open access publication

Article, 2024

Alzheimer's Disease and Small Vessel Disease Differentially Affect White Matter Microstructure

Annals of Clinical and Translational Neurology, ISSN 2328-9503, Volume 11, 6, Pages 1541-1556, 10.1002/acn3.52071

Contributors

Tranfa, Mario 0000-0002-4451-4746 (Corresponding author) [1] [2] Lorenzini, Luigi 0000-0002-9756-881X [2] [3] Collij, Lyduine E 0000-0001-6263-1762 [2] [3] [4] García, David Vállez 0000-0003-3308-3167 [2] [3] Ingala, Silvia [2] [3] [5] [6] Pontillo, Giuseppe [2] Pieperhoff, Leonard [2] [3] Maranzano, Alessio 0000-0002-3642-9584 [7] Wolz, Robin [8] Haller, Sven 0000-0001-7433-0203 [9] [10] [11] [12] Blennow, Kaj [13] [14] Frisoni, Giovanni [15] [16] Sudre, Carole Helene 0000-0001-5753-428X [14] [17] [18] Chételat, G Aël [19] Ewers, Michael Christopher 0000-0003-1240-0522 [20] Payoux, Pierre 0000-0002-1374-1620 [21] [22] Waldman, Adam [23] [24] Martinez‐Lage, Pablo [25] Schwarz, Adam James 0000-0002-9743-6171 [26] [27] Ritchie, Craig William 0000-0002-6202-6906 [24] [28] [29] Wardlaw, Joanna Marguerite 0000-0002-9812-6642 [24] Gispert, Juan Domingo [30] [31] [32] [33] Brunetti, Arturo [1] Mutsaerts, Henk-Jan M M 0000-0003-0894-0307 [3] [34] Wink, Alle Meije 0000-0002-8197-0118 [2] [3] Barkhof, Frederick 0000-0003-3543-3706 [2] [18]

Affiliations

  1. [1] University of Naples Federico II
    2. [NORA names: Italy; Europe, EU; OECD];
  2. [2] Vrije Universiteit Amsterdam
    3. [NORA names: Netherlands; Europe, EU; OECD];
  3. [3] Amsterdam Neuroscience
    4. [NORA names: Netherlands; Europe, EU; OECD];
  4. [4] Lund University
    5. [NORA names: Sweden; Europe, EU; Nordic; OECD];
  5. [5] Cerebriu (Denmark)
    6. [NORA names: Other Companies; Private Research; Denmark; Europe, EU; Nordic; OECD];

Abstract

OBJECTIVE: Alzheimer's disease (AD) and cerebral small vessel disease (cSVD), the two most common causes of dementia, are characterized by white matter (WM) alterations diverging from the physiological changes occurring in healthy aging. Diffusion tensor imaging (DTI) is a valuable tool to quantify WM integrity non-invasively and identify the determinants of such alterations. Here, we investigated main effects and interactions of AD pathology, APOE-ε4, cSVD, and cardiovascular risk on spatial patterns of WM alterations in non-demented older adults. METHODS: Within the prospective European Prevention of Alzheimer's Dementia study, we selected 606 participants (64.9 ± 7.2 years, 376 females) with baseline cerebrospinal fluid samples of amyloid β1-42 and p-Tau181 and MRI scans, including DTI scans. Longitudinal scans (mean follow-up time = 1.3 ± 0.5 years) were obtained in a subset (n = 223). WM integrity was assessed by extracting fractional anisotropy and mean diffusivity in relevant tracts. To identify the determinants of WM disruption, we performed a multimodel inference to identify the best linear mixed-effects model for each tract. RESULTS: AD pathology, APOE-ε4, cSVD burden, and cardiovascular risk were all associated with WM integrity within several tracts. While limbic tracts were mainly impacted by AD pathology and APOE-ε4, commissural, associative, and projection tract integrity was more related to cSVD burden and cardiovascular risk. AD pathology and cSVD did not show any significant interaction effect. INTERPRETATION: Our results suggest that AD pathology and cSVD exert independent and spatially different effects on WM microstructure, supporting the role of DTI in disease monitoring and suggesting independent targets for preventive medicine approaches.

Keywords

AD pathology, APOE-e4, Alzheimer, Alzheimer's disease, MRI, MRI scans, WM alterations, WM disruption, WM integrity, WM microstructure, adults, age, alterations, anisotropy, approach, associated with WM integrity, association, baseline, burden, cardiovascular risk, cerebral small vessel disease, cerebral small vessel disease burden, changes, dementia, dementia studies, determination, different effects, diffusion, diffusion tensor imaging, diffusion tensor imaging scans, disease, disease monitoring, disruption, effect, fractional anisotropy, healthy aging, images, independent targets, inference, integration, interaction, interaction effects, investigate main effects, limbic tracts, linear mixed-effects models, longitudinal scans, main effect, matter, mean diffusivity, medicine approach, microstructure, mixed-effects models, model, monitoring, multimodel inference, non-demented older adults, non-invasive, older adults, p-tau, p-tau<sub>181</sub>, participants, pathology, patterns of WM alterations, physiological changes, preventive medicine approach, project, risk, scanning, significant interaction effect, small vessel disease, spatial patterns, spatially, study, subsets, target, tensor imaging, tract, tract integrity, vessel disease, white matter

Funders

  • Fondation Leducq
  • Fondation Vaincre Alzheimer
  • Inserm
  • Eli Lilly (United States)
  • British Heart Foundation
  • Hartstichting
  • Alzheimer's Society
  • Alzheimer Nederland
  • Roche (Switzerland)
  • Medical Research Council
  • Association France Alzheimer
  • Agence Nationale de la Recherche
  • Engineering and Physical Sciences Research Council
  • National Institute for Health and Care Research
  • Biogen (United States)
  • Netherlands Enterprise Agency
  • Netherlands Organisation for Health Research and Development
  • Alzheimer’s Research UK
  • Novo Nordisk (Denmark)
  • General Electric (United States)
  • European Commission
  • Fondation pour la Recherche Médicale

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