Mediating role of Interleukin-6 in the predictive association of diabetes with Hippocampus atrophy, Amyloid, Tau, and Neurofilament pathology at pre-clinical stages of diabetes-related cognitive impairment
Introduction: Type-2 diabetes (T2DM) has been associated with higher dementia risks, but the mechanisms are still unclear, and there is increasing evidence of the role of cytokines. Interleukin-6 (IL-6) mediating effect has never been explored. Methods: The study included a subset of 1927 community-...
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Elsevier
2025-08-01
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666354625000894 |
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| author | Asma Hallab Sid E. O'Bryant Kristine Yaffe Arthur Toga Robert Rissman Leigh Johnson Meredith Braskie Kevin King James R. Hall Melissa Petersen Raymond Palmer Robert Barber Yonggang Shi Fan Zhang Rajesh Nandy Roderick McColl David Mason Bradley Christian Nicole Phillips Stephanie Large Joe Lee Badri Vardarajan Monica Rivera Mindt Amrita Cheema Lisa Barnes Mark Mapstone Annie Cohen Amy Kind Ozioma Okonkwo Raul Vintimilla Zhengyang Zhou Michael Donohue Rema Raman Matthew Borzage Michelle Mielke Beau Ances Ganesh Babulal Jorge Llibre-Guerra Carl Hill Rocky Vig |
| author_facet | Asma Hallab Sid E. O'Bryant Kristine Yaffe Arthur Toga Robert Rissman Leigh Johnson Meredith Braskie Kevin King James R. Hall Melissa Petersen Raymond Palmer Robert Barber Yonggang Shi Fan Zhang Rajesh Nandy Roderick McColl David Mason Bradley Christian Nicole Phillips Stephanie Large Joe Lee Badri Vardarajan Monica Rivera Mindt Amrita Cheema Lisa Barnes Mark Mapstone Annie Cohen Amy Kind Ozioma Okonkwo Raul Vintimilla Zhengyang Zhou Michael Donohue Rema Raman Matthew Borzage Michelle Mielke Beau Ances Ganesh Babulal Jorge Llibre-Guerra Carl Hill Rocky Vig |
| author_sort | Asma Hallab |
| collection | DOAJ |
| description | Introduction: Type-2 diabetes (T2DM) has been associated with higher dementia risks, but the mechanisms are still unclear, and there is increasing evidence of the role of cytokines. Interleukin-6 (IL-6) mediating effect has never been explored. Methods: The study included a subset of 1927 community-dwelling participants from the Health and Aging Brain Study: Healthy Disparities (HABS-HD) cohort with complete data. Cross-sectional and longitudinal analyses were performed. Associations were studied using multivariable linear, logistic, and mediation analysis with non-parametric bootstrapping. Results: T2DM and IL-6 were associated with worse executive function, Hippocampus atrophy, lower Aß42/Aß40 ratio, and higher Aß40, Aß42, total Tau, and NfL levels. IL-6 mediated 5 % of the association of T2DM with Aß40 ([1.5 %–10 %], p-value<2 × 10−16), 4 % with Aß42 ([0.7 %–11 %], p-value = 0.014), 8 % with TMT-B ([0.2 %–35 %], p-value = 0.046), 11 % with total Tau ([2.5 %–40 %], p-value = 0.010), 5 % with NfL ([1.6 %–8 %], p-value<2 × 10−16), and 12 % Hippocampus atrophy ([3 %–49 %], p-value = 0.004). The results, except TMT-B, were replicated in the longitudinal analysis of long-lasting T2DM on non-previously diagnosed cognitive impairment. Conclusions: The study captured a pre-clinical stage of the T2DM-dementia association. The mediating effect of IL-6 is a novelty that has to be further explored and accounted for in risk stratification and preventive measures, particularly in ethnic minorities. |
| format | Article |
| id | doaj-art-5f39be69bb4947029a05b776b4fc8fc7 |
| institution | Kabale University |
| issn | 2666-3546 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Elsevier |
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| series | Brain, Behavior, & Immunity - Health |
| spelling | doaj-art-5f39be69bb4947029a05b776b4fc8fc72025-08-20T03:31:34ZengElsevierBrain, Behavior, & Immunity - Health2666-35462025-08-014710103110.1016/j.bbih.2025.101031Mediating role of Interleukin-6 in the predictive association of diabetes with Hippocampus atrophy, Amyloid, Tau, and Neurofilament pathology at pre-clinical stages of diabetes-related cognitive impairmentAsma Hallab0Sid E. O'BryantKristine YaffeArthur TogaRobert RissmanLeigh JohnsonMeredith BraskieKevin KingJames R. HallMelissa PetersenRaymond PalmerRobert BarberYonggang ShiFan ZhangRajesh NandyRoderick McCollDavid MasonBradley ChristianNicole PhillipsStephanie LargeJoe LeeBadri VardarajanMonica Rivera MindtAmrita CheemaLisa BarnesMark MapstoneAnnie CohenAmy KindOzioma OkonkwoRaul VintimillaZhengyang ZhouMichael DonohueRema RamanMatthew BorzageMichelle MielkeBeau AncesGanesh BabulalJorge Llibre-GuerraCarl HillRocky VigPsychiatry Neuroimaging Laboratory - Psychiatry and Radiology Departments – Mass General Brigham, Harvard Medical School, Boston, MA, USA; Biologie Intégrative et Physiologie (BIP) – Parcours Neurosciences. Faculté des Sciences et Ingénierie, Sorbonne Université, Paris, France; Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin. Berlin, Germany; Pathologies Du Sommeil. Faculté de Médecine Pitié-Salpêtrière, Sorbonne Université, Paris, France; Corresponding author. Asma Hallab. Charité Universitätsmedizin – Berlin. Chariteplatz 1, 10117, Berlin,Germany.Introduction: Type-2 diabetes (T2DM) has been associated with higher dementia risks, but the mechanisms are still unclear, and there is increasing evidence of the role of cytokines. Interleukin-6 (IL-6) mediating effect has never been explored. Methods: The study included a subset of 1927 community-dwelling participants from the Health and Aging Brain Study: Healthy Disparities (HABS-HD) cohort with complete data. Cross-sectional and longitudinal analyses were performed. Associations were studied using multivariable linear, logistic, and mediation analysis with non-parametric bootstrapping. Results: T2DM and IL-6 were associated with worse executive function, Hippocampus atrophy, lower Aß42/Aß40 ratio, and higher Aß40, Aß42, total Tau, and NfL levels. IL-6 mediated 5 % of the association of T2DM with Aß40 ([1.5 %–10 %], p-value<2 × 10−16), 4 % with Aß42 ([0.7 %–11 %], p-value = 0.014), 8 % with TMT-B ([0.2 %–35 %], p-value = 0.046), 11 % with total Tau ([2.5 %–40 %], p-value = 0.010), 5 % with NfL ([1.6 %–8 %], p-value<2 × 10−16), and 12 % Hippocampus atrophy ([3 %–49 %], p-value = 0.004). The results, except TMT-B, were replicated in the longitudinal analysis of long-lasting T2DM on non-previously diagnosed cognitive impairment. Conclusions: The study captured a pre-clinical stage of the T2DM-dementia association. The mediating effect of IL-6 is a novelty that has to be further explored and accounted for in risk stratification and preventive measures, particularly in ethnic minorities.http://www.sciencedirect.com/science/article/pii/S2666354625000894CognitionInsulin resistanceAgingBrainCytokineNeuroinflammation |
| spellingShingle | Asma Hallab Sid E. O'Bryant Kristine Yaffe Arthur Toga Robert Rissman Leigh Johnson Meredith Braskie Kevin King James R. Hall Melissa Petersen Raymond Palmer Robert Barber Yonggang Shi Fan Zhang Rajesh Nandy Roderick McColl David Mason Bradley Christian Nicole Phillips Stephanie Large Joe Lee Badri Vardarajan Monica Rivera Mindt Amrita Cheema Lisa Barnes Mark Mapstone Annie Cohen Amy Kind Ozioma Okonkwo Raul Vintimilla Zhengyang Zhou Michael Donohue Rema Raman Matthew Borzage Michelle Mielke Beau Ances Ganesh Babulal Jorge Llibre-Guerra Carl Hill Rocky Vig Mediating role of Interleukin-6 in the predictive association of diabetes with Hippocampus atrophy, Amyloid, Tau, and Neurofilament pathology at pre-clinical stages of diabetes-related cognitive impairment Brain, Behavior, & Immunity - Health Cognition Insulin resistance Aging Brain Cytokine Neuroinflammation |
| title | Mediating role of Interleukin-6 in the predictive association of diabetes with Hippocampus atrophy, Amyloid, Tau, and Neurofilament pathology at pre-clinical stages of diabetes-related cognitive impairment |
| title_full | Mediating role of Interleukin-6 in the predictive association of diabetes with Hippocampus atrophy, Amyloid, Tau, and Neurofilament pathology at pre-clinical stages of diabetes-related cognitive impairment |
| title_fullStr | Mediating role of Interleukin-6 in the predictive association of diabetes with Hippocampus atrophy, Amyloid, Tau, and Neurofilament pathology at pre-clinical stages of diabetes-related cognitive impairment |
| title_full_unstemmed | Mediating role of Interleukin-6 in the predictive association of diabetes with Hippocampus atrophy, Amyloid, Tau, and Neurofilament pathology at pre-clinical stages of diabetes-related cognitive impairment |
| title_short | Mediating role of Interleukin-6 in the predictive association of diabetes with Hippocampus atrophy, Amyloid, Tau, and Neurofilament pathology at pre-clinical stages of diabetes-related cognitive impairment |
| title_sort | mediating role of interleukin 6 in the predictive association of diabetes with hippocampus atrophy amyloid tau and neurofilament pathology at pre clinical stages of diabetes related cognitive impairment |
| topic | Cognition Insulin resistance Aging Brain Cytokine Neuroinflammation |
| url | http://www.sciencedirect.com/science/article/pii/S2666354625000894 |
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