Examining the relationship between plasma pTau181 and cognitive decline, structural brain integrity, and biological ageing in midlife

INTRODUCTIONAlthough plasma pTau181 has been shown to accurately discriminate patients with Alzheimers disease from healthy older adults, its utility as a preclinical biomarker in middle-aged community-based cohorts is unclear. METHODSParticipants were members of the Dunedin Multidisciplinary Health and Development Study, a longitudinal study of 1037 people born in New Zealand in 1972-1973. Plasma pTau181, MRI-based brain structure, and DunedinPACE (an epigenetic biomarker of biological ageing) were measured at age 45; cognition was measured in childhood and age 45. RESULTSWe observed a wide range of pTau181 concentrations in our same-aged sample (n=856; M=13.6pg/mL, SD=9.1pg/mL). Males had significantly higher pTau181 concentrations than females. No statistically significant associations were observed with cognitive decline, lower structural brain integrity, or accelerated biological ageing. DISCUSSIONIn this midlife cohort, wide variation in pTau181 concentrations was present by age 45, but was not associated with patterns of AD-risk in cognition, brain structure, or biological ageing. Research in contextO_ST_ABSSystematic reviewC_ST_ABSAuthors reviewed the literature using PubMed and Web of Science databases. While research on plasma biomarkers of AD has largely focused on older people with mild cognitive impairment or AD, there are few studies of plasma biomarkers among general middle-aged populations. Given the potential utility of plasma biomarkers of AD such as pTau181 in early screening for disease risk, examining the concentrations of pTau181 among a younger cohort free of dementia is important for possible future clinical implementation. InterpretationPlasma pTau181 concentrations varied widely among our same-aged sample, yet higher pTau181 was not associated with cognitive decline, lower MRI-estimated structural brain integrity, or accelerated biological ageing. These findings indicate that variability in pTau181 exists in middle-age, but independently of other AD risk factors. Future directionsUnderstanding how variability in pTau181 concentrations in midlife may predict later AD and to what extent this is distinct from other risk factors is important for shaping the translational pathway from lab to clinic.