Amyloid Negative, Highly Tau Positive: Clinical Characterization of a Rare Biomarker Profile

Abstract

BackgroundThe majority of individuals with unambiguously positive tau biomarkers (T++) have positive amyloid biomarkers. Here we describe cases with clinical features associated with an unusual biomarker profile: very high tau PET binding and negative amyloid PET (A‐T++).MethodWe searched the Longitudinal Early‐Onset Alzheimer’s Disease (AD) Study, University of California San Francisco AD Research Center and the AD Neuroimaging Initiative cohorts on 09/01/2021 for participants with completed amyloid PET (Florbetapir, Florbetaben, Pittsburgh Compound B) and Tau PET (Flortaucipir (FTP)) scans and identified 1420 participants (mean age 69, 49.7% male). Using a pathology‐based, neocortical centiloid threshold of 24.4 (amyloid positivity) and a pre‐defined region of interest (Temporal MetaROI) standardized uptake value ratio (SUVR) > 1.27 threshold (tau positivity), we identified 64 amyloid negative, tau positive cases. An additional MetaROI FTP‐SUVR threshold > 2.0 (based on visual plot of data) was then applied to identify 7 A‐T++ cases (Figure 1).ResultAmong A‐T++ individuals mean age was 66.2 (range 53.8 ‐ 77.1), 4/7 were female, mean years of education was 15 (range 12 ‐ 20), mean MMSE was 20 (range 14‐29), 3/7 were APOE e3/e4 and clinical phenotypes included amnestic and atypical AD phenotypes (Table 1).Mean neocortical centiloid value was 11.4 (range: ‐1.39 ‐ 17.11) among A‐T++ cases and 4/7 had centiloid values between 12.2 ‐ 24.4 (may be indicative of early positivity). Mean FTP SUVR was 2.28 (range 2.03 ‐ 2.63) (Table 2). All A‐T++ cases demonstrated FTP tracer binding within the middle temporal cortex, medial temporal structures, and posterior cingulate regions (Figure 2). Neuropathological data from 1 case (UCSF3) revealed frequent CERAD Neuritic Plaques, Thal Amyloid Plaque Phase 5, and Braak Neurofibrillary Degeneration Stage 6 (autopsy performed 1 year after amyloid PET).ConclusionA‐T++ individuals were heterogeneous clinically but all displayed FTP tracer binding in AD‐signature regions. Four cases had amyloid centiloid values above 12.2 (threshold to detect moderate‐to‐frequent CERAD scores) but below 24.4 (threshold to detect intermediate‐to high Alzheimer’s disease neuropathologic change (ADNC) levels). Pathological data available for 1 case revealed a high level of ADNC. False negative amyloid PET in A‐T++ individuals is an important consideration; future studies are needed.

Exploring discordant low amyloid beta and high neocortical tau positron emission tomography cases

“…PET pattern consistent with a pattern typically observed in AD in the majority of cases reported, but in contrast to this study, four of seven participants had an atypical clinical phenotype. 46 There may be different Aβ conformations that are undetected by the ligand, and this has been observed in non-human primates that have the same amino acid sequence as human Aβ, but the aggregates have a different conformation. 47,48 In one report, a patient was found to lack high-affinity binding sites for 3H-PiB, despite detection of extensive Aβ deposition.…”

“…The patterns of tau tracer retention, relative discordance between the Aβ and tau PET findings, and alternative biomarker evidence suggesting a diagnosis of AD in these four participants raises the possibility that these participants have Aβ deposits undetected by the PET ligand. To our knowledge, there are no reports of this occurring with 18 F‐NAV4694; however, a handful of cases have been reported using 11 C‐PiB, 12–18 and it has been reported in a multi‐center study in which participants were scanned using 11 C‐PiB, as well as Aβ ligands 18 F‐Florbetapir and 18 F‐Florbetaben 46 . Similar to the current study, participants with low Aβ and high tau in a meta‐temporal composite ROI in this latter multi‐center study were young (mean age of 66.2), four of seven were APOE ε4 negative, and had a tau ( 18 F‐Flortaucipir) PET pattern consistent with a pattern typically observed in AD in the majority of cases reported, but in contrast to this study, four of seven participants had an atypical clinical phenotype 46 …”

“…To our knowledge, there are no reports of this occurring with 18 F‐NAV4694; however, a handful of cases have been reported using 11 C‐PiB, 12–18 and it has been reported in a multi‐center study in which participants were scanned using 11 C‐PiB, as well as Aβ ligands 18 F‐Florbetapir and 18 F‐Florbetaben 46 . Similar to the current study, participants with low Aβ and high tau in a meta‐temporal composite ROI in this latter multi‐center study were young (mean age of 66.2), four of seven were APOE ε4 negative, and had a tau ( 18 F‐Flortaucipir) PET pattern consistent with a pattern typically observed in AD in the majority of cases reported, but in contrast to this study, four of seven participants had an atypical clinical phenotype 46 …”