Journal Article

DZNE-2024-01148

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Association of Vascular Risk Factors and Cerebrovascular Pathology With Alzheimer Disease Pathologic Changes in Individuals Without Dementia.

Lorenzini, L. ; Maranzano, A. ; Ingala, S. ; Collij, L. E. ; Tranfa, M. ; Blennow, K. ; Di Perri, C. ; Foley, C. ; Fox, N. C. ; Frisoni, G. B. ; Haller, S. ; Martinez-Lage, P. ; Mollison, D. ; O'Brien, J. ; Payoux, P. ; Ritchie, C. ; Scheltens, P. ; Schwarz, A. J. ; Sudre, C. H. ; Tijms, B. M. ; Verde, F. ; Ticozzi, N. ; Silani, V. ; Visser, P. J. ; Waldman, A. ; Wolz, R. ; Chételat, G. ; Ewers, M.DZNE* ; Wink, A. M. ; Mutsaerts, H. ; Gispert, J. D. ; Wardlaw, J. M. ; Barkhof, F.

2024
Ovid [Erscheinungsort nicht ermittelbar]

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Please use a persistent id in citations: doi:10.1212/WNL.0000000000209801

Abstract: Vascular risk factors (VRFs) and cerebral small vessel disease (cSVD) are common in patients with Alzheimer disease (AD). It remains unclear whether this coexistence reflects shared risk factors or a mechanistic relationship and whether vascular and amyloid pathologies have independent or synergistic influence on subsequent AD pathophysiology in preclinical stages. We investigated links between VRFs, cSVD, and amyloid levels (Aβ1-42) and their combined effect on downstream AD biomarkers, that is, CSF hyperphosphorylated tau (P-tau181), atrophy, and cognition.This retrospective study included nondemented participants (Clinical Dementia Rating < 1) from the European Prevention of Alzheimer's Dementia (EPAD) cohort and assessed VRFs with the Framingham risk score (FRS) and cSVD features on MRI using visual scales and white matter hyperintensity volumes. After preliminary linear analysis, we used structural equation modeling (SEM) to create a 'cSVD severity' latent variable and assess the direct and indirect effects of FRS and cSVD severity on Aβ1-42, P-tau181, gray matter volume (baseline and longitudinal), and cognitive performance (baseline and longitudinal).A total cohort of 1,592 participants were evaluated (mean age = 65.5 ± 7.4 years; 56.16% F). We observed positive associations between FRS and all cSVD features (all p < 0.05) and a negative association between FRS and Aβ1-42 (β = -0.04 ± 0.01). All cSVD features were negatively associated with CSF Aβ1-42 (all p < 0.05). Using SEM, the cSVD severity fully mediated the association between FRS and CSF Aβ1-42 (indirect effect: β = -0.03 ± 0.01), also when omitting vascular amyloid-related markers. We observed a significant indirect effect of cSVD severity on P-tau181 (indirect effect: β = 0.12 ± 0.03), baseline and longitudinal gray matter volume (indirect effect: β = -0.10 ± 0.03; β = -0.12 ± 0.05), and baseline cognitive performance (indirect effect: β = -0.16 ± 0.03) through CSF Aβ1-42.In a large nondemented population, our findings suggest that cSVD is a mediator of the relationship between VRFs and CSF Aβ1-42 and affects downstream neurodegeneration and cognitive impairment. We provide evidence of VRFs indirectly affecting the pathogenesis of AD, highlighting the importance of considering cSVD burden in memory clinics for AD risk evaluation and as an early window for intervention. These results stress the role of VRFs and cerebrovascular pathology as key biomarkers for accurate design of anti-amyloid clinical trials and offer new perspectives for patient stratification.

Keyword(s): Humans (MeSH) ; Alzheimer Disease: pathology (MeSH) ; Alzheimer Disease: cerebrospinal fluid (MeSH) ; Alzheimer Disease: diagnostic imaging (MeSH) ; Male (MeSH) ; Female (MeSH) ; Aged (MeSH) ; Risk Factors (MeSH) ; Amyloid beta-Peptides: cerebrospinal fluid (MeSH) ; Retrospective Studies (MeSH) ; Cerebral Small Vessel Diseases: diagnostic imaging (MeSH) ; Cerebral Small Vessel Diseases: complications (MeSH) ; Cerebral Small Vessel Diseases: pathology (MeSH) ; tau Proteins: cerebrospinal fluid (MeSH) ; Peptide Fragments: cerebrospinal fluid (MeSH) ; Middle Aged (MeSH) ; Magnetic Resonance Imaging (MeSH) ; Biomarkers: cerebrospinal fluid (MeSH) ; Brain: pathology (MeSH) ; Brain: diagnostic imaging (MeSH) ; Atrophy: pathology (MeSH) ; Amyloid beta-Peptides ; tau Proteins ; Peptide Fragments ; amyloid beta-protein (1-42) ; Biomarkers

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Contributing Institute(s):

1. Clinical Research (Munich) (Clinical Research (Munich))

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2024

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Database coverage:
; ; ; Allianz-Lizenz ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Essential Science Indicators ; IF >= 5 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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