Higher Vascular Risk Indirectly Predicts Lower Plasma Aß42/40 in APOE ɛ4 Carriers

Shraddha Sapkota, PhD

Findings from a cross-sectional analysis of 2 cohorts of nondemented older adults revealed that higher vascular risk score was indirectly associated with the level of plasma amyloid-ß (Aß)42/40 through cerebral amyloid burden only in apolipoprotein (APOE) ɛ4 carriers.

Led by Shraddha Sapkota, PhD, Department of Neurology, University of California, the analysis took a multifactorial approach to examining how vascular and genetic risk work together using patients from the University of California, Davis-Alzheimer’s Disease Research Center (UCD-ADRC) study (n = 96). The group originally hypothesized that higher vascular risk indirectly predicts plasma Aß42/40 levels through cerebral amyloid burden and that this association will be stronger in APOE ɛ4 carriers. Findings were validated through the Alzheimer’s Disease Neuroimaging Initiative (n = 104) as a confirmatory study cohort (CSC).

Published in Stroke, vascular risk score was obtained as the sum of hypertension, diabetes, hyperlipidemia, coronary artery disease, and cerebrovascular disease. Confirming previous reported, findings not stratified by APOE ɛ4+ risk showed that higher cerebral amyloid burden was associated with lower plasma Aß42/40 in both UCD-ADRC (ß = –0.012 [SE, 0.006]; P = .039) and ADNI (ß = –0.015 [SE, 0.006]; P = .013) cohorts. Higher vascular risk score predicted greater amyloid burden in ADNI (ß = 0.043 [SE, 0.016]; P = .006) but not in the UCD-ADRC cohort (ß = 0.096 [SE, 0.050]; P = .053).

Overall, the data “suggest that monitoring and enhanced management of vascular risk factors in this patient population may provide those with a genetic risk an added layer of protection associated with high cerebral amyloid burden and lower plasma Aß42/40,” study investigators wrote. "Vascular integrity in combination with genetic vulnerability are key components of preclinical trajectories. Thus, applying a multifaceted approach with established (cerebral aβ) and noninvasive (plasma aβ) biomarkers for earlier detection of older adults at high risk and personalized intervention programs will be key to offsetting projected increasesin dementia incidence and prevalence."

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Across the 2 cohorts, investigators observed inconsistent findings on the direct association of vascular risk. Specifically, higher vascular risk was associated with higher plasma amyloid Aß42/40 levels—opposite of what was expected—in UCD-ADRC (ß = 0.008 [SE, 0.003]; P = .007) but not in ADNI (ß = –0.001 [SE, 0.000]; P = .416). Inconsistent associations continued to persist between the 2 cohorts for the indirect association of vascular risk on plasma amyloid Aß 42/40 levels through cerebral amyloid burden.

In this indirect analysis, higher vascular risk indirectly predicted lower plasma amyloid Aß42/40 levels in the whole group in ADNI (ß = –0.001; 90% CI, –0.002 to 0.000; [SE, 0.000]; P = .006), but not in the UCD-ADRC cohort (ß = –0.001; 90% CI, –0.003 to 0.000 [SE, 0.001; P = .078). However, when stratified by APOE ɛ4+ risk, there was a significant indirect association in both cohorts for APOE ɛ4 carriers (UCD-ADRC: ß = –0.004 [90% CI, –0.009 to –0.002]; SE, 0.002; P = .030; ADNI: ß = –0.002 [90% CI, –0.004 to –0.001]; SE, 0.001; P = .027). These associations did not remain in the APOE ɛ4­– group (UCD-ADRC: ß = –0.001 [90% CI, –0.002 to 0.000]; SE, 0.001; P = .474; ADNI: ß = 0.000 [90% CI, –0.001 to 0.000]; SE, 0.000; P = .515).

The study has several strengths, including that the findings were validated in "an ethnoracially diverse cohort (composed of Blacks, Hispanics, and Whites) through community recruitment to a large longitudinal observational study composed of mainly Whites recruited across the United States and Canada. We confirmed our findings even in highly differing populations. Second, by identifying how plasma amyloid is associated with other established non-modifiable and modifiable dementia markers, we contribute to the large literature and potential clinical application of blood-based biomarkers to detect high risk individuals," the study investigators wrote.

REFERENCE
1. Sapkota S, Erickson K, Fletcher E, Farias SE, Jin LW, DeCarli C. Vascular risk predicts plasma amyloid ß42/40 through cerebral amyloid burden in Apolipoprotein Ee4 carriers. STROKEAHA. 2023;54:1227-1235. doi:10.1161/STROKEAHA.122.041854