Plasma phosphorylated tau‐217 exhibits sex‐specific prognostication of cognitive decline and brain atrophy in cognitively unimpaired adults

Abstract

INTRODUCTIONAccumulating evidence indicates disproportionate tau burden and tau‐related clinical progression in females. However, sex differences in plasma phosphorylated tau (p‐tau)217 prediction of subclinical cognitive and brain changes are unknown.METHODSWe measured baseline plasma p‐tau217, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) in 163 participants (85 cognitively unimpaired [CU], 78 mild cognitive impairment [MCI]). In CU, linear mixed effects models examined sex differences in plasma biomarker prediction of longitudinal domain‐specific cognitive decline and brain atrophy. Cognitive models were repeated in MCI.RESULTSIn CU females, baseline plasma p‐tau217 predicted verbal memory and medial temporal lobe trajectories such that trajectories significantly declined once p‐tau217 concentrations surpassed 0.053 pg/ml, a threshold that corresponded to early levels of cortical amyloid aggregation in secondary amyloid positron emission tomography analyses. CU males exhibited similar rates of cognitive decline and brain atrophy, but these trajectories were not dependent on plasma p‐tau217. Plasma GFAP and NfL exhibited similar female‐specific prediction of medial temporal lobe atrophy in CU. Plasma p‐tau217 exhibited comparable prediction of cognitive decline across sex in MCI.DISCUSSIONPlasma p‐tau217 may capture earlier Alzheimer's disease (AD)‐related cognitive and brain atrophy hallmarks in females compared to males, possibly reflective of increased susceptibility to AD pathophysiology.

Blood Biomarkers of Alzheimer’s Disease and Cognition: A Literature Review

“…Blood-based Tau biomarkers, including p-Tau181, p-Tau217, p-Tau231, and t-Tau, consistently demonstrate a negative correlation with cognitive performance. Furthermore, studies within our review suggest that blood-based p-Tau measures show stronger associations with cognition than other blood-based biomarkers [29,34,[43][44][45]66,67,70]. Thus, these findings suggest that plasma p-Tau measures are a sensitive marker in AD-related cognitive impairment.…”

“…Regarding the plasma p-Tau217 levels in CU participants, a study also identified a significant inverse relationship with longitudinal worsening in the MMSE, PACC, and verbal memory (RAVLT scores) measures [44]. Similarly, Saloner et al (2023) [67] observed a strong correlation between higher plasma p-Tau217 levels and verbal memory decline (CVLT scores) in female CU individuals. Another finding described a strong association between plasma p-Tau217 levels and annual change in PACC scores in SCD participants [39].…”

“…Along this same line, another study, involving MCI with positive AD biomarkers, found that higher plasma GFAP was associated with annual ACE-R scores slopes [37]. However, a recent study conducted by Saloner et al (2023) [67] showed weaker associations between GFAP and cognitive trajectories in MCI subjects.…”

“…Furthermore, higher baseline plasma p-Tau217 levels have also been associated with a steeper cognitive decline across language tasks (SF and BNT) and attention/EF tasks (DS backwards, TMT, SCWT, LT, and Design fluency) in individuals with MCI. This association was also observed across memory tasks, the California Verbal Learning Test (CVLT), and the Benson Figure test but only in male MCI subjects [67]. Regarding the plasma t-Tau levels in MCI subjects, a study has reported a decrease in MMSE scores during the first few years [32].…”

Alzheimer’s and neurodegenerative disease biomarkers in blood predict brain atrophy and cognitive decline

“…Finally, the present study did not include measurement of the pTau-217 isoform, which compared to pTau-181, has demonstrated greater accuracy for prediction of cortical AD pathology [ 60 , 61 ]. Further, the addition of pTau-217 may have enabled us to detect differences in brain volume and cognition as a function of sex, as prior work has demonstrated that higher pTau-217 is related to declines in verbal memory and brain atrophy for cognitively unimpaired women but not men [ 62 ].…”