Alzheimer's Imaging Consortium

¹⁸F-Flortaucipir is widely used for positron emission tomography (PET) imaging of Alzheimer's disease (AD)-type tau, but its sensitivity in early Braak stages has been questioned, and hippocampal uptake is at least partially confounded by off-target binding. We investigated associations between antemortem PET uptake and digitally-quantified tau and TDP-43 neuropathology.

Participants (n = 14, Figure 1) included 5 people with no/low AD neuropathologic change (ADNC) at autopsy, 2 intermediate, and 7 high. Clinical diagnoses included normal cognition (n = 2), AD (n = 5), dementia with Lewy bodies (n = 2), Parkinson's disease dementia (n = 1), corticobasal syndrome (n = 2), and posterior cortical atrophy (n = 2). We used the Automated Segmentation of Hippocampal Subfields T1 MRI pipeline to segment anterior and posterior hippocampus, Brodmann's areas (BA) 35 (transentorhinal cortex) & 36, and entorhinal cortex. ¹⁸F-Flortaucipir standardized uptake value ratios (SUVRs) were computed relative to inferior cerebellar grey matter and averaged across hemispheres. Postmortem sampling comprised hippocampal subiculum, CA1, CA2, CA3, and dentate gyrus; BA35 and BA36; and entorhinal cortex. FFPE-brain tissue was immunostained using PHF1 and phospho-specific TDP-43 antibodies and digitally imaged. Two different weakly supervised learning algorithms, Wildcat, were trained to identify tau tangles and threads; or somatic and neuritic phosphorylated TDP-43 (pTDP-43) inclusions. Each pathology type was quantified by summary statistics on Wildcat heatmaps, averaged over hippocampal subfields; and over BA35/entorhinal cortex (Denning et al., 2024). We computed non-parametric correlations between SUVRs and pathology measures at a=0.05 with false discovery rate correction.

Tangles were associated with SUVRs in BA35/entorhinal cortex (Spearman's r=0.59, p = 0.029; Figure 2A). The mean hippocampal tangle measure was associated with SUVRs in both anterior (r=0.77, p = 0.002) and posterior (r=0.77, p = 0.002) hippocampus (Figure 2B-C). Associations between SUVR and tau threads were marginally significant (Figure 2D-F). In BA35/entorhinal cortex, 9/9 intermediate-high ADNC cases had SUVRs above an established positivity cutoff of 1.23 (Figure 3). PET SUVRs were not associated with somatic or neuritic pTDP-43 measures.

Results suggest ¹⁸F-flortaucipir is sensitive to tau burden in early Braak-stage regions and primarily reflects neurofibrillary tangles rather than thread-like tau inclusions.