17 May 24. Featured Paper

Link to paper on Wiley Online Library

Authors

Mario Tranfa, Luigi Lorenzini, Lyduine E. Collij, David Vállez García, Silvia Ingala, Giuseppe Pontillo, Leonard Pieperhoff, Alessio Maranzano, Robin Wolz, Sven Haller, Kaj Blennow, Giovanni Frisoni, Carole H. Sudre, Gael Chételat, Michael Ewers, Pierre Payoux, Adam Waldman, Pablo Martinez-Lage, Adam J. Schwarz, Craig W. Ritchie, Joanna M. Wardlaw, Juan Domingo Gispert, Arturo Brunetti, Henk J. M. M. Mutsaerts, Alle Meije Wink, Frederik Barkhof 

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 β_1-42 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:

• Alzheimer's disease
• cerebral small vessel disease