Age of onset moderates the effects of Vascular Risk Factors on Neurodegeneration, Blood-Brain-Barrier permeability, and cognitive decline in Alzheimer's Disease

Abstract

Background: The role of Vascular risk factors (VRFs) in the progression of Alzheimer's Disease (AD) and cognitive decline remains to be elucidated, with previous studies resulting in conflicting findings. The possible impact of age-specific mechanisms of resilience/vulnerability is an under addressed issue. We evaluated the association of VRFs with markers of amyloid deposition, neurodegeneration, and blood-brain-barrier (BBB) permeability (Albumin quotient, Qalb), stratifying patients into early-onset (< 65, EOAD), classic late-onset (65-75, cLOAD) and very late-onset (> 75, vLOAD), to evaluate the moderating effect of age of onset. Moreover, we explored the effects of VRFs on cognitive decline at one year follow-up (ΔMMSE).

Methods: For 368 patients with biologically confirmed AD, we computed eight risk factors in a composite measure of cumulative vascular risk (vascular score, VS). Stratifying patients according to age of onset, we regressed VS and main individual VRFs on p-tau/Aβ42, t-tau and Qalb, and used bootstrapped mediation analysis to test direct and indirect associations of VS with t-tau, using Qalb as mediator. In a subset of 105 patients, we performed multivariate backward regressions to assess the effects of sex, APOE, Qalb, VS, p-tau/Aβ42 and t-tau on ΔMMSE.

Results: VS was positively associated with CSF t-tau in more vulnerable groups burdened by more aggressive disease progression (EOAD: β = 0.256, p = 0.019) or aging (vLOAD: β = 0.007, p < 0.001). Conversely, in patients with classic age of onset VS was associated with higher BBB permeability (cLOAD: β = 0.173, p = 0.015), which simultaneously causes the decrease of CSF t-tau, as a possible resilience response. Cognitive decline was not associated with VS in any of the subgroups. Instead, it was affected by both higher CSF t-tau and increased Qalb values in those with very early or very late onset (EOAD and vLOAD), but by Qalb alone in patients with classic age of onset, where CSF t-tau levels might be buffered by BBB permeability.

Conclusions: Our results show that age of onset weighs on the heterogeneous effects played by VRFs in AD, which do not seem to have direct impact on cognitive decline. These findings stress the importance of a tailored patient-centered approach to the application of vascular prevention strategies in AD.

Keywords: Blood-brain barrier; Cognitive decline; Early-onset; Late-onset; Vascular risk.

Fig. 1

Legend: Patient selection flowchart summarizing enrolment procedures for the cross-sectional and longitudinal studies

Fig. 2

legend: Associations between Vascular Score (VS), CSF t-tau levels and Qalb in patients with AD. Results on All AD are reported in gray, EOAD are displayed in pink, cLOAD in blue and vLOAD in green. All models are controlled for sex and APOE status. (A) Cross-sectional linear regressions between VS and CSF t-tau, (B) and between VS and Qalb, in All AD (gray) EOAD (pink), cLOAD (blue) and vLOAD (green). Colored areas represent 95% confidence interval. Standardized beta-estimates (β) and p-values were derived from linear regressions. (C) Cross-sectional mediation analyses with VS as predictor, Qalb as mediator, and CSF t-tau as the dependent variable in All AD, EOAD, cLOAD and vLOAD. Standardized Beta-estimates (β) and p-values for each path are displayed on the respective arrow. The average causal mediation effect (ACME) and the average direct effect (ADE) are reported under each mediation triangle