Amyloid and tau PET in sporadic early- onset Alzheimer- s disease: Preliminary results from LEADS

Abstract

BackgroundPrevious studies have reported that age modifies the distribution and burden of tau (and, to a lesser extent, amyloid) pathology in sporadic Alzheimer- s disease (AD). Here we present preliminary baseline amyloid and tau PET results from the Longitudinal Early- Onset Alzheimer- s Disease Study (LEADS), a multi- site longitudinal study of sporadic early- onset AD.Method135 patients meeting clinical criteria for MCI or probable AD and 50 cognitively normal controls (all age<65 at enrollment) were enrolled at 12 US centers between August 2018 and December 2019 (Table 1). 18F- Florbetaben amyloid- PET (FBB) was used to assign patients to EOAD (amyloid- positive) or EOnonAD (amyloid- negative) subgroups based on visual rating and semi- quantification. 130 patients and all controls had 18F- Flortaucipir tau- PET (FTP). Regional Standardized Uptake Value Ratios (SUVR) for FBB (whole cerebellum reference) and FTP (inferior cerebellar gray reference) were extracted using co- registered 3T- MRI.Result98 patients (72.6%) were amyloid PET- positive (EOAD) and 37 (27.4%) were amyloid PET- negative (EOnonAD). Compared to EOAD, EOnonAD patients had higher MMSE, MOCA and CDR sum- of- boxes (CDR- SB) and were more frequently male (Table 1). Patients with EOAD showed elevated FBB and FTP SUVR in temporoparietal and frontal cortex compared to CN and EOnonAD (Figures 1- 2). In EOAD, MMSE, MOCA and CDR- SB were significantly correlated with FTP SUVR (Figure 3), while no significant correlations were found with FBB SUVR. EOnonAD patients showed variable FTP binding ranging from negative to mildly elevated binding in anterior temporal and frontal cortex and underlying white matter. Two EOnonAD cases showed intense FTP binding comparable to typical EOAD cases, despite visually and quantitatively negative FBB scans.ConclusionPatients with clinically mild, sporadic EOAD typically show an extensive distribution and burden of tau pathology in the setting of positive amyloid PET. Global clinical measures correlate with tau but not amyloid PET. Over 25% of patients meeting clinical criteria for early- onset MCI/probable AD have negative amyloid PET, suggesting alternative etiologies for cognitive decline. These findings will inform future design of drug trials in this important and under- studied population.