Differential impact of APOE on associations between phosphorylated tau 181 and multi‐domain cognitive outcomes using cerebrospinal fluid and plasma markers

Abstract

AbstractBackgroundBiomarkers of phosphorylated tau have previously been linked to cognitive function in prodromal Alzheimer’s disease (AD). However, the differential dynamics of various biomarker methods used as indicators of tau accumulation remain under investigation, particularly with respect to their associations with cognitive function and the moderating influence of APOE.MethodData for 741 participants from the Alzheimer’s Disease Neuroimaging Initiative with concurrent plasma, cerebrospinal fluid (CSF), and neuropsychological data were included. T‐tests assessed for cognitive classification (cognitively unimpaired [CU] vs mild cognitive impairment [MCI]) and APOE ε4 [carrier vs. non‐carrier] differences in levels of tau phosphorylated at threonine 181 (p‐tau181) measured in plasma and CSF. Multiple linear regression assessed for a main effect of plasma and CSF p‐tau181 on domains of memory, language, and executive function, as well as the moderating effect of APOE ε4 status, adjusting for age, sex, education, and cognitive classification. Sensitivity analyses included CSF amyloid‐beta 1‐42 as a covariate and stratified by cognitive classification.ResultResults indicated that both the MCI group and the APOE ε4 carrier group had significantly higher levels of plasma (cognitive group t=5.84, p<.001; APOE group t=4.89, p<.001) and CSF p‐tau181 (cognitive group t=5.14, p<.001; APOE group t=10.18, p<.001). For plasma p‐tau181, a main effect was observed only for memory (t=‐2.20, p=.03), whereas APOE ε4 interactions were observed only for language (t=‐2.65, p=.01) and executive function (t=‐2.19, p=.03) with ε4 carriers exhibiting a stronger negative association. For CSF p‐tau181, both a main effect (t=‐5.04, p<.001) and APOE ε4 interaction (t=‐2.10, p=.04) were observed only for memory. Sensitivity analyses revealed that these findings were driven by the MCI group and were largely unchanged when including amyloid‐beta 1‐42 as a covariate.ConclusionPlasma and CSF p‐tau181 are both elevated in the context of increased AD risk and both are associated with poorer memory. However, different patterns for plasma p‐tau181 emerge across other cognitive domains (i.e., language, executive function) when APOE ε4 carrier status is considered. However, future research (particularly in more representative samples) is needed given prior research demonstrating increased sensitivity of CSF relative to plasma.