Glucose and lipid metabolic disorders are involved in the impairment of cognitive function. However, it remains unclear the link between a new indicator of glucose-lipid metabolism index (GLMI) and cognitive impairment.
Objective
This study investigates the relationship between GLMI and multidimensional cognitive function in adults aged ≥ 60 years.
Methods
GLMI was derived from glucose and lipid metabolism parameters. Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Word Learning test, Animal Fluency Test (AFT) and Digit Symbol Substitution Test (DSST) were used to evaluate the cognitive abilities of participants. Linear regression, subgroup analyses, multivariable adjustments, and restricted cubic spline (RCS) models were employed to evaluate GLMI-cognition associations.
Results
Among 787 participants from NHANES 2011–2014, diabetic individuals exhibited higher GLMI levels and more severe cognitive impairment than non-diabetic counterparts. In non-diabetic adults, GLMI showed linear correlations with CERAD and DSST assessed cognitive deficits. Subgroup analyses confirmed high GLMI as an independent risk factor for cognitive dysfunction in CERAD and DSST assessment. Multivariable regression revealed increased GLMI significantly elevated cognitive decline risk. ROC analysis identified 581.41 as the optimal GLMI cutoff (specificity: 86.0%) for predicting DSST impairment, outperforming traditional indices (TyG/HOMA-IR). RCS models demonstrated nonlinear GLMI-cognition associations, with a dose-dependent risk curve (200–800 range) and critical threshold at 545.
Conclusions
This study establishes that a high score of GLMI is associated with great severity of cognitive impairment in non-diabetic population.
WangXLiTLiH, et al.Association of dietary inflammatory potential with blood inflammation: the prospective markers on mild cognitive impairment. Nutrients2022; 14: 2417.
SelfWKHoltzmanDM. Emerging diagnostics and therapeutics for Alzheimer disease. Nat Med2023; 29: 2187–2199.
5.
ScheltensPDe StrooperBKivipeltoM, et al.Alzheimer's disease. Lancet2021; 397: 1577–1590.
6.
WangMSongWMMingC, et al.Guidelines for bioinformatics of single-cell sequencing data analysis in Alzheimer's disease: review, recommendation, implementation and application. Mol Neurodegener2022; 17: 17.
7.
SunMWangLGuoY, et al.The association among inflammatory diet, glycohemoglobin, and cognitive function impairment in the elderly: based on the NHANES 2011–2014. J Alzheimers Dis2022; 87: 1713–1723.
8.
MichailidisMMoraitouDTataDA, et al.Alzheimer's disease as type 3 diabetes: common pathophysiological mechanisms between Alzheimer's disease and type 2 diabetes. Int J Mol Sci2022; 23: 2687.
SachdevaPNarayananKBSinhaJK, et al.Recent advances in drug delivery systems targeting insulin signalling for the treatment of Alzheimer's disease. J Alzheimers Dis2024; 98: 1169–1179.
11.
TamtajiORHeidari-SoureshjaniRMirhosseiniN, et al.Probiotic and selenium co-supplementation, and the effects on clinical, metabolic and genetic status in Alzheimer's disease: a randomized, double-blind, controlled trial. Clin Nutr2019; 38: 2569–2575.
12.
ChatterjeeSPetersSAWoodwardM, et al.Type 2 diabetes as a risk factor for dementia in women compared with men: a pooled analysis of 2.3 million people comprising more than 100,000 cases of dementia. Diabetes Care2016; 39: 300–307.
13.
KahnSECooperMEDel PratoS. Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future. Lancet2014; 383: 1068–1083.
14.
Flores-CorderoJAPérez-PérezAJiménez-CorteganaC, et al.Obesity as a risk factor for dementia and Alzheimer's disease: the role of leptin. Int J Mol Sci2022; 23: 5202.
15.
TsaiCLPanCYChenFC, et al.Differences in neurocognitive performance and metabolic and inflammatory indices in male adults with obesity as a function of regular exercise. Exp Physiol2019; 104: 1650–1660.
16.
PugazhenthiSQinLReddyPH. Common neurodegenerative pathways in obesity, diabetes, and Alzheimer's disease. Biochim Biophys Acta Mol Basis Dis2017; 1863: 1037–1045.
17.
ProfennoLAPorsteinssonAPFaraoneSV. Meta-analysis of Alzheimer's disease risk with obesity, diabetes, and related disorders. Biol Psychiatry2010; 67: 505–512.
18.
Ramos-VeraCSaintilaJO’DianaAG, et al.Identifying latent comorbidity patterns in adults with perceived cognitive impairment: network findings from the behavioral risk factor surveillance system. Front Public Health2022; 10: 981944.
JinUParkSJParkSM. Cholesterol metabolism in the brain and its association with Parkinson's disease. Exp Neurobiol2019; 28: 554–567.
21.
DyeLBoyleNBChampC, et al.The relationship between obesity and cognitive health and decline. Proc Nutr Soc2017; 76: 443–454.
22.
Abi SalehRLiretteSTBenjaminEJ, et al.Mediation effects of diabetes and inflammation on the relationship of obesity to cognitive impairment in African Americans. J Am Geriatr Soc2022; 70: 3021–3029.
23.
FitzpatrickALKullerLHLopezOL, et al.Midlife and late-life obesity and the risk of dementia: cardiovascular health study. Arch Neurol2009; 66: 336–342.
24.
YuRSunYYeKX, et al.Cohort profile: the diet and healthy aging (DaHA) study in Singapore. Aging (Albany NY)2020; 12: 23889–23899.
25.
ArnoldSEArvanitakisZMacauley-RambachSL, et al.Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums. Nat Rev Neurol2018; 14: 168–181.
26.
BaroneEDi DomenicoFPerluigiM, et al.The interplay among oxidative stress, brain insulin resistance and AMPK dysfunction contribute to neurodegeneration in type 2 diabetes and Alzheimer disease. Free Radic Biol Med2021; 176: 16–33.
27.
WangHRuanSWuZ, et al.Prognostic significance of glucose-lipid metabolic index in pancreatic cancer patients with diabetes mellitus. Cancer Med2024; 13: e7108.
28.
DangKWangXHuJ, et al.The association between triglyceride-glucose index and its combination with obesity indicators and cardiovascular disease: NHANES 2003–2018. Cardiovasc Diabetol2024; 23: 8.
29.
LiHShiZChenX, et al.Relationship between six insulin resistance surrogates and nonalcoholic fatty liver disease among older adults: a cross-sectional study. Diabetes Metab Syndr Obes2023; 16: 1685–1696.
30.
FillenbaumGGMohsR. CERAD (Consortium to establish a registry for Alzheimer's disease) neuropsychology assessment battery: 35 years and counting. J Alzheimers Dis2023; 93: 1–27.
31.
MorrisJCHeymanAMohsRC, et al.The consortium to establish a registry for Alzheimer's disease (CERAD). part I. Clinical and neuropsychological assessment of Alzheimer's disease. Neurology1989; 39: 1159–1165.
32.
WengXTanYFeiQ, et al.Association between mixed exposure of phthalates and cognitive function among the U.S. Elderly from NHANES 2011–2014: three statistical models. Sci Total Environ2022; 828: 154362.
33.
MirraSSHeymanAMcKeelD, et al.The consortium to establish a registry for Alzheimer's disease (CERAD). part II. Standardization of the neuropathologic assessment of Alzheimer's disease. Neurology1991; 41: 479–486.
34.
LiYQiuLZhangC. Healthy dietary pattern improves cognitive function in elderly persons with periodontitis: a cross-sectional study of NHANES. Int Dent J2025; 75: 545–553.
35.
SunXYuWWangM, et al.Association between rest-activity rhythm and cognitive function in the elderly: the U.S. National health and nutrition examination survey, 2011–2014. Front Endocrinol (Lausanne)2023; 14: 1135085.
36.
LuZChenCZhangJ, et al.The relationship between alternative healthy diet Index and cognitive function in the older adults: the mediating effect of depressive symptoms. Nutrients2022; 14: 2856.
37.
MaoJHuHZhaoY, et al.Association between composite dietary antioxidant Index and cognitive function among aging Americans from NHANES 2011–2014. J Alzheimers Dis2024; 98: 1377–1389.
38.
BalzanoJChiaravallotiNLengenfelderJ, et al.Does the scoring of late responses affect the outcome of the paced auditory serial addition task (PASAT)?Arch Clin Neuropsychol2006; 21: 819–825.
39.
YangZGSunXHanX, et al.Relationship between social determinants of health and cognitive performance in an older American population: a cross-sectional NHANES study. BMC Geriatr2025; 25: 25.
40.
BrodyDJKramarowEATaylorCA, et al.Cognitive performance in adults aged 60 and over: national health and nutrition examination survey, 2011–2014. Natl Health Stat Report2019; 126: 1–23.
41.
SalthouseTA. What do adult age differences in the digit symbol substitution test reflect?J Gerontol1992; 47: P121–P128.
42.
MarrugantiCBaimaGAimettiM, et al.Periodontitis and low cognitive performance: a population-based study. J Clin Periodontol2023; 50: 418–429.
43.
TuligengaRHDugravotATabákAG, et al.Midlife type 2 diabetes and poor glycaemic control as risk factors for cognitive decline in early old age: a post-hoc analysis of the whitehall II cohort study. Lancet Diabetes Endocrinol2014; 2: 228–235.
44.
BiesselsGJDespaF. Cognitive decline and dementia in diabetes mellitus: mechanisms and clinical implications. Nat Rev Endocrinol2018; 14: 591–604.
45.
AltschulDMStarrJMDearyIJ. Cognitive function in early and later life is associated with blood glucose in older individuals: analysis of the lothian birth cohort of 1936. Diabetologia2018; 61: 1946–1955.
46.
HongSHanKParkCY. The insulin resistance by triglyceride glucose index and risk for dementia: population-based study. Alzheimers Res Ther2021; 13: 9.
47.
HenquinJC. Regulation of insulin secretion: a matter of phase control and amplitude modulation. Diabetologia2009; 52: 739–751.
48.
JeongJHLeeDHSongJ. HMGB1 Signaling pathway in diabetes-related dementia: blood-brain barrier breakdown, brain insulin resistance, and Aβ accumulation. Biomed Pharmacother2022; 150: 112933.
49.
HoscheidtSMKellawanJMBermanSE, et al.Insulin resistance is associated with lower arterial blood flow and reduced cortical perfusion in cognitively asymptomatic middle-aged adults. J Cereb Blood Flow Metab2017; 37: 2249–2261.
50.
LivingstonJMMcDonaldMWGagnonT, et al.Influence of metabolic syndrome on cerebral perfusion and cognition. Neurobiol Dis2020; 137: 104756.
51.
Ponce-LopezTGonzález Álvarez TostadoJADiasF, et al.Metformin prevents NDEA-induced memory impairments associated with attenuating beta-amyloid, tumor necrosis factor-alpha, and interleukin-6 levels in the hippocampus of rats. Biomolecules2023; 13: 1289.
52.
EnnisGEBetthauserTJKoscikRL, et al.The relationship of insulin resistance and diabetes to tau PET SUVR in middle-aged to older adults. Alzheimers Res Ther2023; 15: 55.
53.
NieYChuCQinQ, et al.Lipid metabolism and oxidative stress in patients with Alzheimer's disease and amnestic mild cognitive impairment. Brain Pathol2024; 34: e13202.
54.
XuMWangLMengY, et al.The role of lipid metabolism in cognitive impairment. Arq Neuropsiquiatr2025; 83: 1–13.
55.
MinhasPSLatif-HernandezAMcReynoldsMR, et al.Restoring metabolism of myeloid cells reverses cognitive decline in ageing. Nature2021; 590: 122–128.
56.
SchragMMuellerCZabelM, et al.Oxidative stress in blood in Alzheimer's disease and mild cognitive impairment: a meta-analysis. Neurobiol Dis2013; 59: 100–110.
57.
HansenSBWangH. The shared role of cholesterol in neuronal and peripheral inflammation. Pharmacol Ther2023; 249: 108486.
58.
LingENemeshJGoldmanM, et al.A concerted neuron-astrocyte program declines in ageing and schizophrenia. Nature2024; 627: 604–611.
59.
Sala-VilaAFlemingJKris-EthertonP, et al.Impact of α-linolenic acid, the vegetable ω-3 fatty acid, on cardiovascular disease and cognition. Adv Nutr2022; 13: 1584–1602.
60.
LiuYYangXGaoJ, et al.Association between triglyceride glucose index and cognitive decline: a meta-analysis. J Affect Disord2024; 359: 70–77.
61.
EmotoMNishizawaYMaekawaK, et al.Homeostasis model assessment as a clinical index of insulin resistance in type 2 diabetic patients treated with sulfonylureas. Diabetes Care1999; 22: 818–822.
62.
MatthewsDRHoskerJPRudenskiAS, et al.Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia1985; 28: 412–419.
63.
KhaliliDKhayamzadehMKohansalK, et al.Are HOMA-IR and HOMA-B good predictors for diabetes and pre-diabetes subtypes?BMC Endocr Disord2023; 23: 39.
64.
ParadelaRSJustoAFOPaesVR, et al.Association between APOE-ε4 allele and cognitive function is mediated by Alzheimer's disease pathology: a population-based autopsy study in an admixed sample. Acta Neuropathol Commun2023; 11: 205.
65.
ZouHLuoSLiuH, et al.Genotypic effects of the TOMM40'523 variant and APOE on longitudinal cognitive change over 4 years: the TOMMORROW study. J Prev Alzheimers Dis2023; 10: 886–894.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
