Florbetapir PET-assessed demyelination is associated with faster tau accumulation in an APOE ε4-dependent manner
Copyright policy )Florbetapir PET-assessed demyelination is associated with faster tau accumulation in an APOE ε4-dependent manner
Abstract Purpose The main objectives were to test whether (1) a decrease in myelin is associated with enhanced rate of fibrillar tau accumulation and cognitive decline in Alzheimer’s disease, and (2) whether apolipoprotein E (APOE) ε4 genotype is associated with worse myelin decrease and thus tau accumulation. Methods To address our objectives, we repurposed florbetapir-PET as a marker of myelin in the white matter (WM) based on previous validation studies showing that beta-amyloid (Aβ) PET tracers bind to WM myelin. We assessed 43 Aβ-biomarker negative (Aβ−) cognitively normal participants and 108 Aβ+ participants within the AD spectrum with florbetapir-PET at baseline and longitudinal flortaucipir-PET as a measure of fibrillar tau (tau-PET) over ~ 2 years. In linear regression analyses, we tested florbetapir-PET in the whole WM and major fiber tracts as predictors of tau-PET accumulation in a priori defined regions of interest (ROIs) and fiber-tract projection areas. In mediation analyses we tested whether tau-PET accumulation mediates the effect of florbetapir-PET in the whole WM on cognition. Finally, we assessed the role of myelin alteration on the association between APOE and tau-PET accumulation. Results Lower florbetapir-PET in the whole WM or at a given fiber tract was predictive of faster tau-PET accumulation in Braak stages or the connected grey matter areas in Aβ+ participants. Faster tau-PET accumulation in higher cortical brain areas mediated the association between a decrease in florbetapir-PET in the WM and a faster rate of decline in global cognition and episodic memory. APOE ε4 genotype was associated with a worse decrease in the whole WM florbetapir-PET and thus enhanced tau-PET accumulation. Conclusion Myelin alterations are associated in an APOE ε4 dependent manner with faster tau progression and cognitive decline, and may therefore play a role in the etiology of AD.
Florbetapir-PET, Apolipoprotein E4, genetics [Alzheimer Disease], Acquired Cognitive Impairment (rcdc), Apolipoprotein E4 (mesh), Clinical Research (rcdc), Biomedical Imaging (rcdc), Aging (rcdc), metabolism [Cognitive Dysfunction], Brain Disorders (rcdc), Amyloid beta-Peptides (mesh), Cognitive Dysfunction (mesh), Demyelinating Diseases (mesh), 1103 Clinical Sciences (for), Dementia (rcdc), 32 Biomedical and Clinical Sciences (for-2020), Neurosciences (rcdc), genetics [Apolipoprotein E4], Neurodegenerative (rcdc), Alzheimer Disease (mesh), Humans (mesh), 0299 Other Physical Sciences (for), Alzheimer's Disease (rcdc), Aniline Compounds, Original Article ; Myelin ; Florbetapir-PET ; Tau ; APOE ; Medical and Health Sciences, Brain, Nuclear Medicine & Medical Imaging (science-metrix), Myelin, APOE ; Cognitive Dysfunction/metabolism [MeSH] ; Demyelinating Diseases/metabolism [MeSH] ; Amyloid beta-Peptides/metabolism [MeSH] ; Humans [MeSH] ; Myelin ; Aniline Compounds [MeSH] ; Alzheimer Disease/diagnostic imaging [MeSH] ; Florbetapir-PET ; Original Article ; Brain/metabolism [MeSH] ; Ethylene Glycols [MeSH] ; Tau ; Apolipoproteins E [MeSH] ; Positron-Emission Tomography [MeSH] ; Alzheimer Disease/genetics [MeSH] ; Apolipoprotein E4/genetics [MeSH] ; Alzheimer Disease/metabolism [MeSH] ; tau Proteins/metabolism [MeSH], metabolism [Demyelinating Diseases], florbetapir, Ethylene Glycols (mesh), Original Article, Ethylene Glycols, metabolism [Alzheimer Disease], APOE, Aniline Compounds (mesh), Positron-Emission Tomography (mesh), 610, metabolism [Amyloid beta-Peptides], tau Proteins, 618, Brain (mesh), Apolipoproteins E, Alzheimer Disease, Humans, Cognitive Dysfunction, 3202 Clinical Sciences (for-2020), Amyloid beta-Peptides, Neurological (hrcs-hc), 4.1 Discovery and preclinical testing of markers and technologies (hrcs-rac), 2.1 Biological and endogenous factors (hrcs-rac), Alzheimer’s Disease Neuroimaging Initiative, 3202 Clinical sciences (for-2020), metabolism [tau Proteins], Apolipoproteins E (mesh), metabolism [Brain], Positron-Emission Tomography, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) (rcdc), Tau, tau Proteins (mesh), diagnostic imaging [Alzheimer Disease], Demyelinating Diseases, ddc: ddc:, ddc: ddc:610
Florbetapir-PET, Apolipoprotein E4, genetics [Alzheimer Disease], Acquired Cognitive Impairment (rcdc), Apolipoprotein E4 (mesh), Clinical Research (rcdc), Biomedical Imaging (rcdc), Aging (rcdc), metabolism [Cognitive Dysfunction], Brain Disorders (rcdc), Amyloid beta-Peptides (mesh), Cognitive Dysfunction (mesh), Demyelinating Diseases (mesh), 1103 Clinical Sciences (for), Dementia (rcdc), 32 Biomedical and Clinical Sciences (for-2020), Neurosciences (rcdc), genetics [Apolipoprotein E4], Neurodegenerative (rcdc), Alzheimer Disease (mesh), Humans (mesh), 0299 Other Physical Sciences (for), Alzheimer's Disease (rcdc), Aniline Compounds, Original Article ; Myelin ; Florbetapir-PET ; Tau ; APOE ; Medical and Health Sciences, Brain, Nuclear Medicine & Medical Imaging (science-metrix), Myelin, APOE ; Cognitive Dysfunction/metabolism [MeSH] ; Demyelinating Diseases/metabolism [MeSH] ; Amyloid beta-Peptides/metabolism [MeSH] ; Humans [MeSH] ; Myelin ; Aniline Compounds [MeSH] ; Alzheimer Disease/diagnostic imaging [MeSH] ; Florbetapir-PET ; Original Article ; Brain/metabolism [MeSH] ; Ethylene Glycols [MeSH] ; Tau ; Apolipoproteins E [MeSH] ; Positron-Emission Tomography [MeSH] ; Alzheimer Disease/genetics [MeSH] ; Apolipoprotein E4/genetics [MeSH] ; Alzheimer Disease/metabolism [MeSH] ; tau Proteins/metabolism [MeSH], metabolism [Demyelinating Diseases], florbetapir, Ethylene Glycols (mesh), Original Article, Ethylene Glycols, metabolism [Alzheimer Disease], APOE, Aniline Compounds (mesh), Positron-Emission Tomography (mesh), 610, metabolism [Amyloid beta-Peptides], tau Proteins, 618, Brain (mesh), Apolipoproteins E, Alzheimer Disease, Humans, Cognitive Dysfunction, 3202 Clinical Sciences (for-2020), Amyloid beta-Peptides, Neurological (hrcs-hc), 4.1 Discovery and preclinical testing of markers and technologies (hrcs-rac), 2.1 Biological and endogenous factors (hrcs-rac), Alzheimer’s Disease Neuroimaging Initiative, 3202 Clinical sciences (for-2020), metabolism [tau Proteins], Apolipoproteins E (mesh), metabolism [Brain], Positron-Emission Tomography, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) (rcdc), Tau, tau Proteins (mesh), diagnostic imaging [Alzheimer Disease], Demyelinating Diseases, ddc: ddc:, ddc: ddc:610
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