O1‐03‐06: EARLY INCREASE IN TAU‐PET SIGNAL IS ASSOCIATED WITH Aβ BURDEN, CSF P‐TAU LEVELS AND COGNITION IN COGNITIVELY NORMAL LATE‐MIDDLE‐AGED ADULTS

The role of early cortical tau accumulation and its associations with amyloid-β (Aβ), cerebrospinal fluid (CSF) biomarkers, and cognition in pre-symptomatic stages of Alzheimer's disease (AD) remain unclear. Using PET imaging, we aimed to investigate these associations in cognitively normal, late-middle-aged individuals at increased risk of developing AD. Eighty-four cognitively normal adults with a familial history of AD (PREVENT-AD cohort, mage=67±5) underwent tau-PET ([18F]AV-1451), Aβ-PET ([18F]NAV-4694) and cognitive evaluation (Repeated Battery for Assessment of Neuropsychological Status; RBANS). CSF phosphorylated (p)-tau levels were assayed for 53 subjects using the Innotest ELISA assay (Fujirebio; Ghent, Belgium). SUVRs were extracted from the Freesurfer Desikan regions using the cerebellum grey matter as the reference region. Tau and Aβ positivity thresholds shown in Fig.1 were based on pre-established cutoffs for entorhinal cortex (EC) tau (Maass et al., 2017) and global Aβ (Mielke et al., 2012). We investigated whether there were regional tau SUVR differences between Aβ-positive and Aβ-negative subjects using t-tests. In the identified regions, we then assessed whether tau SUVR was related to CSF p-tau and cognition using linear regression models. Distribution of entorhinal AV1451 (A) and cortical Aβ (B) SUVRs 1A) Distribution of cortical Aβ SUVR across all subjects. Based on a cutoff of 1.4 (dashed line), fifteen individuals are classified as Aβ-positive. 1B) Distribution of entorhinal AV1451 SUVR across all subjects. Based on a cutoff of 1.3 (dashed line), three individuals are classified as tau-positive. Red circles = Aβ-positive individuals; black circles= Aβ- negative. Only three individuals were classified as tau-positive (EC SUVR≥1.3), while 15 were Aβ-positive (SUVR≥1.4; Fig.1a-b). Despite low tau signal, Aβ-positive individuals had higher AV1451 SUVRs than Aβ-negative ones in the EC, amygdala, inferior temporal, lateral occipital, fusiform and parahippocampal gyri (all p≤0.03; Fig.2a-c). AV1451 SUVRs in all aforementioned regions (except inferior temporal and fusiform gyri) were positively associated with CSF p-tau (p<0.05; Fig.3a). Finally, higher EC, amygdala, inferior temporal and lateral occipital AV1451 SUVRs were associated with lower delayed memory, language, and total RBANS index scores (p<0.05; Fig.3b). There was no Aβ status * AV1451-SUVR interaction on CSF p-tau or cognition. When the three tau-positive subjects were removed from the analyses, results remained similar. Mean AV1451 SUVR across all regions in Aβ+ and Aβ- groups 2A) Mean AV1451 SUVR across all FreeSurfer Desikan regions in Aβ-positive (red) and Aβ-negative (gray) groups. * indicates regions in which AV1451 SUVR is significantly different between the Aβ + and Aβ- groups. 2B) Table of Freesurfer Desikan regions indices corresponding to the x-axis of 2A. Regions with significantly increased AV1451 SUVR between Aβ+ and Aβ- are highlighted in orange. 2C) P-values of the significant regions are projected onto a brain template. Notably, Aβ-positive and Aβ-negative did not differ in terms of age and education. These findings indicate that, even in late-middle-aged adults with relatively low AV1451 SUVRs, AV1451 binding in AD signature regions is significantly increased among Aβ-positive individuals. Higher tau binding is also associated with higher CSF p-tau and lower cognitive performance. Overall, this suggests that early tau-PET changes in AD-typical regions are clinically meaningful.

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