Stage-dependent associations of Cardiovascular-Kidney-Metabolic Syndrome with Cognitive Decline, Depression, and Neuroimaging Signatures in multi-regional older adults
Abstract
BackgroundCardiovascular-Kidney-Metabolic (CKM) syndrome is a multisystem condition associated with adverse outcomes, yet its impact on age-related cognitive health remains understudied. We examined associations of CKM with neurocognitive and neuropsychiatric outcomes, modifiable physical and psychosocial factors contributing to cognitive impairment across CKM stages, and neuroimaging correlates.
MethodsGlobal aging cohorts (mean follow-up 6.5 years) and the Cohort Studies of Memory in an International Consortium (5.4 years) were used. CKM stages (0-4) were defined according to AHA framework. Longitudinal domain-specific cognitive changes were assessed using linear mixed-effects models, and depressive symptoms using generalized linear regression with individual participant data approach. Population-attributable fractions were estimated for six modifiable factors associated with cognitive impairment across CKM stages. Cross-sectional associations with 34 neuroimaging biomarkers were examined in UK Biobank.
ResultsAmong 28,242 participants, advanced CKM stages (3-4) were associated with accelerated cognitive decline, particularly in attention, executive function, and language. Associations were stronger in younger individuals, men, and those with less education, but not modified by APOE {varepsilon}4 status. Advanced CKM stages were associated with depressive symptoms among cognitively unimpaired individuals. Modifiable factors accounted for 24.8% of cognitive impairment risk across CKM stages, mainly social isolation (7.0%), depressive symptoms (5.2%), and physical inactivity (5.2%). Advanced CKM stages were linked to widespread MRI alterations (27 biomarkers), especially white matter hyperintensity.
ConclusionAdvanced CKM stages are associated with accelerated cognitive decline and greater cerebrovascular burden. Addressing psychosocial factors and physical inactivity, alongside management of CKM risk factors, may help reduce cognitive impairment.
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BibTeX
@misc{zhang2026stagedependent,
title = {{Stage-dependent associations of Cardiovascular-Kidney-Metabolic Syndrome with Cognitive Decline, Depression, and Neuroimaging Signatures in multi-regional older adults}},
author = {Haoran Zhang and Yingqi Liao and Wanheng Zhang and Zhiying Lin and Darren M. Lipnicki and Hongwei Ji and Yifan Yan and Yaping Zhang and Henry Brodaty and Wei Wen and Nicole Kochan and Katya Numbers and Elena Rolandi and Sabrina Noel and Nikolaos Scarmeas and Dan Zhou and Xiao Tan and Perminder S. Sachdev and Tien Yin Wong and Kamen A. Tsvetanov and Xu Xin},
howpublished = {medRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.21.26366180},
url = {https://www.medrxiv.org/content/10.64898/2026.10.21.26366180v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Stage-dependent associations of Cardiovascular-Kidney-Metabolic Syndrome with Cognitive Decline, Depression, and Neuroimaging Signatures in multi-regional older adults
AU - Haoran Zhang
AU - Yingqi Liao
AU - Wanheng Zhang
AU - Zhiying Lin
AU - Darren M. Lipnicki
AU - Hongwei Ji
AU - Yifan Yan
AU - Yaping Zhang
AU - Henry Brodaty
AU - Wei Wen
AU - Nicole Kochan
AU - Katya Numbers
AU - Elena Rolandi
AU - Sabrina Noel
AU - Nikolaos Scarmeas
AU - Dan Zhou
AU - Xiao Tan
AU - Perminder S. Sachdev
AU - Tien Yin Wong
AU - Kamen A. Tsvetanov
AU - Xu Xin
PY - 2026
DA - 2026/10/21
PB - medRxiv
DO - 10.64898/2026.10.21.26366180
UR - https://www.medrxiv.org/content/10.64898/2026.10.21.26366180v1
AB - BackgroundCardiovascular-Kidney-Metabolic (CKM) syndrome is a multisystem condition associated with adverse outcomes, yet its impact on age-related cognitive health remains understudied. We examined associations of CKM with neurocognitive and neuropsychiatric outcomes, modifiable physical and psychosocial factors contributing to cognitive impairment across CKM stages, and neuroimaging correlates. MethodsGlobal aging cohorts (mean follow-up 6.5 years) and the Cohort Studies of Memory in an International Consortium (5.4 years) were used. CKM stages (0-4) were defined according to AHA framework. Longitudinal domain-specific cognitive changes were assessed using linear mixed-effects models, and depressive symptoms using generalized linear regression with individual participant data approach. Population-attributable fractions were estimated for six modifiable factors associated with cognitive impairment across CKM stages. Cross-sectional associations with 34 neuroimaging biomarkers were examined in UK Biobank. ResultsAmong 28,242 participants, advanced CKM stages (3-4) were associated with accelerated cognitive decline, particularly in attention, executive function, and language. Associations were stronger in younger individuals, men, and those with less education, but not modified by APOE {varepsilon}4 status. Advanced CKM stages were associated with depressive symptoms among cognitively unimpaired individuals. Modifiable factors accounted for 24.8% of cognitive impairment risk across CKM stages, mainly social isolation (7.0%), depressive symptoms (5.2%), and physical inactivity (5.2%). Advanced CKM stages were linked to widespread MRI alterations (27 biomarkers), especially white matter hyperintensity. ConclusionAdvanced CKM stages are associated with accelerated cognitive decline and greater cerebrovascular burden. Addressing psychosocial factors and physical inactivity, alongside management of CKM risk factors, may help reduce cognitive impairment.
ER -