{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T18:12:24Z","timestamp":1768414344076,"version":"3.49.0"},"reference-count":63,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2022,9,24]],"date-time":"2022-09-24T00:00:00Z","timestamp":1663977600000},"content-version":"vor","delay-in-days":23,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005416","name":"Norwegian Research Council","doi-asserted-by":"crossref","award":["NRC 311993"],"award-info":[{"award-number":["NRC 311993"]}],"id":[{"id":"10.13039\/501100005416","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Helse S\u00f8r-\u00d8st and Helse-Nord","award":["HNF1410-18"],"award-info":[{"award-number":["HNF1410-18"]}]},{"name":"Helse S\u00f8r-\u00d8st and Helse-Nord","award":["HNF1540-20"],"award-info":[{"award-number":["HNF1540-20"]}]},{"DOI":"10.13039\/501100004359","name":"Swedish Research Council","doi-asserted-by":"crossref","award":["2017-00915"],"award-info":[{"award-number":["2017-00915"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100002565","name":"Alzheimer Drug Discovery Foundation","doi-asserted-by":"crossref","award":["RDAPB-201809-2016615"],"award-info":[{"award-number":["RDAPB-201809-2016615"]}],"id":[{"id":"10.13039\/100002565","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Swedish Alzheimer Foundation","award":["AF-742881"],"award-info":[{"award-number":["AF-742881"]}]},{"name":"Swedish Alzheimer Foundation","award":["ALFGBG-715986"],"award-info":[{"award-number":["ALFGBG-715986"]}]},{"name":"European Union Joint Programme for Neurodegenerative Disorders","award":["JPND2019-466-236"],"award-info":[{"award-number":["JPND2019-466-236"]}]},{"name":"National Institute of Health","award":["1R01AG068398-01"],"award-info":[{"award-number":["1R01AG068398-01"]}]},{"DOI":"10.13039\/100000957","name":"Alzheimer\u2019s Association","doi-asserted-by":"crossref","award":["ZEN-21-848495"],"award-info":[{"award-number":["ZEN-21-848495"]}],"id":[{"id":"10.13039\/100000957","id-type":"DOI","asserted-by":"crossref"}]},{"name":"ZonMw","award":["733051111"],"award-info":[{"award-number":["733051111"]}]},{"name":"Ministry of Education, Science and Sport, Republic of Slovenia"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Cerebrospinal fluid (CSF) \u03b2-site amyloid precursor protein cleaving enzyme 1 (BACE1), neurogranin and the neurogranin\/BACE1 ratio are proposed markers for Alzheimer\u2019s disease. BACE1 is also a drug target. However, CSF levels may differ between early-stage amyloid plaque formation (A) and later stage downstream tau-tangle pathology (T) and neurodegeneration (N) and may be expressed as an A\/T\/N stage (e.g. A+\/T\u2212\/N or A+\/T+\/N+). Whether BACE1 and neurogranin levels are persistent traits or change with disease progression is unknown. The aim of this study was to investigate whether CSF neurogranin and BACE1 concentrations differ between A\/T\/N stages, whether these change over time and correlate with memory decline. This may have implications for patient selection in future trials. We used CSF markers to determine A\/T\/N stage using amyloid beta42\/40 ratio, p-tau181 and total-tau respectively in predementia Alzheimer\u2019s disease cases (n = 176) [including cases that progressed to dementia (n = 10)] and controls (n = 74) from the Norwegian Dementia Disease Initiation cohort. We selected cases at the presumed early (A+\/T\u2212\/N\u2212, n = 86) and late stages (A+\/T+\/N+, n = 90) of the Alzheimer\u2019s disease continuum and controlled with normal markers (A\u2212\/T\u2212\/N\u2212, n = 74). A subset of subjects in all A\/T\/N groups underwent repeat CSF sampling at approximately 2-year intervals up to 6 years from baseline. Using linear mixed models, longitudinal measurements of CSF BACE1 and neurogranin levels in A+\/T\u2212\/N\u2212 and A+\/T+\/N+ as compared to A\u2212\/T\u2212\/N\u2212 healthy controls were performed. Next, we measured changes in CSF BACE1 and neurogranin levels in cases that progressed from A\u2212\/T\u2212\/N\u2212 to A+\/T\u2212\/N\u2212 (n = 12), from A+\/T\u2212\/N\u2212 to A+\/T or N+ (n = 12), remained stable A+\/T\u2212\/N\u2212 (n = 26), remained stable A+\/T+\/N+ (n = 28) compared with controls remaining stable A\u2212\/T\u2212\/N\u2212 (n = 33). Lastly, associations between these markers and memory decline were assessed. Compared with A\u2212\/T\u2212\/N\u2212 healthy controls, neurogranin was unaltered in A+\/T\u2212\/N\u2212 (n.s.) but higher in A+\/T+\/N+ (P &amp;lt; 0.0001). In contrast, BACE1 was lower in A+\/T\u2212\/N\u2212 (P &amp;lt; 0.05) and higher in A+\/T+\/N+ (P &amp;lt; 0.0001). The neurogranin\/BACE1 ratio was increased in both A+\/T\u2212\/N\u2212 (P &amp;lt; 0.05) and A+\/T+\/N+ (P &amp;lt; 0.0001) groups as compared to A-\/T-\/N- healthy controls and was more strongly associated with memory decline (b = \u22120.29, P = 0.0006) than neurogranin (b = \u22120.20, P = 0.002) and BACE1 (b = \u22120.13, P = 0.046). Neurogranin and BACE1 level differences remained stable over time not only within A\/T\/N groups but also in patients progressing to more pathological A\/T\/N stages (e.g. progressing from A+\/T\u2212\/N\u2212 to A + T or N+) and in cases progressing to dementia. Our results suggest that neurogranin and BACE1 levels may differentiate pathomechanistic Alzheimer\u2019s disease subgroups, putatively with different options for treatment.<\/jats:p>","DOI":"10.1093\/braincomms\/fcac244","type":"journal-article","created":{"date-parts":[[2022,9,23]],"date-time":"2022-09-23T21:03:05Z","timestamp":1663966985000},"source":"Crossref","is-referenced-by-count":11,"title":["Stable cerebrospinal fluid neurogranin and \u03b2-site amyloid precursor protein cleaving enzyme 1 levels differentiate predementia Alzheimer\u2019s disease patients"],"prefix":"10.1093","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1413-9578","authenticated-orcid":false,"given":"Bj\u00f8rn Eivind","family":"Kirsebom","sequence":"first","affiliation":[{"name":"Department of Neurology, University Hospital of North Norway , 9038 Troms\u00f8 , Norway"},{"name":"Department of Psychology, Faculty of Health Sciences, UiT, The Arctic University of Norway , 9019 Troms\u00f8 , Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Grit","family":"Richter","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Hospital of North Norway , 9038 Troms\u00f8 , Norway"},{"name":"Department of clinical medicine, Faculty of Health Sciences, UiT The Arctic University of Norway , 9019 Troms\u00f8 , Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5897-6394","authenticated-orcid":false,"given":"Kaja","family":"Nordengen","sequence":"additional","affiliation":[{"name":"Department of Neurology, Akershus University Hospital , 1478 L\u00f8renskog , Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dag","family":"Aarsland","sequence":"additional","affiliation":[{"name":"Centre for Age-Related Medicine, Stavanger University Hospital , 4068 Stavanger , Norway"},{"name":"Department of Old Age Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College London , London SES 8AF , UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Geir","family":"Br\u00e5then","sequence":"additional","affiliation":[{"name":"Department of Neuromedicine and Movement Science, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology , 7491 Trondheim , Norway"},{"name":"Department of Neurology and Clinical Neurophysiology, University Hospital of Trondheim , 7030 Trondheim , Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2612-1797","authenticated-orcid":false,"given":"Betty M","family":"Tijms","sequence":"additional","affiliation":[{"name":"Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC - Location VUmc , 1007 MB Amsterdam , The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pieter Jelle","family":"Visser","sequence":"additional","affiliation":[{"name":"Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC - Location VUmc , 1007 MB Amsterdam , The Netherlands"},{"name":"Alzheimer Center Limburg, School for Mental Health and Neuroscience, Maastricht University , 6200 MD Maastricht , The Netherlands"},{"name":"Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics, Karolinska Institutet , 171 77 Stockholm , Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johanna","family":"Nilsson","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg , 413 45 Gothenburg , Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Per","family":"Selnes","sequence":"additional","affiliation":[{"name":"Department of Neurology, Akershus University Hospital , 1478 L\u00f8renskog , Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Milica G","family":"Kramberger","sequence":"additional","affiliation":[{"name":"Centre for cognitive impairments, Department of Neurology, University Medical Centre , 1000 Ljubljana , Slovenia"},{"name":"Department of Neurology, Medical faculty, University of Ljubljana , 1000 Ljubljana , Slovenia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bengt","family":"Winblad","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics, Karolinska Institutet , 171 77 Stockholm , Sweden"},{"name":"Karolinska University Hospital, Theme Inflammation and Aging , 141 86 Stockholm , Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Knut","family":"Waterloo","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Hospital of North Norway , 9038 Troms\u00f8 , Norway"},{"name":"Department of Psychology, Faculty of Health Sciences, UiT, The Arctic University of Norway , 9019 Troms\u00f8 , Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Berglind","family":"G\u00edslad\u00f3ttir","sequence":"additional","affiliation":[{"name":"Department of Neurology, Akershus University Hospital , 1478 L\u00f8renskog , Norway"},{"name":"Clinical Molecular Biology (EpiGen), Medical Division, University of Oslo , 1478 Ahus, L\u00f8renskog , Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaj","family":"Blennow","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg , 413 45 Gothenburg , Sweden"},{"name":"Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital , 431 30 M\u00f6lndal , 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