. 2024 Apr;20(4):2968-2979.

doi: 10.1002/alz.13740. Epub 2024 Mar 12.

Link among apolipoprotein E E4, gait, and cognition in neurodegenerative diseases: ONDRI study

Ryota Sakurai^{1

2}, Frederico Pieruccini-Faria^{2

3}, Benjamin Cornish⁴, Julia Fraser⁴, Malcolm A Binns⁵, Derek Beaton⁶, Allison Ann Dilliott⁷, Donna Kwan⁸, Joel Ramirez⁹, Brian Tan⁵, Christopher J M Scott⁵, Kelly M Sunderland⁵, Carmela Tartaglia^{10

11}, Elizabeth Finger¹², Lorne Zinman^{13

14}, Morris Freedman^{5

14

15}, Paula M McLaughlin¹⁶, Richard H Swartz^{13

14}, Sean Symons⁹, Anthony E Lang¹⁷, Robert Bartha¹⁸, Sandra E Black⁹, Mario Masellis⁹, Robert A Hegele^{19

20}, William McIlroy²¹; ONDRI Investigators¹; Manuel Montero-Odasso^{2

22

23}

Affiliations

¹ Research Team for Social Participation and Healthy Aging, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Itabashi-ku, Tokyo, Japan.
² Gait & Brain Lab, St. Joseph' Health Care London, Lawson Health Research, Western University, Division of Geriatric Medicine, London, Ontario, Canada.
³ Department of Medicine, Division of Geriatric Medicine, Parkwood Hospital, Western University, Parkwood Institute, London, Ontario, Canada.
⁴ Neuroscience, Mobility and Balance Lab, Department of Kinesiology and Health Sciences, University of Waterloo, Waterloo, Ontario, Canada.
⁵ Rotman Research Institute, Baycrest Health Sciences, Toronto, Ontario, Canada.
⁶ Data Science and Advanced Analytics, St. Michael's Hospital, Unity Health Toronto, Toronto, Ontario, Canada.
⁷ Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada.
⁸ Centre for Neuroscience Studies, Queen's University, Kingston, Ontario, Canada.
⁹ L.C. Campbell Cognitive Neurology Research Unit, Hurvitz Brain Sciences Program, Department of Medicine (Neurology), Sunnybrook Research Institute, Sunnybrook HSC, University of Toronto, Toronto, Ontario, Canada.
¹⁰ Krembil Brain Institute, University Health Network Memory Clinic, Toronto Western Hospital, Toronto, Ontario, Canada.
¹¹ Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada.
¹² Department of Clinical Neurological Sciences, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
¹³ Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
¹⁴ Department of Medicine (Neurology), University of Toronto, Toronto, Ontario, Canada.
¹⁵ Division of Neurology, Baycrest Health Sciences, Toronto, Ontario, Canada.
¹⁶ Halifax Clinical Psychology Residency Program, Nova Scotia Health Authority, Halifax, Nova Scotia, Canada.
¹⁷ Division of Neurology, Department of Medicine, Edmond J Safra Program in Parkinson's Disease and Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada.
¹⁸ Department of Medical Biophysics, Schulich School of Medicine and Dentistry, Robarts Research Institute, Western University, London, Ontario, Canada.
¹⁹ Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
²⁰ Robarts Research Institute, Western University, London, Ontario, Canada.
²¹ Neuroscience, Mobility and Balance Laboratory, Department of Kinesiology and Health Sciences, University of Waterloo, Waterloo, Ontario, Canada.
²² Gait and Brain Lab, Division of Geriatric Medicine, and Lawson Health Research Institute, Parkwood Institute, Western University, London, Ontario, Canada.
²³ Division of Geriatric Medicine, Department of Medicine, Schulich School of Medicine and Dentistry, Western University, Parkwood Institute, London, Ontario, Canada.

PMID: 38470007
PMCID: PMC11032526
DOI: 10.1002/alz.13740

Link among apolipoprotein E E4, gait, and cognition in neurodegenerative diseases: ONDRI study

Ryota Sakurai et al. Alzheimers Dement. 2024 Apr.

. 2024 Apr;20(4):2968-2979.

doi: 10.1002/alz.13740. Epub 2024 Mar 12.

Authors

Affiliations

¹ Research Team for Social Participation and Healthy Aging, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Itabashi-ku, Tokyo, Japan.
² Gait & Brain Lab, St. Joseph' Health Care London, Lawson Health Research, Western University, Division of Geriatric Medicine, London, Ontario, Canada.
³ Department of Medicine, Division of Geriatric Medicine, Parkwood Hospital, Western University, Parkwood Institute, London, Ontario, Canada.
⁴ Neuroscience, Mobility and Balance Lab, Department of Kinesiology and Health Sciences, University of Waterloo, Waterloo, Ontario, Canada.
⁵ Rotman Research Institute, Baycrest Health Sciences, Toronto, Ontario, Canada.
⁶ Data Science and Advanced Analytics, St. Michael's Hospital, Unity Health Toronto, Toronto, Ontario, Canada.
⁷ Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada.
⁸ Centre for Neuroscience Studies, Queen's University, Kingston, Ontario, Canada.
⁹ L.C. Campbell Cognitive Neurology Research Unit, Hurvitz Brain Sciences Program, Department of Medicine (Neurology), Sunnybrook Research Institute, Sunnybrook HSC, University of Toronto, Toronto, Ontario, Canada.
¹⁰ Krembil Brain Institute, University Health Network Memory Clinic, Toronto Western Hospital, Toronto, Ontario, Canada.
¹¹ Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada.
¹² Department of Clinical Neurological Sciences, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
¹³ Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
¹⁴ Department of Medicine (Neurology), University of Toronto, Toronto, Ontario, Canada.
¹⁵ Division of Neurology, Baycrest Health Sciences, Toronto, Ontario, Canada.
¹⁶ Halifax Clinical Psychology Residency Program, Nova Scotia Health Authority, Halifax, Nova Scotia, Canada.
¹⁷ Division of Neurology, Department of Medicine, Edmond J Safra Program in Parkinson's Disease and Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada.
¹⁸ Department of Medical Biophysics, Schulich School of Medicine and Dentistry, Robarts Research Institute, Western University, London, Ontario, Canada.
¹⁹ Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
²⁰ Robarts Research Institute, Western University, London, Ontario, Canada.
²¹ Neuroscience, Mobility and Balance Laboratory, Department of Kinesiology and Health Sciences, University of Waterloo, Waterloo, Ontario, Canada.
²² Gait and Brain Lab, Division of Geriatric Medicine, and Lawson Health Research Institute, Parkwood Institute, Western University, London, Ontario, Canada.
²³ Division of Geriatric Medicine, Department of Medicine, Schulich School of Medicine and Dentistry, Western University, Parkwood Institute, London, Ontario, Canada.

PMID: 38470007
PMCID: PMC11032526
DOI: 10.1002/alz.13740

Abstract

Introduction: Apolipoprotein E E4 allele (APOE E4) and slow gait are independently associated with cognitive impairment and dementia. However, it is unknown whether their coexistence is associated with poorer cognitive performance and its underlying mechanism in neurodegenerative diseases.

Methods: Gait speed, APOE E4, cognition, and neuroimaging were assessed in 480 older adults with neurodegeneration. Participants were grouped by APOE E4 presence and slow gait. Mediation analyses were conducted to determine if brain structures could explain the link between these factors and cognitive performance.

Results: APOE E4 carriers with slow gait had the lowest global cognitive performance and smaller gray matter volumes compared to non-APOE E4 carriers with normal gait. Coexistence of APOE E4 and slow gait best predicted global and domain-specific poorer cognitive performances, mediated by smaller gray matter volume.

Discussion: Gait slowness in APOE E4 carriers with neurodegenerative diseases may indicate extensive gray matter changes associated with poor cognition.

Highlights: APOE E4 and slow gait are risk factors for cognitive decline in neurodegenerative diseases. Slow gait and smaller gray matter volumes are associated, independently of APOE E4. Worse cognition in APOE E4 carriers with slow gait is explained by smaller GM volume. Gait slowness in APOE E4 carriers indicates poorer cognition-related brain changes.

Keywords: APOE E4; cognition; gait; gray matter volume; neurodegenerative diseases.

PubMed Disclaimer

Conflict of interest statement

The authors report no competing interests regarding this research. Author disclosures are available in the supporting information.

Figures

**FIGURE 1**
Comparisons of MoCA score across all four groups, stratified by *APOE* E4 genotype and slow gait. Diamond‐shaped plots represent mean variables. *APOE* E4, apolipoprotein E ε4 allele; MoCA, Montreal Cognitive Assessment. * p < 0.05, ** p < 0.01

**FIGURE 2**
Comparisons of the cerebral structure across all four groups, stratified by *APOE* E4 genotype and slow gait. Diamond‐shaped plots represent mean variables. *APOE* E4, apolipoprotein E ε4 allele; WMHs, white matter hyperintensities. * p < 0.05, ** p < 0.01

**FIGURE 3**
Association between variables in the mediation analysis. Non‐*APOE* E4 carriers without slow gait was the reference group in the analysis. Significant associations are shown in bold numbers and arrows. *APOE* E4, apolipoprotein E ε4 allele; GM, gray matter volume; HV, hippocampal volume; WM, white matter volume; WMHs, white matter hyperintensities

See this image and copyright information in PMC

Cited by

Mapping the neural substrate of high dual-task gait cost in older adults across the cognitive spectrum.
Ali P, Dinomais M, Labriffe M, Pieruccini-Faria F, Montero-Odasso M, Bartha R, Annweiler C. Ali P, et al. Brain Struct Funct. 2025 Jan 4;230(1):25. doi: 10.1007/s00429-024-02873-6. Brain Struct Funct. 2025. PMID: 39755775 Free PMC article.
Updates in Alzheimer's disease: from basic research to diagnosis and therapies.
Liu E, Zhang Y, Wang JZ. Liu E, et al. Transl Neurodegener. 2024 Sep 4;13(1):45. doi: 10.1186/s40035-024-00432-x. Transl Neurodegener. 2024. PMID: 39232848 Free PMC article. Review.

References

1. Farrer LA, Cupples LA, Haines JL, et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta‐analysis. APOE and Alzheimer disease meta‐analysis consortium. JAMA. 1997;278(16):1349‐1356. - PubMed
1. Camicioli R, Howieson D, Oken B, Sexton G, Kaye J. Motor slowing precedes cognitive impairment in the oldest old. Neurology. 1998;50(5):1496‐1498. - PubMed
1. Montero‐Odasso M, Almeida QJ, Bherer L, et al. Consensus on shared measures of mobility and cognition: from the Canadian consortium on neurodegeneration in aging (CCNA). J Gerontol A Biol Sci Med Sci. 2019;74(6):897‐909. doi:10.1093/gerona/gly148 - DOI - PMC - PubMed
1. Montero‐Odasso MM, Barnes B, Speechley M, et al. Disentangling cognitive‐frailty: results from the gait and brain study. J Gerontol A Biol Sci Med Sci. 2016;71(11):1476‐1482. doi:10.1093/gerona/glw044 - DOI - PubMed
1. Sakurai R, Fujiwara Y, Yasunaga M, et al. Regional cerebral glucose metabolism and gait speed in healthy community‐dwelling older women. J Gerontol A Biol Sci Med Sci. 2014;69(12):1519‐1527. doi:10.1093/gerona/glu093 - DOI - PubMed

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Link among apolipoprotein E E4, gait, and cognition in neurodegenerative diseases: ONDRI study

Affiliations

Link among apolipoprotein E E4, gait, and cognition in neurodegenerative diseases: ONDRI study

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous

Abstract

Conflict of interest statement

Figures

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Related information

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous