et al., 2017).”
Remyelination: A Potential Therapeutic Strategy for Alzheimer’s Disease?
Sun, J., Zhou, H., Bai, F., Zhang, Z., & Ren, Q. (2017) · Journal of Alzheimer s Disease · doi:10.3233/jad-170036 · Cited by 22 · see citing works
Triebswetter, C., Kiely, M., Khattar, N., Ferrucci, L., Resnick, S., Spencer, R. G., & Bouhrara, M. (2022) · NeuroImage · doi:10.1016/j.neuroimage.2022.118988 · Cited by 19 · see citing works
“Using advanced MRI physics and technology, a whole-brain MWF map can now be obtained in less than 15 min using the multicomponent driven equilibrium single pulse observation of T1 and T2 (mcDESPOT) analysis (21-24).”
MethodFacchinetti, R., Valenza, M., Gomiero, C., Mancini, G. F., Steardo, L., Campolongo, P., & Scuderi, C. (2022) · Biomedicines · doi:10.3390/biomedicines10061236 · Cited by 22 · see citing works
“Myelin damage coincides indeed with Aβ accumulation and concurrent impairment in OPCs maturation in the brains of AD patients [21].”
BackgroundOta, M., Sato, N., Kimura, Y., Shigemoto, Y., Kunugi, H., & Matsuda, H. (2019) · Dementia and Geriatric Cognitive Disorders Extra · doi:10.1159/000493937 · Cited by 21 · see citing works
- 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
- Health Sciences › Medicine › Physiology › 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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