. 2024 Mar;20(3):1753-1770.

doi: 10.1002/alz.13560. Epub 2023 Dec 17.

Association of plasma biomarkers with cognition, cognitive decline, and daily function across and within neurodegenerative diseases: Results from the Ontario Neurodegenerative Disease Research Initiative

Erlan Sanchez¹, Tim Wilkinson¹, Gillian Coughlan², Saira Mirza^{1

3}, Andrée-Ann Baril⁴, Joel Ramirez⁵, Malcolm A Binns^{6

7}, Sandra E Black^{3

5}, Michael Borrie^{8

9}, Allison A Dilliott¹⁰, Roger A Dixon¹¹, Dar Dowlatshahi^{12

13}, Sali Farhan¹⁰, Elizabeth Finger^{8

9}, Corinne E Fischer¹⁴, Andrew Frank¹⁵, Morris Freedman^{3

6

16}, Rafaella A Goncalves¹⁷, David A Grimes^{12

13

18}, Ayman Hassan¹⁹, Robert A Hegele^{9

20}, Sanjeev Kumar^{21

22}, Anthony E Lang^{3

23}, Connie Marras²³, Paula M McLaughlin^{24

25}, Joseph B Orange^{26

27}, Stephen H Pasternak^{28

29}, Bruce G Pollock^{21

22

30}, Tarek K Rajji^{21

22}, Angela C Roberts^{26

27}, John F Robinson^{9

20}, Ekaterina Rogaeva³¹, Demetrios J Sahlas³², Gustavo Saposnik^{3

33}, Michael J Strong^{9

34}, Richard H Swartz^{3

35}, David F Tang-Wai^{3

36}, Maria Carmela Tartaglia^{31

36}, Angela K Troyer^{37

38}, Hlin Kvartsberg^{39

40}, Henrik Zetterberg^{39

40

41

42

43}, Douglas P Munoz¹⁷; ONDRI Investigators; Mario Masellis^{1

3}

Affiliations

¹ L.C. Campbell Cognitive Neurology Research Unit, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, Canada.
² Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
³ Division of Neurology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
⁴ Douglas Mental Health University Institute, McGill University, Montreal, Quebec, Canada.
⁵ Dr. Sandra Black Centre for Brain Resilience & Recovery, Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, Toronto, Ontario, Canada.
⁶ Rotman Research Institute, Baycrest Health Sciences, Toronto, Ontario, Canada.
⁷ Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
⁸ Lawson Health Research Institute, London, Ontario, Canada.
⁹ Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada.
¹⁰ Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montreal, Quebec, Canada.
¹¹ Department of Psychology, Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada.
¹² Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
¹³ Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
¹⁴ Keenan Research Centre for Biomedical Research, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
¹⁵ Bruyere Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
¹⁶ Department of Medicine, Mt. Sinai Hospital, Toronto, Ontario, Canada.
¹⁷ Centre for Neuroscience Studies, Queen's University, Kingston, Ontario, Canada.
¹⁸ Brain and Mind Research Institute, Ottawa, Ontario, Canada.
¹⁹ Thunder Bay Regional Research Institute, Northern Ontario School of Medicine, Thunder Bay, Ontario, Canada.
²⁰ Robarts Research Institute, Western University, London, Ontario, Canada.
²¹ Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
²² Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
²³ Edmond J. Safra Program in Parkinson's Disease and the Morton and Gloria Shulman Movement Disorders Centre, Toronto Western Hospital, Toronto, Ontario, Canada.
²⁴ Nova Scotia Health, Halifax, Nova Scotia, Canada.
²⁵ Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.
²⁶ School of Communication Sciences and Disorders, Western University, London, Ontario, Canada.
²⁷ Canadian Centre for Activity and Aging, Western University, London, Ontario, Canada.
²⁸ Department of Clinical Neurological Sciences, Robarts Research Institute, Western University, London, Ontario, Canada.
²⁹ Parkwood Institute, St. Joseph's Health Care Centre, Western University, London, Ontario, Canada.
³⁰ Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
³¹ Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada.
³² McMaster University, Hamilton, Ontario, Canada.
³³ Stroke Outcomes and Decision Neuroscience Unit, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
³⁴ Canadian Institutes for Health Research, Ottawa, Ontario, Canada.
³⁵ Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
³⁶ Krembil Brain Institute Memory Clinic, University Health Network, Toronto, Ontario, Canada.
³⁷ Department of Psychology, University of Toronto, Toronto, Ontario, Canada.
³⁸ Neuropsychology and Cognitive Health, Baycrest Health Sciences, Toronto, Ontario, Canada.
³⁹ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
⁴⁰ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
⁴¹ Dementia Research Institute, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK.
⁴² Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China.
⁴³ Wisconsin Alzheimer's Disease Research Center, University of Wisconsin, Madison, Wisconsin, USA.

PMID: 38105605
PMCID: PMC10984487
DOI: 10.1002/alz.13560

Association of plasma biomarkers with cognition, cognitive decline, and daily function across and within neurodegenerative diseases: Results from the Ontario Neurodegenerative Disease Research Initiative

Erlan Sanchez et al. Alzheimers Dement. 2024 Mar.

. 2024 Mar;20(3):1753-1770.

doi: 10.1002/alz.13560. Epub 2023 Dec 17.

Authors

Affiliations

¹ L.C. Campbell Cognitive Neurology Research Unit, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, Canada.
² Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
³ Division of Neurology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
⁴ Douglas Mental Health University Institute, McGill University, Montreal, Quebec, Canada.
⁵ Dr. Sandra Black Centre for Brain Resilience & Recovery, Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, Toronto, Ontario, Canada.
⁶ Rotman Research Institute, Baycrest Health Sciences, Toronto, Ontario, Canada.
⁷ Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
⁸ Lawson Health Research Institute, London, Ontario, Canada.
⁹ Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada.
¹⁰ Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montreal, Quebec, Canada.
¹¹ Department of Psychology, Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada.
¹² Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
¹³ Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
¹⁴ Keenan Research Centre for Biomedical Research, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
¹⁵ Bruyere Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
¹⁶ Department of Medicine, Mt. Sinai Hospital, Toronto, Ontario, Canada.
¹⁷ Centre for Neuroscience Studies, Queen's University, Kingston, Ontario, Canada.
¹⁸ Brain and Mind Research Institute, Ottawa, Ontario, Canada.
¹⁹ Thunder Bay Regional Research Institute, Northern Ontario School of Medicine, Thunder Bay, Ontario, Canada.
²⁰ Robarts Research Institute, Western University, London, Ontario, Canada.
²¹ Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
²² Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
²³ Edmond J. Safra Program in Parkinson's Disease and the Morton and Gloria Shulman Movement Disorders Centre, Toronto Western Hospital, Toronto, Ontario, Canada.
²⁴ Nova Scotia Health, Halifax, Nova Scotia, Canada.
²⁵ Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.
²⁶ School of Communication Sciences and Disorders, Western University, London, Ontario, Canada.
²⁷ Canadian Centre for Activity and Aging, Western University, London, Ontario, Canada.
²⁸ Department of Clinical Neurological Sciences, Robarts Research Institute, Western University, London, Ontario, Canada.
²⁹ Parkwood Institute, St. Joseph's Health Care Centre, Western University, London, Ontario, Canada.
³⁰ Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
³¹ Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada.
³² McMaster University, Hamilton, Ontario, Canada.
³³ Stroke Outcomes and Decision Neuroscience Unit, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
³⁴ Canadian Institutes for Health Research, Ottawa, Ontario, Canada.
³⁵ Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
³⁶ Krembil Brain Institute Memory Clinic, University Health Network, Toronto, Ontario, Canada.
³⁷ Department of Psychology, University of Toronto, Toronto, Ontario, Canada.
³⁸ Neuropsychology and Cognitive Health, Baycrest Health Sciences, Toronto, Ontario, Canada.
³⁹ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
⁴⁰ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
⁴¹ Dementia Research Institute, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK.
⁴² Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China.
⁴³ Wisconsin Alzheimer's Disease Research Center, University of Wisconsin, Madison, Wisconsin, USA.

PMID: 38105605
PMCID: PMC10984487
DOI: 10.1002/alz.13560

Abstract

Introduction: We investigated whether novel plasma biomarkers are associated with cognition, cognitive decline, and functional independence in activities of daily living across and within neurodegenerative diseases.

Methods: Glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), phosphorylated tau (p-tau)181 and amyloid beta (Aβ)_42/40 were measured using ultra-sensitive Simoa immunoassays in 44 healthy controls and 480 participants diagnosed with Alzheimer's disease/mild cognitive impairment (AD/MCI), Parkinson's disease (PD), frontotemporal dementia (FTD) spectrum disorders, or cerebrovascular disease (CVD).

Results: GFAP, NfL, and/or p-tau181 were elevated among all diseases compared to controls, and were broadly associated with worse baseline cognitive performance, greater cognitive decline, and/or lower functional independence. While GFAP, NfL, and p-tau181 were highly predictive across diseases, p-tau181 was more specific to the AD/MCI cohort. Sparse associations were found in the FTD and CVD cohorts and for Aβ_42/40 .

Discussion: GFAP, NfL, and p-tau181 are valuable predictors of cognition and function across common neurodegenerative diseases, and may be useful in specialized clinics and clinical trials.

Keywords: activities of daily living; amyloid; amyloid beta; blood; blood-based; cognition; dementia; glial fibrillary acidic protein; longitudinal; neurofilament light chain; neuropsychiatric; phosphorylated tau; protein; tau; vascular.

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Conflict of interest statement

H.Z. has served on scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave; has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche; and is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). D.A.G. has received honorarium for speaking from Ipsen, and honorarium for consulting from Allergan and Abbvie. M.F. is listed on a patent related to methods and kits for differential diagnosis of Alzheimer disease versus frontotemporal dementia using blood biomarkers. M.B. received royalties/licenses from Roche, and consulting fees from Biogen. RHS reports ownership in FollowMD Inc., a vascular risk reduction clinic. T.K.R. participated in 2021 and 2022 in an advisory activity for Biogen Canada Inc. T.K.R. is also an inventor on the United States Provisional Patent No. 17/396,030 that describes cell‐based assays and kits for assessing serum cholinergic receptor activity. Unrelated to this work, M.M. reports personal fees from Henry Stewart Talks, Alector, Biogen Canada, and Wave Life Sciences; as well as grants from Roche, Alector and Washington University. E.S., T.W., G.C., S.M., A.A.B., J.R., M.A.B., S.E.B., A.A.D., R.A.D., D.D., S.F., E.F., C.E.F., A.F., R.A.G., A.H., R.A.H., S.K., A.E.L., C.M., P.M.M., J.B.O., S.H.P., B.G.P., A.C.R., J.F.R., E.R., D.J.S., G.S., M.J.S., D.F.T., M.C.T., A.K.T., H.K., and D.P.M. report no conflicts. Author disclosures are available in the supporting information.

Figures

**FIGURE 1**
Cognitive domains at baseline and follow‐up visits across diseases. Composite z scores are relative to the mean and standard deviation of pooled disease groups at baseline, with the observed effects of age, sex, and education removed. Truncated violin plots do not extend past maximal values. Language and visuospatial function graphs’ y axes are cut at −7 for display purposes, excluding only a few participants for language (FTD, n = 1; 1y‐FTD, n = 1; 2y‐AD/MCI, n = 1) and visuospatial function (1y‐CVD, n = 1). 1y, 1‐year; 2y, 2‐year; AD/MCI, Alzheimer's disease/mild cognitive impairment; CVD, cerebrovascular disease; FTD, frontotemporal dementia; PD, Parkinson's disease.

**FIGURE 2**
Significant plasma biomarker associations with baseline cognitive domains and independence in activities of daily living across pooled diseases regardless of given diagnosis. Age, sex, years of education, and *APOE* ε4 carrier status were accounted for in statistical models or at initial computing of cognitive domain scores. Raw data are plotted and P values are derived from the combined group linear mixed effect models. (A) Significant GFAP associations. (B) Significant NfL associations. (C) Significant p‐tau181 associations. The gray area represents the 95% confidence interval. *APOE*, apolipoprotein E; GFAP, glial fibrillary acidic protein; iADL, instrumental activities of daily living; NfL, neurofilament light chain; p‐tau, phosphorylated tau.

**FIGURE 3**
Significant plasma biomarker associations with baseline cognitive domains and independence in activities of daily living in AD/MCI. Age, sex, years of education, and *APOE* ε4 carrier status were accounted for in statistical models or at initial computing of cognitive domain scores. Raw data are plotted and P values are derived from the AD/MCI group linear mixed effect models. (A) Significant GFAP associations. (B) Significant NfL associations. (C) Significant p‐tau181 associations. The gray area represents the 95% confidence interval. AD/MCI, Alzheimer's disease/mild cognitive impairment; *APOE*, apolipoprotein (E) GFAP, glial fibrillary acidic protein; iADL, instrumental activities of daily living; NfL, neurofilament light chain; p‐tau, phosphorylated tau.

**FIGURE 4**
Significant plasma biomarker associations with baseline cognitive domains and independence in activities of daily living in PD. Age, sex, years of education, and *APOE* ε4 carrier status were accounted for in statistical models or at initial computing of cognitive domain scores. Raw data are plotted and P values are derived from the PD group linear mixed effect models. (A) Significant NfL associations. (B) Significant GFAP associations. (C) Significant Aβ_42/40 associations. The gray area represents the 95% confidence interval. Aβ, amyloid beta; *APOE*, apolipoprotein (E) GFAP, glial fibrillary acidic protein; iADL, instrumental activities of daily living; NfL, neurofilament light chain; PD, Parkinson's disease; p‐tau, phosphorylated tau.

**FIGURE 5**
Significant plasma biomarker associations with baseline cognitive domains and independence in activities of daily living in CVD. Age, sex, years of education, and *APOE* ε4 carrier status were accounted for in statistical models or at initial computing of cognitive domain scores. Raw data are plotted and P values are derived from the CVD group linear mixed effect models. (A) Significant GFAP associations. (B) Significant NfL associations. (C) Significant p‐tau181 associations. The gray area represents the 95% confidence interval. *APOE*, apolipoprotein E; CVD, cardiovascular disease; GFAP, glial fibrillary acidic protein; iADL, instrumental activities of daily living; NfL, neurofilament light chain; p‐tau, phosphorylated tau.

**FIGURE 6**
Simplified summary of the associative value of plasma biomarkers with outcome measures in the ONDRI sample. Black dot: significant associations with two or more cognitive domains, at baseline or longitudinally, or significant associations with any functional independence scale. Crosshatched dot: significant or statistically indeterminate (P < 0.1) association with one cognitive domain, at baseline or longitudinally. The five cognitive domains are: attention and working memory, executive function, language, memory, visuospatial function. The ADLs category includes % of independence in basic and/or instrumental ADLs. Aβ, amyloid beta; ADLs, activities of daily living; AD/MCI, Alzheimer's disease/mild cognitive impairment; CVD, cardiovascular disease; FTD, frontotemporal dementia; GFAP, glial fibrillary acidic protein; iADL, instrumental activities of daily living; NfL, neurofilament light chain; ONDRI, Ontario Neurodegenerative Disease Research Initiative; PD, Parkinson's disease; p‐tau, phosphorylated tau.

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References

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Association of plasma biomarkers with cognition, cognitive decline, and daily function across and within neurodegenerative diseases: Results from the Ontario Neurodegenerative Disease Research Initiative

Affiliations

Association of plasma biomarkers with cognition, cognitive decline, and daily function across and within neurodegenerative diseases: Results from the Ontario Neurodegenerative Disease Research Initiative

Authors

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Abstract

Conflict of interest statement

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