Biomarkers.

Area of Science:

• Neuroimaging
• Alzheimer's Disease Research
• Biomarker Discovery

Background:

• Interpreting amyloid-positive, tau-negative (A+T-) PET profiles in clinically impaired individuals is challenging for diagnosis and prognosis.
• Early-onset Alzheimer's Disease (EOAD) presents unique diagnostic hurdles.

Purpose of the Study:

• To determine the frequency of the A+T- PET profile in a cohort of early-onset Alzheimer's Disease patients.
• To characterize the clinical and neuroimaging features of individuals with an A+T- profile.

Main Methods:

• Analysis of 568 participants from the LEADS cohort with baseline amyloid-PET ([¹⁸F]florbetaben) and tau-PET ([¹⁸F]flortaucipir) scans.
• Amyloid positivity (A+) defined by [¹⁸F]florbetaben PET (≥25 Centiloid).
• Tau-PET status assessed via expert visual reads and quantitative SUVR measures, with comparisons between A+T- and A+T+ groups using Kruskal-Wallis/Fisher exact tests and linear mixed-effects models for longitudinal decline (CDR-SB).

Main Results:

• The A+T- profile was infrequent (3-7%) among amyloid-positive (A+) cognitively impaired (CI) participants, irrespective of the tau-PET assessment method.
• The A+T- group exhibited milder clinical impairment compared to the A+T+ group, despite being older and having higher rates of APOE-e4, hypercholesterolemia, and smoking.
• Longitudinally, the A+T- group showed slower clinical progression (CDR-SB increase) than the A+T+ group, with lower baseline amyloid burden and larger hippocampal volumes.

Conclusions:

• In A+ patients with EOAD, tau-PET positivity is highly prevalent (93-97%), regardless of the definition used.
• The rare A+T- profile in EOAD likely represents an early disease stage where tau pathology is below the detection threshold of PET imaging.
• This suggests that the A+T- profile in EOAD may be a transient state or indicative of alternative underlying pathologies.