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The following is a summary of “Association of vascular risk factors and cerebrovascular pathology with Alzheimer disease pathologic changes in individuals without dementia,” published in the September 2024 issue of Neurology by Lorenzini et al.
The association between vascular risk factors (VRFs), cerebral small vessel disease (CVD), and Alzheimer’s disease (AD), mainly in the preclinical stages, is undefined, with questions regarding risk factors, mechanistic links, and the independent or synergistic effects of vascular and amyloid pathologies.
Researchers conducted a retrospective study to analyze the relationships between VRFs, cSVD, amyloid levels (Aβ1-42), and their combined effects on downstream AD biomarkers such as CSF hyperphosphorylated tau (P-tau181), atrophy, and cognition.
They examined nondemented participants (Clinical Dementia Rating < 1) from the European Prevention of Alzheimer’s Dementia (EPAD) cohort, VRFs were assessed by the Framingham risk score (FRS), and cSVD characteristics were estimated on MRI using visual scales and white matter hyperintensity volumes. After preliminary linear analysis, structural equation modeling (SEM) was used to develop a “cSVD severity” latent variable and evaluate 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).
The results showed 1,592 participants (mean age = 65.5 ± 7.4 years; 56.16% F). A positive association between FRS and all cSVD features (all P< 0.05) and a negative association between FRS and Aβ1-42 (β = −0.04 ± 0.01) was observed. 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), when using vascular amyloid-related markers and 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 was observed.
They concluded that in a large nondemented population, cSVD mediates VRFs and amyloid levels, affecting neurodegeneration and cognitive impairment, underlining the importance of cSVD burden in memory clinics for early risk evaluation and intervention, thereby emphasizing VRFs and cerebrovascular pathology as key biomarkers for accurate anti-amyloid clinical trial design and patient stratification.
Source: neurology.org/doi/10.1212/WNL.0000000000209801
