Data‐Driven Methods Highlight Early Signals of Tau in Patients Lacking Global Uptake: Facilitating Enrollment in Clinical Trials

• Published in: Alzheimer's & dementia Vol. 18; no. S5
• Main Authors: Rathore, Saima, Southekal, Sudeepti, Kennedy, Ian Andrew, Kotari, Vikas, Pontecorvo, Michael J.
• Format: Journal Article
• Language: English
• Published: 01.12.2022
• ISSN: 1552-5260; 1552-5279
• DOI: 10.1002/alz.067320

Background Alzheimer’s Disease (AD) patients showing neocortical Flortaucipir (FTP) tau levels above predetermined cutoffs based on the likelihood of disease progression are enrolled in Lilly trials. However, patients below the cutoffs can also exhibit disease progression, and clinical decline. These patients might be earlier in the course of disease progression and may benefit the most from therapy. The objective of this study is to apply data‐driven methods on regional tau measurements at baseline to identify a relatively homogeneous patient population showing earlier signals of tau. Method A standardized uptake value ratio (SUVr) from a weighted composite region (MUBADA;Devous et al,JNM,2017) with respect to cerebral white matter reference signal intensity (Southekal et al,JNM,2018) was calculated using baseline FTP (n=1093) images from AVID FTP development studies (AV1451‐A05:NCT02016560) and Lilly clinical trials (EXPEDITION‐3:NCT01900665, NAVIGATE‐AD:NCT02791191, and AMARANTH:NCT02245737). Using the cutoff of 1.11, we identified a cohort of 431 subjects that were negative by MUBADA. Diagnostic breakdown included 67 cognitively‐normal, 135 mild‐cognitive‐impairment, and 229 AD subjects. Within this cohort, we calculated reference‐region independent, min‐max scaled regional tau measurements in 68 regions from FreeSurfer FsAverage template. An affinity propagation clustering analysis was applied to detect homogeneous subgroups showing patterns of similar tau uptake. Two distinct subgroups—FTPEarly (n=151), and FTPUndetected (n=280), names reflecting their tau uptake levels— emerged in the cohort. The groups were compared on clinical, cognitive, and genetic characteristics using Analysis‐Of‐Covariance. Result FTPEarly group demonstrated relatively higher baseline plasma‐tau levels (p‐tau217) and pattern of elevated FTP uptake in inferior‐temporal, fusiform, entorhinal, and para‐hippocampal regions (P<0.01 for all) compared to FTPUndetected group. In FTPEarly group, 98% were MCI or AD, 90% were amyloid+, and 69% were APOE4‐carriers, whereas in FTPUndetected group, the prevalence of MCI or AD, amyloid positivity, and APOE4‐carriers dropped to 76%, 43%, and 37%, respectively. When evaluated on longitudinal sub‐population, FTPEarly patients progressed faster than FTPUndetected patients on FTP SUVr (P<0.01) and cognitive measures (ADAS; P<0.01). Conclusion Data‐driven methods identify visually difficult to recognize FTPEarly group characterized by distinct neuroimaging patterns and paralleled by relatively homogeneous clinical, genetic, and cognitive profile. These methods hold promise for targeting enrollment of FTPEarly patient populations into clinical trials.