Association of genetic scores related to insulin resistance with neurological outcomes in ancestrally diverse cohorts from the Trans-Omics for Precision Medicine (TOPMed) program

Authors: SARNOWSKI, CHLOE - University Of Texas Health Science Center; ZHANG, YIXIN - Boston University School Of Public Health; AMMOUS, FARAH - University Of Michigan; SHADE, LINCOLN - University Of Kentucky; DICORPO, DANIEL - Boston University School Of Public Health; JIAN, XUEQIU - University Of Texas At San Antonio; ARNETT, DONNA - University Of South Carolina; AUSTIN, THOMAS - University Of Washington; BEISER, ALEXA - Boston University School Of Public Health; BIS, JOSHUA - University Of Washington; BLANGERO, JOHN - University Of Texas Rio Grande Valley; BOERWINKLE, ERIC - University Of Texas Health Science Center; BRESSLER, JAN - University Of Texas Health Science Center; CURRAN, JOANNE - University Of Texas Rio Grande Valley; DECARLI, CHARLES - University Of California, Davis; DODDAPANENI, HARSHA - Baylor College Of Medicine; DUPUIS, JOSEE - Boston University School Of Public Health; FARDO, DAVID - University Of Kentucky; FLOREZ, JOSE - Massachusetts General Hospital; GABRIEL, STACEY - Broad Institute Of Mit/harvard; GIBBS, RICHARD - Baylor College Of Medicine; GLAHN, DAVID - Boston Children'S Hospital; GUPTA, NAMRATA - Broad Institute Of Mit/harvard; GONZÁLEZ, HECTOR - University Of California, San Diego; GONZÁLEZ, KEVIN - University Of California, San Diego; HATZIKOTOULAS, KONSTANTINOS - German Research Center For Environmental Health; HAYDEN, KATHLEEN - Wake Forest University School Of Medicine; HECKBERT, SUSAN - University Of Washington; HIDALGO, BERTHA - University Of Alabama At Birmingham; HUERTA-CHAGOYA, ALICIA - Broad Institute Of Mit/harvard; HUGHES, TIMOTHY - Wake Forest University School Of Medicine; KARDIA, SHARON - University Of Michigan; KOOPERBERG, CHARLES - Fred Hutchinson Cancer Research Center; LAUNER, LENORE - National Institute On Aging (NIA, NIH); LONGSTRETH JR, W - University Of Washington; MANDLA, RAVI - Broad Institute Of Mit/harvard; MATHIAS, RASIKA - Johns Hopkins University School Of Medicine; MORRIS, ANDREW - German Research Center For Environmental Health; MOSLEY, THOMAS - University Of Mississippi Medical Center; NASRALLAH, ILYA - University Of Pennsylvania; NYQUIST, PAUL - Johns Hopkins University School Of Medicine; PSATY, BRUCE - University Of Washington; QI, QIBIN - Harvard School Of Public Health; RAFFIELD, LAURA - University Of North Carolina; RAYNER, NIGEL - German Research Center For Environmental Health; REINER, ALEXANDER - University Of Washington; SATIZABAL, CLAUDIA - Boston University Medical School; SELVIN, ELIZABETH - Johns Hopkins School Of Public Health; SEVILLA-GONZALEZ, MAGDALENA - Broad Institute Of Mit/harvard; SMITH, ALBERT - University Of Michigan; SMITH, JENNIFER - University Of Michigan; SMITH, KIRK - Massachusetts General Hospital; SNIVELY, BEVERLY - Wake Forest University School Of Medicine; SOUTHAM, LORRAINE - German Research Center For Environmental Health; SOFER, TAMAR - Harvard Medical School; SUZUKI, KENT - University Of Manchester; TAYLOR, HENRY - National Institutes Of Health (NIH); UDLER, MIRIAM - Massachusetts General Hospital; VIAUD-MARTINEZ, KARINE - Illumina, Inc; WASSERTHEIL-SMOLLER, SYLVIA - Albert Einstein College Of Medicine; WOOD, ALEXIS - Children'S Nutrition Research Center (CNRC); YANEK, LISA - Johns Hopkins University School Of Medicine; YIN, XIANYONG - University Of Michigan; MANNING, ALISA - Broad Institute Of Mit/harvard; ROTTER, JEROME - Harbor-Ucla Medical Center; RICH, STEPHEN - University Of Virginia; MEIGS, JAMES - Broad Institute Of Mit/harvard; FORNAGE, MYRIAM - University Of Texas Health Science Center; SESHADRI, SUDHA - Boston University Medical School; MORRISON, ALANNA - University Of Texas Health Science Center

Submitted to: Communications Biology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/6/2025
Publication Date: 9/24/2025
Citation: Sarnowski, C., Zhang, Y., Ammous, F., Shade, L.M., DiCorpo, D., Jian, X., Arnett, D.K., Austin, T.R., Beiser, A., Bis, J.C., Blangero, J., Boerwinkle, E., Bressler, J., Curran, J.E., DeCarli, C.S., Doddapaneni, H., Dupuis, J., Fardo, D.W., Florez, J.C., Gabriel, S., Gibbs, R.A., Glahn, D.C., Gupta, N., González, H.M., González, K.A., Hatzikotoulas, K., Hayden, K.M., Heckbert, S.R., Hidalgo, B., Huerta-Chagoya, A., Hughes, T.M., Kardia, S.L., Kooperberg, C.L., Launer, L.J., Longstreth Jr, W.T., Mandla, R., Mathias, R.A., Morris, A.P., Mosley, T.H., Nasrallah, I.M., Nyquist, P., Psaty, B.M., Qi, Q., Raffield, L.M., Rayner, N.W., Reiner, A.P., Satizabal, C.L., Selvin, E., Sevilla-Gonzalez, M.D., Smith, A.V., Smith, J.A., Smith, K., Snively, B.M., Southam, L., Sofer, T., Suzuki, K., Taylor, H.J., Udler, M.S., Viaud-Martinez, K.A., Wassertheil-Smoller, S., Wood, A.C., Yanek, L.R., Yin, X., Manning, A.K., Rotter, J.I., Rich, S.S., Meigs, J.B., Fornage, M., Seshadri, S., Morrison, A.C. 2025. Association of genetic scores related to insulin resistance with neurological outcomes in ancestrally diverse cohorts from the Trans-Omics for Precision Medicine (TOPMed) program. Communications Biology. 8(1):Article 1352. https://doi.org/10.1038/s42003-025-08674-9.
DOI: https://doi.org/10.1038/s42003-025-08674-9

Interpretive Summary: Insulin resistance, a key feature of type 2 diabetes, is also linked to increased risk of cognitive decline and dementia, but the biological pathways connecting these conditions are not fully understood. This study examined genetic predisposition to insulin resistance by creating polygenic scores that capture variation in fasting insulin and related metabolic traits across diverse populations. Using data from more than 17,000 adults in the TOPMed program, the researchers found that people with a higher genetic tendency toward insulin resistance had smaller brain volumes and poorer cognitive function. Specific genetic pathways linked to metabolic syndrome, obesity, and lipodystrophy appeared to contribute most strongly to these neurological changes. These findings provide new evidence that insulin resistance may directly influence brain structure and function, beyond its well-known effects on blood sugar regulation. The results could help scientists identify biological targets for preventing dementia, inform clinicians about shared risk factors for diabetes and cognitive decline, and guide nutritionists in developing dietary strategies to reduce insulin resistance and support brain health.

Technical Abstract: To better characterize the potential biological mechanisms underlying insulin resistance (IR) and dementia, we derive cross-population and population specific polygenic scores [PSs] for fasting insulin and IR-related partitioned PSs [pPSs]. We conduct a cross-sectional study of the associations of these genetic scores with neurological outcomes in >17k participants (36% men, mean age 55 yrs) from the Trans-Omics for Precision Medicine (TOPMed) program (50% Non-Hispanic White, 23% Black/African American, 21% Hispanic/Latino American, and 4% Asian American). We report significant negative associations (P<0.002) of the cross-population (P=1.3×10**-5) and European (PEA=3.0×10**-8) fasting insulin PSs with total cranial volume, and of a metabolic syndrome European PS with general cognitive function (BEA=-0.13, PEA=0.0002) and lateral ventricular volume (BEA=0.09, PEA=0.002). We identify suggestive negative associations (P<0.007) of metabolic syndrome and obesity pPSs with general cognitive function, and of lipodystrophy pPSs with total cranial volume. A higher genetic predisposition to IR is associated with lower brain size, and a genetic predisposition to specific IR-related type 2 diabetes subtypes, such as metabolic syndrome and mechanisms of IR mediated through obesity and lipodystrophy, is potentially involved in cognitive decline.