Uncovering Hidden Risk: the Impact of Low Premorbid Intellectual Ability and Ethnicity on the Relationship between Alzheimer’s Disease Biomarkers and Cognition

Abstract Objective Individuals with intellectual disability (ID) without Down syndrome (DS) face a heightened risk for Alzheimer’s disease (AD), yet research using the AT(N) biomarker framework in this population is sparse. This study aims to examine the effects of premorbid intellectual ability (pIQ) using a word reading proxy for IQ—on plasma AD biomarkers and cognition in a community sample, and to explore moderating roles of APOE ε4 genotype and ethnicity on these relationships. Method 2374 participants from the Health & Aging Brain Study – Health Disparities were categorized into low (z ≤ −2.00) and average (z = 0.00 ± 1.00) pIQ groups based on word reading scores. Plasma levels of Aβ40, Aβ42, p-Tau181, NfL, and t-tau were analyzed using SIMOA. Plasma samples were genotyped for APOE ε4. Neuropsychological performance was assessed and regression analyses were conducted. Low pIQ was associated with higher p-Tau181, NfL, and t-tau (p < 0.05). Results NfL, p-tau 181, and t-tau were differentially associated with cognitive performance by ethnicity, with varying strength based on pIQ. APOE ε4 presence further amplified the deleterious effect on cognition, with stronger effects for those with low pIQ; ethnicity moderated these effects. Conclusion Findings suggest that low pIQ heightens biological and cognitive vulnerability to AD pathophysiology. Unlike conventional cognitive assessments or neuroimaging methods—which may be misclassify baseline abilities and be less accessible for individuals with low intellectual ability—biological staging stratified by pIQ may allow for more accurate differentiation between lifelong cognitive impairment and true cognitive decline, and reduces the risk of diagnostic bias. Future directions will integrate machine learning to predict pIQ groups from exposome and blood-based AD biomarker predictors.