Independent and joint associations of cardiometabolic multimorbidity and depression on cognitive function: findings from multi-regional cohorts and generalisation from community to clinic

Xuhao Zhao¹, Xiaolin Xu^{1

2}, Yifan Yan¹, Darren M Lipnicki³, Ting Pang¹, John D Crawford³, Christopher Chen^{4

5}, Ching-Yu Cheng⁶, Narayanaswamy Venketasubramanian⁷, Eddie Chong⁴, Sergio Luis Blay⁸, Maria Fernanda Lima-Costa⁹, Erico Castro-Costa¹⁰, Richard B Lipton^{11

12}, Mindy J Katz¹¹, Karen Ritchie^{13

14}, Nikolaos Scarmeas^{15

16}, Mary Yannakoulia¹⁷, Mary H Kosmidis¹⁸, Oye Gureje¹⁹, Akin Ojagbemi¹⁹, Toyin Bello¹⁹, Hugh C Hendrie²⁰, Sujuan Gao^{21

22}, Ricardo Oliveira Guerra²³, Mohammad Auais²⁴, José Fernando Gomez²⁵, Elena Rolandi^{26

27}, Annalisa Davin²⁶, Michele Rossi²⁶, Steffi G Riedel-Heller²⁸, Margit Löbner²⁸, Susanne Roehr^{28

29

30}, Mary Ganguli³¹, Erin P Jacobsen³², Chung-Chou H Chang³³, Allison E Aiello³⁴, Roger Ho^{35

36

37}, Pascual Sanchez-Juan³⁸, Meritxell Valentí-Soler³⁸, Teodoro Del Ser³⁸, Antonio Lobo^{39

40

41}, Concepción De-la-Cámara^{39

40

41}, Elena Lobo⁴², Perminder S Sachdev³, Xin Xu^{1

4}; for Cohort Studies of Memory in an International Consortium (COSMIC)

Affiliations

¹ School of Public Health, The Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou, China.
² School of Public Health, Faculty of Medicine, The University of Queensland, Brisbane, Australia.
³ Centre for Healthy Brain Ageing, Discipline of Psychiatry & Mental Health, School of Clinical Medicine, University of New South Wales, Sydney, Australia.
⁴ Memory, Ageing, and Cognition Centre (MACC), Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
⁵ National University Health System, NUHS, Singapore.
⁶ Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.
⁷ Raffles Neuroscience Centre, Raffles Hospital, Singapore.
⁸ Center for Studies in Public Health and Aging, Belo Horizonte, Brazil.
⁹ Instituto Rene' Rachou, Fundac¸ão Oswaldo Cruz, Rio de Janeiro, Brazil.
¹⁰ Department of Psychiatry- Federal University of Sao Paulo- UNIFESP, Sao Paulo, Brazil.
¹¹ Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA.
¹² Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.
¹³ Institut for Neurosciences of Montpellier, University Montpellier, National Institute for Health and Medical Research, Montpellier, France.
¹⁴ Institut du Cerveau Trocadéro, Paris, France.
¹⁵ First Department of Neurology, Aiginition Hospital, National and Kapodistrian University of Athens, Athens, Greece.
¹⁶ Department of Neurology, Columbia University, New York, USA.
¹⁷ Department of Nutrition and Dietetics, Harokopio University, Athens, Greece.
¹⁸ Lab of Neuropsychology & Behavioral Neuroscience, School of Psychology, Aristotle University of Thessaloniki, Thessaloniki, Greece.
¹⁹ World Health Organization Collaborating Centre for Research and Training in Mental Health, Neuroscience, and Substance Abuse, Department of Psychiatry, College of Medicine, University of Ibadan, Ibadan, Nigeria.
²⁰ Department of Psychiatry and Indiana Alzheimer Disease Center Indiana School of Medicine, Indianapolis, USA.
²¹ Indiana Alzheimer Disease Research Center, Indianapolis.
²² Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, USA.
²³ Department of Physical Therapy, Federal University of Rio Grande do Norte, Brazil.
²⁴ School of Rehabilitation Therapy, Kingston, Ontario, Canada.
²⁵ Research Group on Geriatrics and Gerontology. Faculty of Health Sciences, Universidad de Caldas, Manizales, Colombia.
²⁶ Golgi Cenci Foundation, Abbiategrasso, Italy.
²⁷ Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy.
²⁸ Institute of Social Medicine, Occupational Health and Public Health, Medical Faculty, University of Leipzig, Leipzig, Germany.
²⁹ School of Psychology, Manawatu Campus, Massey University, Palmerston North, New Zealand.
³⁰ Global Brain Health Institute, Trinity College Dublin, Dublin, Ireland.
³¹ Departments of Psychiatry, Neurology, and Epidemiology, School of Medicine and School of Public Health, University of Pittsburgh, USA.
³² Department of Psychiatry, School of Medicine, University of Pittsburgh, USA.
³³ Departments of Medicine and Bioostatistics, School of Medicine and School of Public Health, University of Pittsburgh, USA.
³⁴ Robert N. Butler Columbia Aging Center, Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, USA.
³⁵ Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
³⁶ Department of Psychological Medicine, National University Hospital, Singapore.
³⁷ Institute of Health Innovation and Technology (iHealthtech), National University of Singapore, Singapore.
³⁸ Alzheimer's Centre Reina Sofia-CIEN Foundation-ISCIII, 28031, Madrid, Spain.
³⁹ Department of Medicine and Psychiatry, Universidad de Zaragoza, Zaragoza, Spain.
⁴⁰ Instituto de Investigación Sanitaria Aragón, Zaragoza, Spain.
⁴¹ Centro de Investigación Biomédica en Red de Salud Mental, Madrid, Spain.
⁴² Department of Preventive Medicine and Public Health, Universidad de Zaragoza, Instituto de Investigación Sanitaria Aragón (IIS Aragón), Zaragoza CIBERSAM, Madrid, Spain.

PMID: 39308753
PMCID: PMC11416683
DOI: 10.1016/j.lanwpc.2024.101198

Independent and joint associations of cardiometabolic multimorbidity and depression on cognitive function: findings from multi-regional cohorts and generalisation from community to clinic

Xuhao Zhao et al. Lancet Reg Health West Pac. 2024.

. 2024 Sep 12:51:101198.

doi: 10.1016/j.lanwpc.2024.101198. eCollection 2024 Oct.

Authors

Affiliations

¹ School of Public Health, The Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou, China.
² School of Public Health, Faculty of Medicine, The University of Queensland, Brisbane, Australia.
³ Centre for Healthy Brain Ageing, Discipline of Psychiatry & Mental Health, School of Clinical Medicine, University of New South Wales, Sydney, Australia.
⁴ Memory, Ageing, and Cognition Centre (MACC), Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
⁵ National University Health System, NUHS, Singapore.
⁶ Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.
⁷ Raffles Neuroscience Centre, Raffles Hospital, Singapore.
⁸ Center for Studies in Public Health and Aging, Belo Horizonte, Brazil.
⁹ Instituto Rene' Rachou, Fundac¸ão Oswaldo Cruz, Rio de Janeiro, Brazil.
¹⁰ Department of Psychiatry- Federal University of Sao Paulo- UNIFESP, Sao Paulo, Brazil.
¹¹ Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA.
¹² Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.
¹³ Institut for Neurosciences of Montpellier, University Montpellier, National Institute for Health and Medical Research, Montpellier, France.
¹⁴ Institut du Cerveau Trocadéro, Paris, France.
¹⁵ First Department of Neurology, Aiginition Hospital, National and Kapodistrian University of Athens, Athens, Greece.
¹⁶ Department of Neurology, Columbia University, New York, USA.
¹⁷ Department of Nutrition and Dietetics, Harokopio University, Athens, Greece.
¹⁸ Lab of Neuropsychology & Behavioral Neuroscience, School of Psychology, Aristotle University of Thessaloniki, Thessaloniki, Greece.
¹⁹ World Health Organization Collaborating Centre for Research and Training in Mental Health, Neuroscience, and Substance Abuse, Department of Psychiatry, College of Medicine, University of Ibadan, Ibadan, Nigeria.
²⁰ Department of Psychiatry and Indiana Alzheimer Disease Center Indiana School of Medicine, Indianapolis, USA.
²¹ Indiana Alzheimer Disease Research Center, Indianapolis.
²² Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, USA.
²³ Department of Physical Therapy, Federal University of Rio Grande do Norte, Brazil.
²⁴ School of Rehabilitation Therapy, Kingston, Ontario, Canada.
²⁵ Research Group on Geriatrics and Gerontology. Faculty of Health Sciences, Universidad de Caldas, Manizales, Colombia.
²⁶ Golgi Cenci Foundation, Abbiategrasso, Italy.
²⁷ Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy.
²⁸ Institute of Social Medicine, Occupational Health and Public Health, Medical Faculty, University of Leipzig, Leipzig, Germany.
²⁹ School of Psychology, Manawatu Campus, Massey University, Palmerston North, New Zealand.
³⁰ Global Brain Health Institute, Trinity College Dublin, Dublin, Ireland.
³¹ Departments of Psychiatry, Neurology, and Epidemiology, School of Medicine and School of Public Health, University of Pittsburgh, USA.
³² Department of Psychiatry, School of Medicine, University of Pittsburgh, USA.
³³ Departments of Medicine and Bioostatistics, School of Medicine and School of Public Health, University of Pittsburgh, USA.
³⁴ Robert N. Butler Columbia Aging Center, Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, USA.
³⁵ Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
³⁶ Department of Psychological Medicine, National University Hospital, Singapore.
³⁷ Institute of Health Innovation and Technology (iHealthtech), National University of Singapore, Singapore.
³⁸ Alzheimer's Centre Reina Sofia-CIEN Foundation-ISCIII, 28031, Madrid, Spain.
³⁹ Department of Medicine and Psychiatry, Universidad de Zaragoza, Zaragoza, Spain.
⁴⁰ Instituto de Investigación Sanitaria Aragón, Zaragoza, Spain.
⁴¹ Centro de Investigación Biomédica en Red de Salud Mental, Madrid, Spain.
⁴² Department of Preventive Medicine and Public Health, Universidad de Zaragoza, Instituto de Investigación Sanitaria Aragón (IIS Aragón), Zaragoza CIBERSAM, Madrid, Spain.

PMID: 39308753
PMCID: PMC11416683
DOI: 10.1016/j.lanwpc.2024.101198

Abstract

Background: Cardiometabolic multimorbidity (CMM) and depression are often co-occurring in older adults and associated with neurodegenerative outcomes. The present study aimed to estimate the independent and joint associations of CMM and depression on cognitive function in multi-regional cohorts, and to validate the generalizability of the findings in additional settings, including clinical.

Methods: Data harmonization was performed across 14 longitudinal cohort studies within the Cohort Studies of Memory in an International Consortium (COSMIC) group, spanning North America, South America, Europe, Africa, Asia, and Australia. Three external validation studies with distinct settings were employed for generalization. Participants were eligible for inclusion if they had data for CMM and were free of dementia at baseline. Baseline CMM was defined as: 1) CMM 5, ≥2 among hypertension, hyperlipidemia, diabetes, stroke, and heart disease and 2) CMM 3 (aligned with previous studies), ≥2 among diabetes, stroke, and heart disease. Baseline depression was primarily characterized by binary classification of depressive symptom measurements, employing the Geriatric Depression Scale and the Center for Epidemiological Studies-Depression scale. Global cognition was standardized as z-scores through harmonizing multiple cognitive measures. Longitudinal cognition was calculated as changes in global cognitive z-scores. A pooled individual participant data (IPD) analysis was utilized to estimate the independent and joint associations of CMM and depression on cognitive outcomes in COSMIC studies, both cross-sectionally and longitudinally. Repeated analyses were performed in three external validation studies.

Findings: Of the 32,931 older adults in the 14 COSMIC cohorts, we included 30,382 participants with complete data on baseline CMM, depression, and cognitive assessments for cross-sectional analyses. Among them, 22,599 who had at least 1 follow-up cognitive assessment were included in the longitudinal analyses. The three external studies for validation had 1964 participants from 3 multi-ethnic Asian older adult cohorts in different settings (community-based, memory clinic, and post-stroke study). In COSMIC studies, each of CMM and depression was independently associated with cross-sectional and longitudinal cognitive function, without significant interactions between them (Ps > 0.05). Participants with both CMM and depression had lower cross-sectional cognitive performance (e.g. β = -0.207, 95% CI = (-0.255, -0.159) for CMM5 (+)/depression (+)) and a faster rate of cognitive decline (e.g. β = -0.040, 95% CI = (-0.047, -0.034) for CMM5 (+)/depression (+)), compared with those without either condition. These associations remained consistent after additional adjustment for APOE genotype and were robust in two-step random-effects IPD analyses. The findings regarding the joint association of CMM and depression on cognitive function were reproduced in the three external validation studies.

Interpretation: Our findings highlighted the importance of investigating age-related co-morbidities in a multi-dimensional perspective. Targeting both cardiometabolic and psychological conditions to prevent cognitive decline could enhance effectiveness.

Funding: Natural Science Foundation of China and National Institute on Aging/National Institutes of Health.

Keywords: Cardiometabolic multimorbidity; Cognitive decline; Depression; Multi-regional study.

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Conflict of interest statement

CC declares funding to their institution from the National Medical Research Council of Singapore. RBL declares receiving payments for royalties or licenses from Wolff's Headache (7th and 8th Editions), Oxford University Press (2009), Wiley, and Inform. RBL has received consulting fees, honoraria for lectures, support for attending meetings and/or travel, or served on data safety monitoring boards or advisory boards for AbbVie (Allergan), the American Academy of Neurology, the American Headache Society, Amgen, Avanir, Axon, Axsome, Biohaven, Biovision, Boston Scientific, Dr. Reddy's (Promius), Electrocore, Eli Lilly, eNeura Therapeutics, Equinox, GlaxoSmithKline, Grifols, Lundbeck (Alder), Manistee, Merck, Pernix, Pfizer, Satsuma, Supernus, Teva, Trigemina, Vector, and Vedanta. RBL's institution has received funding from the FDA, the National Institutes of Health (NIH), and the National Institute on Aging (NIA). RBL holds stock in Axon, Biohaven Holdings, CoolTech, and Manistee. MJK declares funding to their institution from the NIH (grant numbers NIA P01 AG03949). NS declares participation as a member of the data safety monitoring board (uncompensated) for the public-private funded Phase II study PRimus AD in Germany and reports that their institution has received funding from Novo Nordisk, unrelated to the submitted work. Both HCH and SG declare funding to their institution from the NIH (grant numbers R01AG009956, P30AG072976, and K07AG076659). MG declares funding to their institution from the NIA (grant number R37AG023651). C–CHC declares that their institution received funding from the NIH. AL, CDC and EL declare that their institution received funding from the Fondo de Investigación Sanitaria, Instituto de Salud Carlos III, Spanish Ministry of Economy and Competitiveness, Madrid, Spain (grant numbers 94/1562, 97/1321E, 98/0103, 01/0255, 03/0815, 06/0617, G03/128, 12/02254, 16/00896, 19/01874), as well as from the European Regional Development Fund (FEDER) of the European Union and the Government of Aragón (grant number B15_17R). CDC also declares receiving support for attending scientific meetings from Almirall, Lilly, Pfizer, Esteve, AstraZeneca, Novartis, Lundbeck, Casen Recordati, Janssen, and Rovi. PSS declares receiving payments for advisory board meetings for Biogen Australia and Roche Australia, honoraria for lectures from Alkem Labs; and funding to their institution from the National Health and Medical Research Council of Australia (grant number APP1169489). Both PSS and DL declare funding to their institution from the NIH (grant number 1RF1AG057531–01). Both PSS and JDC declare funding to their institution from the NIH (grant number 2R01AG057531-02A1). DL holds editor roles in the Frontiers journals. PSS holds leadership roles in the VASCOG Society (Executive Committee; unpaid) and the World Psychiatric Association (Planning Committee; unpaid). All other authors declare no competing interests.

Figures

**Fig. 1**
Study schematic. Schematic diagram showing the study design. CMM: cardiometabolic multimorbidity; CMM(+)/depression (+): both CMM and depression; CMM(+)/depression (−): CMM but no depression; CMM(−)/depression (+): depression but no CMM; and CMM(−)/depression (−): neither depression nor CMM; IPD: individual participant data; COSMIC: Cohort Studies of Memory in an International Consortium. In summary, we first conducted IPD meta analyses in each step (from cross-sectional to interaction analyses), and then replicated the cross-sectional and longitudinal analyses via same analytical procedure using 3 Asian studies for external validation.

**Fig. 2**
Forest plots from the 2-step IPD meta-analysis of the joint associations of CMM and depression on cognitive function in COSMIC studies. Note. Each model was adjusted for age, sex, education years, and current smoking and drinking status. Reference group:CMM(−)/depression (−).

See this image and copyright information in PMC

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Independent and joint associations of cardiometabolic multimorbidity and depression on cognitive function: findings from multi-regional cohorts and generalisation from community to clinic

Affiliations

Independent and joint associations of cardiometabolic multimorbidity and depression on cognitive function: findings from multi-regional cohorts and generalisation from community to clinic

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Grants and funding

LinkOut - more resources

Full Text Sources

Miscellaneous