Alzheimer's Imaging Consortium

The agreement between plasma Aβ42/40 and Aβ-PET is approximately 75%, with a large portion of discrepancies due to positive plasma with negative PET results. Questions remain about whether these reflect brain Aβ changes detectable in plasma before PET-detectable. We aimed to examine these cases over 11 years to assess the risk and timing of progression to Aβ-PET positivity.

Cognitively unimpaired participants from large-scale longitudinal studies of AIBL, OASIS, and ADNI underwent baseline Aβ-PET and plasma Aβ42/40 analysis by IPMS, followed by 1-7 additional PET scans every 1.5-3 years. Aβ-PET was quantified to Centiloid (CL) using the SPM pipeline. Individuals with baseline Aβ-PET < 20 CL (n = 507) were included, with those < 5 CL classified as PET-, and 5-20 CL as PET_Low. Plasma -/+ was based on the Aβ42/40 Youden's Index threshold (0.119) corresponding to Aβ-PET status. We used Kaplan-Meier method and Cox proportional hazards analysis to assess the risk of progression to PET+ (> 20 CL).

Plasma+/PET- (< 5 CL) individuals were at higher risk than Plasma-/PET- of progressing to PET+ (hazard ratio (HR): 3.90 [95% CI: 2.00-7.61], p<0.001), even after matching the groups' baseline CL values (HR: 3.43 [1.43-8.26], p = 0.010), or adjusting for age, sex, APOE ε4 and baseline CL (HR: 2.48 [1.22 - 5.07], p = 0.013) (Figure 1A). Plasma+/PET- accumulated brain Aβ ∼8 times faster than Plasma-/PET- (1.14 CL/year vs. 0.15 CL/year respectively, p <0.001). Plasma+/PET- progressors became PET+, on average, 2 years earlier than Plasma-/PET- progressors. Plasma+/PET_Low group had faster decline in survival probability than Plasma-/PET_Low (HR: 20.82 [11.28 - 38.42], p <0.001 vs. HR: 6.67 [3.51 - 12.65], p <0.001) (Figure 1B) but this was driven by higher CL in the Plasma+ group.

Cognitively unimpaired individuals with abnormal plasma Aβ42/40 but negative Aβ-PET face a significantly increased risk of future positive Aβ-PET. This provides supporting evidence that brain Aβ pathology can be detected in plasma with IPMS before it is PET-detectable. Whether this also applies to plasma Aβ42/40 immunoassays warrants investigation.