Tau PET load in early‐ and late‐onset Alzheimer's disease: A cross‐sectional and longitudinal comparison of the LEADS and ADNI cohorts

Abstract Background We aimed to assess differences in baseline and longitudinal tau PET tracer binding between early‐onset Alzheimer's disease (EOAD) and late‐onset Alzheimer's disease (LOAD) in the LEADS and ADNI cohorts, respectively. Method We analyzed amyloid‐beta PET‐positive, cognitively impaired participants from the LEADS (EOAD; n = 383) and ADNI (LOAD; n = 196) cohorts with available 18 F‐Flortaucipir tau PET data (Table 1). A subset had longitudinal 18 F‐Flortaucipir PET data from LEADS ( n = 232) and ADNI ( n = 94) with average follow‐up intervals of 1.95 and 2.44 years, respectively. All 18 F‐Flortaucipir PET scans were processed using the CenTauR pipeline. Cognitively normal participants from LEADS ( n = 94) and ADNI ( n = 421) with baseline 18 F‐Flortaucipir and amyloid‐beta PET scans were also analyzed for comparison. We performed EOAD vs. LOAD comparisons using multivariate linear and linear mixed‐effects models for cross‐sectional and longitudinal analyses, respectively. Result Baseline comparisons revealed large effect‐size, significant differences in 18 F‐Flortaucipir binding between EOAD and LOAD (Figure 1). EOAD participants had higher 18 F‐Flortaucipir levels in widespread neocortical regions compared to LOAD, after adjusting for covariates. In both groups, tau load was negatively associated with age. In EOAD, a significantly steeper slope was found in the association between amyloid‐beta and 18 F‐Flortaucipir load, as well as between cognitive scores and 18 F‐Flortaucipir load. Longitudinally, EOAD participants exhibited a faster increase in 18 F‐Flortaucipir binding than LOAD, predominantly in frontal and occipital areas (Figure 2), with both groups showing an inverse linear relationship between 18 F‐Flortaucipir accumulation rates and age. Conclusion EOAD patients demonstrate significantly higher tau loads, broader neuroanatomical involvement and faster tau accumulation over time compared to LOAD, independent of disease stage. These findings suggest that earlier age‐of‐onset in AD is linked to a more aggressive tauopathy. The early, extensive tau spread in symptomatic EOAD, even at an early clinical stage, may also limit the efficacy of anti‐amyloid‐beta therapies in this population.