BACE1 Activity in Cerebrospinal Fluid and Its Relation to Markers of AD Pathology

Article type: Research Article

Authors: Mulder, Sandra D.^{a; b; *} | van der Flier, Wiesje M.^{b; c} | Verheijen, Jan H.^d | Mulder, Cees^{a; b} | Scheltens, Philip^{b; c} | Blankenstein, Marinus A.^{a; b} | Hack, C. Erik^a | Veerhuis, Robert^{a; b; e}

Affiliations: [a] Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands | [b] Alzheimer Center, VU University Medical Center, Amsterdam, The Netherlands | [c] Department of Neurology, VU University Medical Center, Amsterdam, The Netherlands | [d] TNO Quality of Life, Business Unit Biosciences, Gaubius Laboratory, Leiden, The Netherlands | [e] Department of Psychiatry, VU University Medical Center, Amsterdam, The Netherlands

Correspondence: [*] Correspondence to: Sandra D. Mulder, Department of Clinical Chemistry, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, the Netherlands. Tel.: +31 20 4443870; Fax: +31 20 4443895; E-mail: [email protected].

Note: [] Handling Associate Editor: Henrik Zetterberg

Abstract: Several studies have shown that reduced amyloid-β 1–42 (Aβ42) and increased tau levels in cerebrospinal fluid (CSF) reflect increased Alzheimer's disease (AD) pathology in the brain. β-site APP cleaving enzyme (BACE1) is thought to be the major β-secretase involved in Aβ production in the brain, and therefore we investigated the relation between BACE1 activity and CSF markers Aβ40, Aβ42, total tau (t-tau), and tau phosphorylated at threonine 181 (p-tau) in CSF of control (n = 12), mild cognitive impairment (n = 18), and AD (n = 17) subjects. Patients were classified according to their Aβ42, t-tau, and p-tau CSF biomarker levels, with either an AD-like biomarker profile (two or three biomarkers abnormal: Aβ42 495 pg/ml in combination with t-tau > 356 pg/ml, and/or p-tau > 54 pg/ml) or a normal biomarker profile (⩽ one biomarker abnormal). This resulted in 19 subjects with an AD-like biomarker profile (66 ± 6 years, 53% female, and Mini-Mental Status Examination (MMSE) score: 23 ± 5) and 28 subjects with a normal biomarker profile (62 ± 11 years, 43% female, and MMSE score: 27 ± 4). Subjects with an AD-like biomarker profile had higher CSF BACE1 activity levels, compared to patients with a normal biomarker profile (20 pg/ml and 16 pg/ml respectively; p = 0.01), when controlled for age and gender. In the whole sample, BACE1 activity correlated with CSF levels of Aβ40, t-tau, and p-tau (r = 0.38, r = 0.63, and r = 0.65; all p < 0.05), but not with Aβ42. These data suggest that increased BACE1 activity in CSF relates to AD pathology in the brain.

Keywords: Aβ₄₀, Aβ₄₂, Alzheimer's disease, BACE1 activity, CSF biomarker profile, p-tau, t-tau

DOI: 10.3233/JAD-2010-1367

Journal: Journal of Alzheimer's Disease, vol. 20, no. 1, pp. 253-260, 2010