Insulin resistance (IR) is a major risk factor for Alzheimer’s Disease (AD) and has been associated with cognitive impairment, dementia, and neurodegeneration. Few genetic loci have been uncovered by genome-wide association studies (GWAS) of IR, limiting the proportion of variance explained (PVE) of IR genetic instruments. We constructed polygenic scores (PSs) for IR based on whole-genome sequencing (WGS) data from the Trans-Omics for Precision Medicine (TOPMed). We derived ancestry-specific PSs using PRS-CSx based on ancestry-specific UK Biobank reference panels and fasting insulin (FI) GWAS summary statistics adjusted for body mass index (BMI). We generated a multi-ancestry PSFI (Multi-PSFI) by fitting a linear combination of the standardized ancestry-specific PSFIs that most accurately predicted HOMA-IR in Nvalidation~17k participants without diabetes (34% European-EA, 28% African-AA, 38% Hispanic-HA), and evaluated its association with AD, dementia, general cognitive function (GENCOG), and four brain volumes in Ntesting~14k participants (66% EA, 22% AA, 11% HA). Logistic or linear mixed-effect models were adjusted for age, sex, study, 11 genetic principal components, and accounted for relatedness using a genetic relationship matrix. IR, GENCOG, and brain volumes analyses were additionally adjusted for BMI, education, and intracranial volume respectively. Statistically significant associations were defined by P<0.05/Ntraits/NPSs=0.05/7/4=0.002. Multi-PSFI was strongly associated with HOMA-IR (PVEJoint=12%). No significant or suggestive association was detected for the Multi-PSFI, the AA-PSFI, or the HA-PSFI with the neurological outcomes. EA-PSFI was significantly associated with intracranial volume (P=7E-07), and suggestively with lateral ventricular (P=0.004) and total brain volumes (P=0.05). By leveraging multi-ancestry and WGS data, we increased the IR PSs PVE and confirmed the association of IR with brain volumes. Funded by NIA K99AG066849.