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

TL;DR

This study compares tau protein buildup in early- and late-onset Alzheimer's disease, finding that early-onset cases have more severe and faster tau accumulation.

Contribution

The study reveals distinct patterns of tau progression in early-onset Alzheimer's compared to late-onset, using longitudinal and cross-sectional data.

Findings

Early-onset Alzheimer's patients show higher baseline tau levels in neocortical regions compared to late-onset patients.

EOAD exhibits faster tau accumulation over time, especially in frontal and occipital brain areas.

Tau accumulation rates are inversely related to age in both early- and late-onset Alzheimer's.

Abstract

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.

We analyzed amyloid‐beta PET‐positive, cognitively impaired participants from the LEADS (EOAD; n = 383) and ADNI (LOAD; n = 196) cohorts with available 18F‐Flortaucipir tau PET data (Table 1). A subset had longitudinal 18F‐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 18F‐Flortaucipir PET scans were processed using the CenTauR pipeline. Cognitively normal participants from LEADS (n = 94) and ADNI (n = 421) with baseline 18F‐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.

Baseline comparisons revealed large effect‐size, significant differences in 18F‐Flortaucipir binding between EOAD and LOAD (Figure 1). EOAD participants had higher 18F‐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 18F‐Flortaucipir load, as well as between cognitive scores and 18F‐Flortaucipir load. Longitudinally, EOAD participants exhibited a faster increase in 18F‐Flortaucipir binding than LOAD, predominantly in frontal and occipital areas (Figure 2), with both groups showing an inverse linear relationship between 18F‐Flortaucipir accumulation rates and age.

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.

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