Cardiovascular Factors Directly Drive Neurodegeneration but Not Cognitive Decline in Alzheimer's Disease: A Longitudinal Study
Chiara Giuseppina Bonomi1, Caterina Motta1, Martina Poli1, Martina Gaia Di Donna1, Nicola Biagio Mercuri1, Giacomo Koch2, Alessandro Martorana1
1University of Rome Tor Vergata, 2IRCCS Santa Lucia Foundation
Objective:
We explored the association of cardiovascular risk factors with CSF markers of amyloid deposition and neurodegeneration stratifying patients with Alzheimer’s Disease (AD) according to age-of-onset: early (< 65,EOAD), classic (65-75,COAD), late (>75,LOAD). Then, we evaluated the effects of vascular comorbidities on cognitive decline and their interplay with albumin quotient (Qalb), accounting for blood-brain-barrier (BBB) integrity, and neurodegeneration.
Background:
Vascular copathology is a very common neuropathological finding in AD, and still much needs to be elucidated on its mechanistic association with AD
Design/Methods:
We enrolled 387 patients with biomarker-confirmed Mild-Cognitive-Impairment due to AD. We computed 8 risk factors in a composite vascular score (VS) and transformed the output to a 0-to-1 percentage. In each group we regressed VS on p-tau/Aβ42 and t-tau, accounting for sex, APOE and Qalb. In a subset of 105 patients, we regressed sex, APOE, Qalb, VS and t-tau on ΔMMSE (negative MMSE-changes after 1 year). A bias-corrected bootstrapped mediation model was used to test the indirect association of VS with ΔMMSE and with t-tau using Qalb as mediator.
Results:
VS was not associated with p-tau/Aβ42 in any group, but positively associated with t-tau in EOAD (p=0.016) and LOAD (p<.001), though not in COAD (p=0.580). ΔMMSE was negatively associated with Qalb (p=<.001) and t-tau (p=0.004), but not with VS (p=0.662). The mediation model confirmed the absence of global effects of VS on ΔMMSE, despite the indirect negative Qalb-mediated repercussions (ADE:−1.097,p=0.406; ADME:−0.678,p=0.027; total:−1.775,p=0.183), but a strong direct positive effect on t-tau, with Qalb as a partial negative mediator (ADE:293.98,p=0.001; ADME:−39.25,p=0.044; total:254.74,p=0.006).
Conclusions:
Cardiovascular risk factors impact neurodegeneration differently depending on AD age-of-onset. Globally, the VS-induced increase of t-tau levels leads to cognitive worsening, but we found no evidence of a direct role of VS on the progression of cognitive decline