32 Elevated Plasma pTau-181 is Associated with Lower Global Cognition and Executive Function in Older Adults

Objective:Aggregation of phosphorylated tau (pTau) is a hallmark feature of Alzheimer’s disease (AD). Novel assays now allow pTau to be measured in plasma. Elevated plasma pTau predicts subsequent development of AD, cortical atrophy and AD-related pathologies in the brain. We aimed to determine whether elevated pTau is associated with cognitive functioning in older adults prior to the development of dementia.Participants and Methods:Independently living older adults (N = 48, mean age = 70.0 years; SD = 7.7; age range 55-88 years; 35.4% male) free of dementia or clinical stroke were recruited from the community and underwent blood draw and neuropsychological assessment. Plasma was assayed using the Quanterix Simoa® pTau-181 V2 Advantage Kit to quantify pTau-181 levels and APOE genotyping was conducted on the blood cell pellet fraction obtained from plasma separation. Global cognition was assessed using the Dementia Rating Scale-2 (DRS-2) and executive function was assessed using the Stroop, D-KEFS-2 Fluency, and Trails Making Test. Diagnosis of mild cognitive impairment (MCI) was determined based on overall neuropsychological performance. Participants were diagnosed as MCI if they scored >1 SD below norm-referenced values on 2 or more tests within a domain (language, executive, memory) or on 3 tests across domains.Results:Multiple linear regression analysis revealed a significant negative association between plasma pTau-181 levels and DRS-2 (B = -2.57, 95% CI (-3.68, -1.47), p <.001), Stroop Color-Word score (B = -2.64, 95% CI (-4.56, - 0.71), p = .009) and Fruits and Vegetables Fluency (B = -1.67, 95% CI (-2.84, -0.49), p = .007), adjusting for age, sex, education and APOE4 status. MCI diagnosis was determined for 43 participants, of which 8 (18.6%) met criteria. Logistic regression analysis revealed that pTau-181 levels are associated with increased odds of MCI diagnosis (OR = 2.18, 95% CI (1.01, 4.68), p = .046), after accounting for age, sex, education and APOE4 status.Conclusions:Elevated plasma pTau-181 is associated with worse cognition, particularly executive function, and predicts MCI diagnosis in older adults. Higher plasma pTau-181 was associated with increased odds of MCI diagnosis. Detection of pTau-181 in plasma allows a novel, non-invasive method to detect burden of one form of AD pathology. These findings lend support to the use of plasma pTau-181 as a valuable marker in detecting even early cognitive changes prior to the development of AD. Additional longitudinal studies are warranted to explore the prognostic value of plasma pTau-181 over time.