Alzheimer's Imaging Consortium.

Area of Science:

• Neuroimaging and Neuropathology
• Alzheimer's Disease Research
• Biomarker Development

Background:

• Older age and male sex are independently associated with reduced Tau-PET uptake in symptomatic Alzheimer's disease (AD).
• Understanding the PET-to-neuropathological correlates of these demographic effects on tau pathology is crucial for accurate diagnosis and research.

Purpose of the Study:

• To investigate the relationship between age, sex, and tau-PET uptake using independent PET and autopsy cohorts.
• To examine the PET-to-neuropathological correspondence of tau-PET with postmortem Braak staging and tangle density, stratified by age and sex.

Main Methods:

• Analysis of [18F]flortaucipir-PET data in 680 amyloid-positive participants with MCI or dementia.
• Analysis of neuropathological data (Braak staging, tangle density) in 947 autopsy cases with moderate-to-frequent CERAD scores.
• Direct PET-to-autopsy correlation in 84 cases, assessing Tau-PET accuracy for Braak-V/VI pathology across age and sex strata.

Main Results:

• Independent PET and autopsy analyses confirmed that older age and male sex were associated with lower Tau-PET uptake and Braak-V/VI neuropathology prevalence.
• In autopsy cases, older age, but not male sex, correlated with lower tangle density among those with Braak-V/VI pathology.
• PET-to-autopsy analyses revealed high specificity of Tau-PET for Braak-V/VI tau, but decreased sensitivity with increasing age and in males, consistent with lower tangle densities.

Conclusions:

• The observed lower Tau-PET uptake and prevalence in older and male individuals are explained by reduced tau tangle densities at autopsy.
• Tau-PET imaging demonstrates a strong correlation with postmortem tangle density, validating its utility as a biomarker.
• The findings highlight that while Tau-PET reflects tau pathology, its sensitivity in detecting advanced Braak stages may be lower in older males due to variations in tangle density.