In vivo ¹⁸F-AV-1451 tau PET signal in <i>MAPT</i> mutation carriers varies by expected tau isoforms.

Abstract

To evaluate ¹⁸F-AV-1451 tau PET binding among microtubule-associated protein tau (<i>MAPT</i>) mutation carriers. Using a case-control study, we quantitatively and qualitatively compared tau PET scans in 10 symptomatic and 3 asymptomatic MAPT mutation carriers (n = 13, age range 42-67 years) with clinically normal (CN) participants (n = 241, age range 42-67 years) and an Alzheimer disease (AD) dementia cohort (n = 30, age range 52-67 years). Eight participants had <i>MAPT</i> mutations that involved exon 10 (N279K n = 5, S305N n = 2, P301L n = 1) and tend to form 4R tau pathology, and 5 had mutations outside exon 10 (V337M n = 2, R406W n = 3) and tend to form mixed 3R/4R tau pathology. Tau PET signal was qualitatively and quantitatively different between participants with AD, CN participants, and <i>MAPT</i> mutation carriers, with the greatest signal intensity in those with AD and minimal regional signal in <i>MAPT</i> mutation carries with mutations in exon 10. However, <i>MAPT</i> mutation carriers with mutations outside exon 10 had uptake levels within the AD range, which was significantly higher than both <i>MAPT</i> mutation carriers with mutations in exon 10 and controls. Tau PET shows higher magnitude of binding in <i>MAPT</i> mutation carriers who harbor mutations that are more likely to produce AD-like tau pathology (e.g., in our series, the non-exon 10 families tend to accumulate mixed 3R/4R aggregates). Exon 10 splicing determines the balance of 3R and 4R tau isoforms, with some mutations involving exon 10 predisposing to a greater proportion of 4R aggregates and consequently a lower level of AV-1451 binding, as seen in this case series, thus supporting the notion that this tau PET ligand has specific binding properties for AD-like tau pathology.