Florbetapir PET-assessed demyelination is associated with faster tau accumulation in an APOE ε4-dependent manner

• Published in: European journal of nuclear medicine and molecular imaging Vol. 51; no. 4; pp. 1035 - 1049
• Main Authors: Rubinski, Anna, Dewenter, Anna, Zheng, Lukai, Franzmeier, Nicolai, Stephenson, Henry, Deming, Yuetiva, Duering, Marco, Gesierich, Benno, Denecke, Jannis, Pham, An-Vi, Bendlin, Barbara, Ewers, Michael
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-03-2024; Springer Nature B.V
• Subjects: Accumulation; Alzheimer Disease - diagnostic imaging; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Aniline Compounds; Apolipoprotein E; Apolipoprotein E4 - genetics; Apolipoproteins E; Biomarkers; Brain - metabolism; Cardiology; Cognition; Cognition & reasoning; Cognitive ability; Cognitive Dysfunction - metabolism; Demyelinating Diseases - metabolism; Demyelination; Ethylene Glycols; Genotypes; Humans; Imaging; Medicine; Medicine & Public Health; Myelin; Neurodegenerative diseases; Nuclear Medicine; Oncology; Original; Original Article; Orthopedics; Positron-Emission Tomography; Radiology; Regression analysis; Substantia alba; Substantia grisea; Tau protein; tau Proteins - metabolism; β-Amyloid; Tau; Florbetapir-PET; APOE; Myelin
• ISSN: 1619-7070; 1619-7089
• DOI: 10.1007/s00259-023-06530-8

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.