. 2025 Jan;21(1):e14376.

doi: 10.1002/alz.14376. Epub 2024 Nov 19.

Homocysteine, neurodegenerative biomarkers, and APOE ε4 in neurodegenerative diseases

William Z Lin^{1

2

3}, Di Yu^{1

2

3}, Lisa Y Xiong^{1

2

3}, Julia Zebarth^{1

2

3}, Ruoding Wang^{1

2

4}, Corinne E Fischer^{5

6}, Tarek K Rajji⁷, David F Tang-Wai^{8

9}, Carmela Tartaglia¹⁰, Gustavo Saposnik¹¹, Richard H Swartz^{2

9

12}, David A Grimes^{13

14

15}, Anthony E Lang^{9

16}, Robert A Hegele^{17

18}, Sali Farhan^{18

19}, Joel Ramirez², Sean Symons², Maged Goubran^{2

20}, Malcolm A Binns²¹, Wendy Lou²², Roger A Dixon²³, Joseph B Orange^{24

25}, Angela C Roberts^{24

25}, Angela K Troyer^{26

27}, Henrik Zetterberg^{28

29

30

31

32

33}, Nathan Herrmann^{2

4

5}, Jennifer S Rabin^{2

9}, Bradley J MacIntosh^{2

20}, Mario Masellis^{2

9}, Krista L Lanctôt^{1

2

12}, Sandra E Black^{2

7

9

12

34}, Walter Swardfager^{1

2

3

34}; ONDRI Investigators

Collaborators, Affiliations

Collaborators

Affiliations

¹ Department of Pharmacology & Toxicology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
² Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, Canada.
³ KITE Research Institute, Toronto Rehabilitation Institute-University Health Network, Toronto, Ontario, Canada.
⁴ Neuropsychopharmacology Research Group, Sunnybrook Research Institute, Toronto, Ontario, Canada.
⁵ Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
⁶ Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.
⁷ Toronto Dementia Research Alliance, University of Toronto, Toronto, Ontario, Canada.
⁸ Krembil Brain Institute, University Health Network, Toronto, Ontario, Canada.
⁹ Division of Neurology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
¹⁰ Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada.
¹¹ Stroke Outcomes and Decision Neuroscience Research Unit, Division of Neurology, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.
¹² Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
¹³ Division of Neurology, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
¹⁴ Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
¹⁵ Brain and Mind Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
¹⁶ Edmond J. Safra Program in Parkinson's Disease, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada.
¹⁷ Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada.
¹⁸ Robarts Research Institute, Western University, London, Ontario, Canada.
¹⁹ Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montreal, Quebec, Canada.
²⁰ Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
²¹ Rotman Research Institute, Baycrest Health Sciences, Toronto, Ontario, Canada.
²² Department of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
²³ Department of Psychology, Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada.
²⁴ School of Communication Sciences and Disorders, Western University, London, Ontario, Canada.
²⁵ Canadian Centre for Activity and Aging, Western University, London, Ontario, Canada.
²⁶ Department of Psychology, University of Toronto, Toronto, Ontario, Canada.
²⁷ Neuropsychology and Cognitive Health, Baycrest Health Sciences, Toronto, Ontario, Canada.
²⁸ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
²⁹ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
³⁰ Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
³¹ UK Dementia Research Institute at UCL, London, UK.
³² Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay, Hong Kong, China.
³³ Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA.
³⁴ Sandra Black Centre for Brain Resilience and Recovery, Sunnybrook Research Institute, Toronto, Ontario, Canada.

PMID: 39559926
PMCID: PMC11775453
DOI: 10.1002/alz.14376

Homocysteine, neurodegenerative biomarkers, and APOE ε4 in neurodegenerative diseases

William Z Lin et al. Alzheimers Dement. 2025 Jan.

. 2025 Jan;21(1):e14376.

doi: 10.1002/alz.14376. Epub 2024 Nov 19.

Authors

Collaborators

Affiliations

¹ Department of Pharmacology & Toxicology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
² Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, Canada.
³ KITE Research Institute, Toronto Rehabilitation Institute-University Health Network, Toronto, Ontario, Canada.
⁴ Neuropsychopharmacology Research Group, Sunnybrook Research Institute, Toronto, Ontario, Canada.
⁵ Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
⁶ Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.
⁷ Toronto Dementia Research Alliance, University of Toronto, Toronto, Ontario, Canada.
⁸ Krembil Brain Institute, University Health Network, Toronto, Ontario, Canada.
⁹ Division of Neurology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
¹⁰ Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada.
¹¹ Stroke Outcomes and Decision Neuroscience Research Unit, Division of Neurology, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.
¹² Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
¹³ Division of Neurology, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
¹⁴ Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
¹⁵ Brain and Mind Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
¹⁶ Edmond J. Safra Program in Parkinson's Disease, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada.
¹⁷ Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada.
¹⁸ Robarts Research Institute, Western University, London, Ontario, Canada.
¹⁹ Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montreal, Quebec, Canada.
²⁰ Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
²¹ Rotman Research Institute, Baycrest Health Sciences, Toronto, Ontario, Canada.
²² Department of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
²³ Department of Psychology, Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada.
²⁴ School of Communication Sciences and Disorders, Western University, London, Ontario, Canada.
²⁵ Canadian Centre for Activity and Aging, Western University, London, Ontario, Canada.
²⁶ Department of Psychology, University of Toronto, Toronto, Ontario, Canada.
²⁷ Neuropsychology and Cognitive Health, Baycrest Health Sciences, Toronto, Ontario, Canada.
²⁸ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
²⁹ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
³⁰ Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
³¹ UK Dementia Research Institute at UCL, London, UK.
³² Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay, Hong Kong, China.
³³ Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA.
³⁴ Sandra Black Centre for Brain Resilience and Recovery, Sunnybrook Research Institute, Toronto, Ontario, Canada.

PMID: 39559926
PMCID: PMC11775453
DOI: 10.1002/alz.14376

Abstract

Introduction: Elevated plasma homocysteine (Hcy) is associated with an increased risk of developing neurodegenerative diseases; however, its relationship with the apolipoprotein E (APOE) ε4 allele has not been well characterized.

Methods: Participants clinically diagnosed with Alzheimer's disease or mild cognitive impairment (AD/MCI), frontotemporal dementia, Parkinson's disease, or cerebrovascular disease were stratified by the presence of the APOE ε4 allele. Volumetric magnetic resonance imaging, plasma amyloid/tau/neurodegeneration biomarkers, and cognitive performance were quantified.

Results: Across all diagnostic groups, Hcy was associated with lower brain parenchymal fraction and greater neurofilament light chain in APOE ε4 non-carriers only. In AD/MCI, Hcy was associated with phosphorylated tau 217 in APOE ε4 non-carriers, but not in carriers. Exploratory analyses revealed interactions between Hcy and APOE ε4 on memory and visuospatial function.

Discussion: Hcy may contribute to neurodegeneration depending on the presence of the APOE ε4 allele and specific disease processes. Trials on vitamin B12 supplementation may consider stratifying by APOE genotype. Highlights Homocysteine (Hcy) was associated with neurodegenerative biomarkers across disease groups. Relationships with Hcy were predominantly found in apolipoprotein E (APOE) ε4 non-carriers. In Alzheimer's disease, associations between Hcy and phosphorylated tau 217 were found in APOE ε4 non-carriers only. Significant interactions existed between Hcy and APOE ε4 status on cognition.

Keywords: Alzheimer's disease; Parkinson's disease; apolipoprotein E; biomarkers; cerebrovascular disease; dementia; frontotemporal dementia; homocysteine; mild cognitive impairment.

PubMed Disclaimer

Conflict of interest statement

All other authors report no relevant conflicts of interest. Author disclosures are available in supporting information.

Figures

**FIGURE 1**
Associations between Hcy and BPF in *APOE* ε4 carriers and non‐carriers in the whole group and across disease cohorts. ADMCI, Alzheimer's disease mild cognitive impairment; *APOE*, apolipoprotein E; BPF, brain parenchymal fraction; CVD, cardiovascular disease; FTD, frontotemporal dementia; Hcy, homocysteine; PD, Parkinson's disease.

**FIGURE 2**
Associations between Hcy and NfL concentrations in *APOE* ε4 carriers and non‐carriers in the whole group and across disease cohorts. ADMCI, Alzheimer's disease mild cognitive impairment; *APOE*, apolipoprotein E; CVD, cardiovascular disease; FTD, frontotemporal dementia; Hcy, homocysteine; NfL, neurofilament light chain; PD, Parkinson's disease.

**FIGURE 3**
Associations between Hcy and cognitive composite scores in *APOE* ε4 carriers and non‐carriers. One outlier was removed for the language composite, which did not affect the relationships. *APOE*, apolipoprotein E; Hcy, homocysteine.

See this image and copyright information in PMC

References

1. Refsum H, Smith AD, Ueland PM, et al. Facts and recommendations about total homocysteine determinations: an expert opinion. Clin Chem. 2004;50(1):3‐32. doi:10.1373/clinchem.2003.021634 - DOI - PubMed
1. Smith AD, Refsum H. Homocysteine—from disease biomarker to disease prevention. J Intern Med. 2021;290(4):826‐854. doi:10.1111/joim.13279 - DOI - PubMed
1. Smith AD, Refsum H, Bottiglieri T, et al. Homocysteine and dementia: an international consensus statement. J Alzheimers Dis. 2018;62(2):561‐570. doi:10.3233/JAD-171042 - DOI - PMC - PubMed
1. Xu R, Huang F, Wang Y, Liu Q, Lv Y, Zhang Q. Gender‐ and age‐related differences in homocysteine concentration: a cross‐sectional study of the general population of China. Sci Rep. 2020;10(1):17401. doi:10.1038/s41598-020-74596-7 - DOI - PMC - PubMed
1. Song Y, Quan M, Li T, Jia J. Serum homocysteine, vitamin B12, folate, and their association with mild cognitive impairment and subtypes of dementia. J Alzheimers Dis. 2022;90(2):681‐691. doi:10.3233/JAD-220410 - DOI - PubMed

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Homocysteine, neurodegenerative biomarkers, and APOE ε4 in neurodegenerative diseases

Collaborators

Affiliations

Homocysteine, neurodegenerative biomarkers, and APOE ε4 in neurodegenerative diseases

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

Figures

References

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