Developing Topics.

Background: The PrecivityAD® blood-test (C2N Diagnostics) predicts cerebral amyloidosis due to Alzheimer's Disease (AD). PrecivityAD® incorporates plasma Aβ42/40, age and apoE proteotype into an algorithm that generates an amyloid probability score (APS) corresponding to the likelihood of a positive amyloid PET scan, defined as ≥25 centiloid (CL). A prototype PrecivityAD algorithm validated against amyloid PET status scored by visual read (VR) was used to improve screening efficiency in INVOKE-2, a phase 2 randomized, double-blind, placebo-controlled trial evaluating TREM2-activating antibody AL002 in early AD.

Methods: VR-validated PrecivityAD (VR-PrecivityAD) used refined thresholds defined as low (VR-APS = 0-31), intermediate (32-57) or high (58-100) likelihood of amyloid positivity. CL-validated PrecivityAD (CL-PrecivityAD) results were scored using established thresholds for low (CL-APS = 0-35), intermediate (36-57) or high (58-100) likelihood of amyloid positivity. INVOKE-2 screening subjects meeting inclusion criteria for Clinical Dementia Rating Global Score (CDR-GS), Mini-Mental State Examination (MMSE), and Repeatable Battery for the Assessment of Neuropsychological Status Delayed Memory Index (RBANS-DMI) (CDR-GS = 0.5-1, MMSE≥20, RBANS-DMI≥95) were required to have a positive VR-PrecivityAD blood-test (intermediate or high VR-APS result) prior to a confirmatory amyloid PET VR or CSF test to establish eligibility. Positive predictive value (PPV) was defined as number of individuals with confirmed positive blood-tests as a percentage of all positive blood-tests.

Results: Positive VR-PrecivityAD results were reported for 51% of individuals (362/710) with a PPV of 87% overall, 91% for high or 82% for intermediate results (Table). Comparison of VR-APS against CL-APS results indicated the INVOKE-2 positivity threshold (VR-APS≥32) was equivalent to an effective CL-APS threshold of ∼25, lower than the established CL-PrecivityAD threshold (CL-APS≥36). In this comparison 58% of individuals would have scored negative on CL-PrecivityAD compared to 49% observed with VR-PrecivityAD. Importantly, 80% (52/65) of discordant individuals with positive VR-PrecvityAD and negative CL-PrecivityAD results had a subsequent positive confirmatory test (Table).

Conclusions: The prototype VR-PrecivityAD blood-test was highly predictive of amyloid positivity, confirmed by VR-PET or CSF, among INVOKE-2 screening subjects. Use of a lower VR-APS threshold was associated with fewer false negatives without a meaningful increase in false positives when compared to the standard CL-PrecivityAD threshold in the INVOKE-2 screening population.