Effect of Vascular Risk Factors on Blood-Brain Barrier and Cerebrospinal Fluid Biomarkers Along the Alzheimer’s Disease Continuum: A Retrospective Observational Study

Article type: Research Article

Authors: Ricci, Francesco^a | Martorana, Alessandro^{a; *} | Bonomi, Chiara G.^a | Serafini, Chiara^a | Mercuri, Nicola B.^b | Koch, Giacomo^{c; d} | Motta, Caterina^a

Affiliations: [a] UOSD Centro Demenze, Policlinico Tor Vergata, University of Rome “Tor Vergata”, Rome, Italy | [b] Neurology Unit, Policlinico Tor Vergata, University of Rome “Tor Vergata”, Rome, Italy | [c] Non Invasive Brain Stimulation Unit, IRCCS SantaLucia, Rome, Italy | [d] Department of Neuroscience and Rehabilitation, Human Physiology Unit, University of Ferrara, Ferrara, Italy

Correspondence: [*] Correspondence to: Prof. Alessandro Martorana, MD, PhD, UOSD Centro Demenze, Policlinico Tor Vergata, University of Rome “Tor Vergata”, viale Oxford, 81, 00133 Roma, Italy. Tel.: +0039 06 20903137; Fax: +0039 06 20903118; E-mail: martorana@med.uniroma2.it

Abstract: Background: Blood-brain barrier (BBB) dysfunction could favor the pathogenesis and progression of Alzheimer’s disease (AD). Vascular risk factors (VRF) could worsen BBB integrity, thus promoting neurode generation. Objective: To investigate BBB permeability and its relation with VRF along the AD continuum (ADc). Cerebrospinal fluid (CSF) Amyloid (A) and p-tau (T) levels were used to stratify patients. Methods: We compared CSF/plasma albumin ratio (QAlb) of 131 AD patients and 24 healthy controls (HC). APOE genotype and VRF were evaluated for each patient. Spearman’s Rho correlation was used to investigate the associations between Qalb and CSF AD biomarkers. Multivariate regression analyses were conducted to explore the relationship between Qalb and AD biomarkers, sex, age, cognitive status, and VRF. Results: QAlb levels did not show significant difference between ADc patients and HC (p = 0.984). However, QAlb was significantly higher in A + T–compared to A + T+ (p = 0.021). In ADc, CSF p-tau demonstrated an inverse correlation with QAlb, a finding confirmed in APOE4 carriers (p = 0.002), but not in APOE3. Furthermore, in APOE4 carriers, sex, hypertension, and hypercholesterolemia were associated with QAlb (p = 0.004, p = 0.038, p = 0.038, respectively), whereas only sex showed an association in APOE3 carriers (p = 0.026). Conclusions: BBB integrity is preserved in ADc. Among AT categories, A + T–have a more permeable BBB than A + T+. In APOE4 carriers, CSF p-tau levels display an inverse association with BBB permeability, which in turn, seems to be affected by VRF. These data suggest a possible relationship between BBB efficiency, VRF and CSF p-tau levels depending on APOE genotype.

Keywords: Alzheimer’s disease, Alzheimer’s disease continuum, APOE, biomarkers, blood-brain barrier, QAlb, vascular risk factors

DOI: 10.3233/JAD-230792

Journal: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 599-607, 2024