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

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.