Cerebrospinal fluid neurogranin/β-site APP-cleaving enzyme 1 predicts cognitive decline in preclinical Alzheimer's disease

Bjørn-Eivind Kirsebom; Kaja Nordengen; Per Selnes; Knut Waterloo; Silje Bøen Torsetnes; Berglind Gísladóttir; Britta Brix; Eugeen Vanmechelen; Geir Bråthen; Erik Hessen; Dag Aarsland; Tormod Fladby

doi:10.1016/j.trci.2018.10.003

Cerebrospinal fluid neurogranin/β-site APP-cleaving enzyme 1 predicts cognitive decline in preclinical Alzheimer's disease

Alzheimers Dement (N Y). 2018 Nov 10:4:617-627. doi: 10.1016/j.trci.2018.10.003. eCollection 2018.

Authors

Bjørn-Eivind Kirsebom^{1

2}, Kaja Nordengen^{3

4}, Per Selnes^{3

4}, Knut Waterloo^{1

2}, Silje Bøen Torsetnes³, Berglind Gísladóttir^{3

5}, Britta Brix⁶, Eugeen Vanmechelen⁷, Geir Bråthen^{8

9}, Erik Hessen^{3

10}, Dag Aarsland^{11

12}, Tormod Fladby^{3

4}

Affiliations

¹ Department of Neurology, University Hospital of North Norway, Tromsø, Norway.
² Department of Psychology, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway.
³ Department of Neurology, Akershus University Hospital, Lørenskog, Norway.
⁴ Institute of Clinical Medicine, Campus Ahus, University of Oslo, Oslo, Norway.
⁵ Molecular Biology (EpiGen), Institute of Clinical Medicine, University of Oslo, Akershus University Hospital, Lørenskog, Norway.
⁶ Euroimmun, Lübeck, Germany.
⁷ ADx NeuroSciences NV, Gent, Belgium.
⁸ Department of Neuromedicine and Movement Science, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway.
⁹ Department of Neurology and Clinical Neurophysiology, University Hospital of Trondheim, Trondheim, Norway.
¹⁰ Department of Psychology, University of Oslo, Oslo, Norway.
¹¹ Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway.
¹² Department of Old Age Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Abstract

Introduction: The cerebrospinal fluid neurogranin (Ng)/β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) ratio may reflect synaptic affection resulting from reduced beta-amyloid (Aβ) clearance. We hypothesize that increased Ng/BACE1 ratio predicts the earliest cognitive decline in Alzheimer's disease.

Methods: We compared Ng/BACE1 levels between cases with subjective cognitive decline (n = 18) and mild cognitive impairment (n = 20) both with amyloid plaques and healthy controls (APOE-ε4+, n = 16; APOE-ε4-, n = 20). We performed regression analyses between cerebrospinal fluid levels, baseline hippocampal and amygdala volumes, and pertinent cognitive measures (memory, attention, Mini Mental State Examination [MMSE]) at baseline and after 2 years.

Results: Ng/BACE1 levels were elevated in both subjective cognitive decline and mild cognitive impairment compared to healthy controls. Higher Ng/BACE1 ratio was associated with lower hippocampal and amygdala volumes; lower baseline memory functions, attention, and MMSE; and significant decline in MMSE and memory function at 2-year follow-up.

Discussion: High Ng/BACE1 ratio predicts cognitive decline also in preclinical cases with amyloid plaques.

Keywords: Alzheimer's disease; CSF BACE1; CSF neurogranin; Cerebrospinal fluid (CSF); Cognition; MCI (mild cognitive impairment); MRI; Memory; SCD (subjective cognitive decline); Synaptic loss.