Detecting amyloid positivity in early Alzheimer disease using plasma biomarkers. (31st December 2021) - Janelidze, Shorena
Abstract: Background: Recent data suggest that blood biomarkers of amyloid‐β (Aβ) pathology (Aβ42/Aβ40), tau pathology (phosphorylated tau [P‐tau]) and neurodegeneration (neurofilament light [NfL]) in Alzheimer disease (AD) become abnormal very early in the disease course, albeit with different dynamics; Aβ42/Aβ40 starts to change first followed next by P‐tau and then by NfL. Method: We studied the usefulness of plasma AD biomarkers measured using mass spectrometry (Aβ42/Aβ40) and immunoassays (P‐tau217 and NfL) to identify abnormal brain Aβ status (according to CSF Aβ42/Aβ40 or Aβ‐PET) in a total of 895 participants with early disease (cognitively unimpaired individuals [CU] and patients with mild cognitive impairment [MCI]) from two independent cohorts (BioFINDER‐1 and BioFINDER‐2). CSF Aβ42/Aβ40 measures were available in all study participants; 159 (26.9%) CU and 175 (57.6%) MCI were CSF Aβ42/Aβ40‐positive. Out of 858 subjects who underwent Aβ‐PET imaging, 142 (24.0%) CU and 169 (55.6%) MCI were Aβ‐PET positive. Result: In CU, a combination of plasma Aβ42/Aβ40 and plasma P‐tau217 accurately detected abnormal CSF Aβ42/Aβ40 status (BioFINDER‐2, area under the curve [AUC]=0.86; BioFINDER‐1, AUC=0.83) with no significant difference in the accuracy compared with the model including all 3 plasma biomarkers (BioFINDER‐2, AUC=0.87, p=0.62; BioFINDER‐1, AUC=0.84, p=0.57). In MCI patients, plasma P‐tau217 alone showed high discriminative accuracy (BioFINDER‐2, AUC=0.88; BioFINDER‐1, AUC=0.86) which was not significantly different from the discriminative accuracy of the model combining all 3 plasma biomarkers (BioFINDER‐2, AUC=0.88, p=0.94; BioFINDER‐1, AUC=0.88, p=0.29). Adding APOE ε4 status improved model fit but did not significantly change the AUCs of the models. The results were similar when using Aβ‐PET as the outcome. Conclusion: These findings suggest that different plasma biomarkers are not equally useful along the AD continuum. In the preclinical phase, plasma Aβ42/Aβ40 and plasma P‐tau217 would be needed to accurately detect abnormal brain Aβ status whereas in prodromal AD plasma P‐tau217 might alone be sufficient.