P3‐274: High CSF TAU is Related to Reduced Hippocampal Volume and Subjective Cognitive Decline in Healthy Elderly with Amyloid Pathology

In preclinical stages of Alzheimer’s disease (AD), questions remain about relationships in cerebrospinal fluid (CSF) between amyloid beta (Aβ) or tau proteins and other markers of AD pathogenesis. In the PREVENT-AD cohort of cognitively normal older adults with a parental history of AD-like dementia, we assessed distributions of CSF Aβ and tau and their relation to brain integrity and cognitive function. We assessed levels of Aβ1-42 and phosphorylated tau (181P-tau) in 93 individuals (age: 63y. s.d. 5.57). Using cut-offs at the 25th percentile, we dichotomized participants as having high (CSF Aβ1-42<869) or low (CSF Aβ1-42>869) Aβ pathology (Fig.1). We then ran general linear models to assess CSF proteins and AD markers using age as a covariate. We measured hippocampal volume (adjusted for intracranial volume) as an important indicator of brain integrity. We relied on total score from the Repeatable Battery for Assessment of Neuropsychological Status (RBANS), and self-report of the participant’s memory compared to 20 years ago to indicate objective and subjective cognitive status respectively. The association between levels of Aβ1-42 and P-tau was clearly dependent on APOE-e4 status (interaction p<0.01, Fig. 2). In e4 carriers, we observed an expected relationship of higher Aβ pathology (lower CSF values) with higher P-tau, but the inverse was found in non-carriers. The association between lower hippocampal volume and higher CSF P-tau was driven by participants with Aβ pathology (interaction p=0.017, Fig. 3). The association between higher P-tau and the presence of a subjective cognitive complaint was also driven by individuals with Aβ pathology (interaction, p=0.04). There was no interaction between Aβ groups and P-tau on cognitive performance, although total RBANS score declines with elevated P-tau (p=0.013, Fig. 4). Our results suggest that in cognitively normal elderly at risk of AD, individuals with both high P-tau and low Aβ1-42 levels already present associations between CSF measurements and brain integrity or subjective cognitive assessment. Aβ1-42 and P-tau CSF markers, when used conjointly, might therefore be valuable markers to identify candidates for preventive trials. Distribution of CSF Aβ42 (left) and phosphorylated tau (right) Regression analysis showing an interactive effect between P-tau and APOE4 on CSF Aβ42. p values: P-tau, ns; ApoE4, ns; interaction P-tau*ApoE4, p < 0.01. Regression analysis showing an interactive effect between P-tau and Aβ1–42 on hippocampal volume (HV). p values: P-tau, ns; Aβ, ns; interaction P-tau*Aβ, p = 0.017. Low Aβ pathology = CSF value > 869 ; High Aβ pathology = CSF value < 869. Regression analysis showing a significant effect of P-tau on RBANS total score, p values: P-tau, p = 0.013; Aβ, ns; P-tau*Aβ, ns. Low Aβ pathology = CSF value > 869 ; High Aβ pathology = CSF value < 869.

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