Relationship between loss of awareness of cognitive decline and tau pathology in the Alzheimer’s disease spectrum: modulatory role of resting‐state functional connectivity

Background Patients with Alzheimer’s disease (AD) often demonstrate anosognosia, which is reduced awareness of cognitive decline. Anosognosia has been associated with tau accumulation (d'Oleire Uquillas et al., 2020) and impaired resting‐state functional connectivity (FC) in self‐referential networks (Vannini et al., 2017, Valera‐Bermejo et al., 2022). The explicit links between AD pathological deposits and large‐scale functional networks associated with anosognosia have yet to be elucidated. Here, we sought to examine whether FC plays a modulatory role in the effect of tau on awareness in participants across the AD spectrum. Method We included 58 participants from two observational cohorts—44 asymptomatic (Clinical Dementia Rating (CDR) global score = 0) and 14 symptomatic (CDR≥0.5) individuals (Table1). Awareness was measured as the participant‐study partner discrepancy on the Cognitive Function Index. Flortaucipir‐PET was used to quantify tau accumulation, and segregation analysis was applied to resting‐state fMRI data to asses within‐network connectivity. For both modalities, the mean value in each of the Yeo 7 networks was used. First, a linear regression model was performed to assess the association between awareness and group (i.e., symptomatic/asymptomatic). Linear regression models were also used to assess the relationship between awareness and tau in the 7 networks, separately. Finally, we examined the effect of the FC×tau interaction on awareness. All models were adjusted for age, sex, and education. Result Holding age, sex, and education constant, mean awareness was 0.18 lower in symptomatic (vs. asymptomatic) participants (p