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000272157 1001_ $$00000-0002-9756-881X$$aLorenzini, Luigi$$b0
000272157 245__ $$aAssociation of Vascular Risk Factors and Cerebrovascular Pathology With Alzheimer Disease Pathologic Changes in Individuals Without Dementia.
000272157 260__ $$a[Erscheinungsort nicht ermittelbar]$$bOvid$$c2024
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000272157 520__ $$aVascular 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.
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000272157 650_7 $$2NLM Chemicals$$aAmyloid beta-Peptides
000272157 650_7 $$2NLM Chemicals$$atau Proteins
000272157 650_7 $$2NLM Chemicals$$aPeptide Fragments
000272157 650_7 $$2NLM Chemicals$$aamyloid beta-protein (1-42)
000272157 650_7 $$2NLM Chemicals$$aBiomarkers
000272157 650_2 $$2MeSH$$aHumans
000272157 650_2 $$2MeSH$$aAlzheimer Disease: pathology
000272157 650_2 $$2MeSH$$aAlzheimer Disease: cerebrospinal fluid
000272157 650_2 $$2MeSH$$aAlzheimer Disease: diagnostic imaging
000272157 650_2 $$2MeSH$$aMale
000272157 650_2 $$2MeSH$$aFemale
000272157 650_2 $$2MeSH$$aAged
000272157 650_2 $$2MeSH$$aRisk Factors
000272157 650_2 $$2MeSH$$aAmyloid beta-Peptides: cerebrospinal fluid
000272157 650_2 $$2MeSH$$aRetrospective Studies
000272157 650_2 $$2MeSH$$aCerebral Small Vessel Diseases: diagnostic imaging
000272157 650_2 $$2MeSH$$aCerebral Small Vessel Diseases: complications
000272157 650_2 $$2MeSH$$aCerebral Small Vessel Diseases: pathology
000272157 650_2 $$2MeSH$$atau Proteins: cerebrospinal fluid
000272157 650_2 $$2MeSH$$aPeptide Fragments: cerebrospinal fluid
000272157 650_2 $$2MeSH$$aMiddle Aged
000272157 650_2 $$2MeSH$$aMagnetic Resonance Imaging
000272157 650_2 $$2MeSH$$aBiomarkers: cerebrospinal fluid
000272157 650_2 $$2MeSH$$aBrain: pathology
000272157 650_2 $$2MeSH$$aBrain: diagnostic imaging
000272157 650_2 $$2MeSH$$aAtrophy: pathology
000272157 7001_ $$00000-0002-3642-9584$$aMaranzano, Alessio$$b1
000272157 7001_ $$aIngala, Silvia$$b2
000272157 7001_ $$00000-0001-6263-1762$$aCollij, Lyduine E$$b3
000272157 7001_ $$00000-0002-4451-4746$$aTranfa, Mario$$b4
000272157 7001_ $$00000-0002-1890-4193$$aBlennow, Kaj$$b5
000272157 7001_ $$aDi Perri, Carol$$b6
000272157 7001_ $$aFoley, Christopher$$b7
000272157 7001_ $$aFox, Nick C$$b8
000272157 7001_ $$0P:(DE-2719)9001538$$aFrisoni, Giovanni B$$b9
000272157 7001_ $$00000-0001-7433-0203$$aHaller, Sven$$b10
000272157 7001_ $$aMartinez-Lage, Pablo$$b11
000272157 7001_ $$aMollison, Daisy$$b12
000272157 7001_ $$aO'Brien, John$$b13
000272157 7001_ $$00000-0002-1374-1620$$aPayoux, Pierre$$b14
000272157 7001_ $$00000-0002-6202-6906$$aRitchie, Craig$$b15
000272157 7001_ $$00000-0002-1046-6408$$aScheltens, Philip$$b16
000272157 7001_ $$aSchwarz, Adam J$$b17
000272157 7001_ $$00000-0001-5753-428X$$aSudre, Carole H$$b18
000272157 7001_ $$aTijms, Betty M$$b19
000272157 7001_ $$aVerde, Federico$$b20
000272157 7001_ $$aTicozzi, Nicola$$b21
000272157 7001_ $$00000-0002-7698-3854$$aSilani, Vincenzo$$b22
000272157 7001_ $$00000-0001-8008-9727$$aVisser, Pieter Jelle$$b23
000272157 7001_ $$aWaldman, Adam$$b24
000272157 7001_ $$00009-0002-5856-0126$$aWolz, Robin$$b25
000272157 7001_ $$00000-0002-4889-7932$$aChételat, Gael$$b26
000272157 7001_ $$0P:(DE-2719)9000543$$aEwers, Michael$$b27
000272157 7001_ $$00000-0002-8197-0118$$aWink, Alle Meije$$b28
000272157 7001_ $$00000-0003-0894-0307$$aMutsaerts, Henk$$b29
000272157 7001_ $$00000-0002-6155-0642$$aGispert, Juan Domingo$$b30
000272157 7001_ $$00000-0002-9812-6642$$aWardlaw, Joanna M$$b31
000272157 7001_ $$00000-0003-3543-3706$$aBarkhof, Frederik$$b32
000272157 773__ $$0PERI:(DE-600)1491874-2$$a10.1212/WNL.0000000000209801$$gVol. 103, no. 7, p. e209801$$n7$$pe209801$$tNeurology$$v103$$x0028-3878$$y2024
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