Developing Topics.

Abstract

Phosphorylated tau (pTau) in cerebrospinal fluid (CSF) is a biomarker of Alzheimer's disease (AD) pathology. Recent studies confirm that pTau levels in plasma may provide a more cost-effective and less invasive method of assessing AD pathology, which have shown to also be relevant in preclinical populations. Neurofilament light (NfL) is a measure of neuroaxonal damage associated with poorer cognitive outcomes. Generalization is a validated cognitive marker of hippocampal dysfunction, with individuals showing deficits years before overt cognitive impairment. Using a computer generalization task sensitive to medial temporal lobe (MTL) pathology, the current study examined the relationship between generalization performance and plasma pTau and NfL levels in a population with elevated AD risk, older African Americans. 130 older, cognitively normal African Americans (M age = 71.60 years, SD = 6.58; M edu = 13.88 years, SD = 2.37; n = 98 women) provided blood samples and completed a hippocampal-dependent cognitive task. Participants' normal cognitive status was confirmed using the Mini-Mental State Examination (M MMSE = 26.98, SD = 2.14) and generalization performance was assessed using the Acquired Equivalence Task. Plasma was extracted from blood samples to assess pTau181, pTau231, and NfL levels. Based on the sample median thresholds, participants were characterized as plasma tau positive (≥16.189 for pTau181 and ≥17.537 for pTau231). Participants positive for plasma pTau231 (n = 76) demonstrated worse generalization performance with increased pTau231 levels, B = -0.296, p = 0.024, as did participants positive for plasma pTau181, B = -0.247. p = 0.042, demonstrating that tau positivity status is related to MTL dysfunction. Moreover, pTau231 was more strongly associated with generalization performance, indicating that it is a more sensitive biomarker than pTau181 among preclinical AD populations. Higher levels of plasma NfL were also significantly associated with lower generalization performance B = -0.243. p = 0.008. Plasma isoforms pTau181 and pTau231 may reflect different phases of tau progression, with plasma pTau231 shown to be better at capturing subtle MTL dysfunction. Plasma tau positivity status and measures of axonal damage along with lower generalization performance scores may be useful indicators of cognitive dysfunction in preclinical AD populations.