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. 2024 Apr:136:88-98.
doi: 10.1016/j.neurobiolaging.2023.12.008. Epub 2024 Jan 10.

Vascular risk burden is a key player in the early progression of Alzheimer's disease

João Pedro Ferrari-Souza  1 , Wagner S Brum  2 , Lucas A Hauschild  3 , Lucas U Da Ros  3 , Pâmela C L Ferreira  4 , Bruna Bellaver  1 , Douglas T Leffa  4 , Andrei Bieger  3 , Cécile Tissot  5 , Firoza Z Lussier  5 , Marco Antônio De Bastiani  3 , Guilherme Povala  4 , Andréa L Benedet  6 , Joseph Therriault  7 , Yi-Ting Wang  7 , Nicholas J Ashton  8 , Henrik Zetterberg  9 , Kaj Blennow  10 , Sheila O Martins  11 , Diogo O Souza  3 , Pedro Rosa-Neto  7 , Thomas K Karikari  12 , Tharick A Pascoal  13 , Eduardo R Zimmer  14 ; Alzheimer’s Disease Neuroimaging Initiative
Affiliations

Vascular risk burden is a key player in the early progression of Alzheimer's disease

João Pedro Ferrari-Souza et al. Neurobiol Aging. 2024 Apr.

Abstract

Understanding whether vascular risk factors (VRFs) synergistically potentiate Alzheimer's disease (AD) progression is important in the context of emerging treatments for preclinical AD. In a group of 503 cognitively unimpaired individuals, we tested whether VRF burden interacts with AD pathophysiology to accelerate neurodegeneration and cognitive decline. Baseline VRF burden was calculated considering medical data and AD pathophysiology was assessed based on cerebrospinal fluid (CSF) amyloid-β1-42 (Aβ1-42) and tau phosphorylated at threonine 181 (p-tau181). Neurodegeneration was assessed with plasma neurofilament light (NfL) and global cognition with the modified version of the Preclinical Alzheimer's Cognitive Composite. The mean (SD) age of participants was 72.9 (6.1) years, and 220 (43.7%) were men. Linear mixed-effects models revealed that an elevated VRF burden synergistically interacted with AD pathophysiology to drive longitudinal plasma NfL increase and cognitive decline. Additionally, VRF burden was not associated with CSF Aβ1-42 or p-tau181 changes over time. Our results suggest that VRF burden and AD pathophysiology are independent processes; however, they synergistically lead to neurodegeneration and cognitive deterioration. In preclinical stages, the combination of therapies targeting VRFs and AD pathophysiology might potentiate treatment outcomes.

Keywords: Alzheimer’s disease; Biomarker; Cognitive decline; Neurodegeneration; Vascular risk factor.

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Conflict of interest statement

Competing interests NJA has given lectures in symposia sponsored by Lilly and Quanterix. HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Pinteon Therapeutics, Red Abbey Labs, reMYND, Passage Bio, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. KB has served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, BioArctic, Biogen, JOMDD/Shimadzu, Julius Clinical, Lilly, MagQu, Novartis, Prothena, Roche Diagnostics, and Siemens Healthineers, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, all unrelated to the work presented in this paper. SOM reports receiving speaker fees from Medtronic, Novartis, Novo Nordisk, Pfizer, Bayer and advisory board fees from Boehringer Ingelheim. PR-N has served on scientific advisory boards and/or as a consultant for Eisai, Novo Nordisk and Roche. ERZ serves on the scientific advisory board of Next Innovative Therapeutics. All other authors declare no competing interests.

Figures

Figure 1.
Figure 1.. Elevated VRF burden accelerates neurodegeneration and cognitive decline in individuals with preclinical AD.
Mean predicted trajectories and 95% confidence interval (CI) estimated from LME models according to baseline VRF burden and AD pathophysiology. (A) Longitudinal neurodegeneration measured by plasma NfL levels over a 4-year follow-up period and (B) longitudinal cognitive trajectory indexed by the mPACC score over a 6-year follow-up period. Each model was adjusted for age, sex, years of education, APOE ε4 status, and their interaction with time.
Figure 2.
Figure 2.. VRF burden is not associated with changes over time in CSF Aβ1–42 and p-tau181 levels.
Mean predicted trajectories and 95% confidence interval (CI) estimated from LME models according to baseline VRF burden. (A) CSF Aβ1–42 longitudinal trajectory over a 6-year follow-up and (B) CSF p-tau181 longitudinal trajectory over a 6-year follow-up period. Each model was adjusted for age, sex, years of education, APOE ε4 status, and their interaction with time.
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