Influence of Aβ and neurofibrillary tau deposition on cognition in Down syndrome across the Alzheimer’s disease continuum

1592 Introduction: Adults with Down syndrome (DS) have a high incidence of Alzheimer’s disease (AD). In late-onset AD, tau has been shown to have greater impact on cognition compared to Aβ, but the effects of tau on cognition have not yet been evaluated in DS. The aim of this study was to examine the association between Aβ and tau with cognition in a large DS cohort. Methods: A total of 161 adults with DS (mean age: 39.2 [8.46] years) and 40 healthy, non-DS sibling controls (43.2 [12.6] years) underwent T1w-MRI, [C-11]PiB and [F-18]AV-1451 PET scans at four imaging sites. MRI images were processed using FreeSurfer v5.3.0 to generate ROI masks encompassing the Braak staging of tau pathology. PiB and AV-1451 SUVr images were generated using a cerebellar gray matter reference region. Global Aβ burden was calculated using the amyloid load metric (AβL). A low-threshold amyloid-positivity (A+) cutoff was defined as 13.3 AβL (~18 Centiloids). Regional tau was assessed using AV-1451 SUVr Z-scores. A Z-score cutoff for tau-positivity (T+) was defined as 3.90 from the sibling control data (97.5th percentile of maximum Z-score values). No corrections for the partial volume effect were performed, so analyses were restricted to Braak regions III-VI. Z-score composite measures of episodic memory and overall cognition (includes measures of episodic memory, dementia symptoms/mental status, visual perception, executive functioning, motor planning and coordination, and verbal fluency) were compared between adults with DS who were A+T- versus A+T+ across each Braak region using two-sample t-tests while adjusting for age, premorbid level of intellectual disability, and imaging site. Results: Of the 20 A+T+ DS individuals, six were cognitively stable (CS-DS), five had mild cognitive impairment (MCI-DS), seven had AD, and two had a consensus of unable to be determined (Figure 1). The cognitive consensus was determined independent of imaging data. There were no participants classified as A-T+. T+ classification resulted in fewer CS-DS cases when compared to A+ classification. Compared to those that were only Braak III T+, Braak IV T+ revealed fewer CS-DS cases. Figure 2 displays the associations between cognition, Aβ, and regional tau. Participants with an A+T+ classification displayed significantly worse cognitive functioning compared to those with an A+T- classification (Table 1). Discussion: These findings reveal that T+ classification was better able to distinguish cases of MCI-DS and AD from CS-DS compared to A+ classification alone. The A+T+ individuals displayed worse cognitive functioning compared to the A+T- individuals, suggesting T+ presence in DS is a better indicator of cognitive decline, similar to the observations in late-onset AD.