Brain | February 15, 2023

Jack CR, Wiste HJ, Algeciras-Schimnich A, Figdore DJ, Schwarz CG, Lowe VJ, Ramanan VK, Vemuri P, Mielke MM, Knopman DS, Graff-Radford J, Boeve BF, Kantarci K, Cogswell PM, Senjem ML, Gunter JL, Therneau TM, Petersen RC. 
Brain. 2023

https://doi.org/10.1093/brain/awad042

Abstract

Staging the severity of Alzheimer’s disease pathology using biomarkers is useful for therapeutic trials and clinical prognosis. Disease staging with amyloid and tau PET has face validity; however, this would be more practical with plasma biomarkers. Our objectives were, first, to examine approaches for staging amyloid and tau PET and, second, to examine prediction of amyloid and tau PET stages using plasma biomarkers.

Participants (N = 1136) were enrolled in either the Mayo Clinic Study of Aging or the Alzheimer’s Disease Research Center, had a concurrent amyloid PET, tau PET, and blood draw, and met clinical criteria for cognitively unimpaired (N = 864), mild cognitive impairment (N = 148), or Alzheimer’s Clinical Syndrome with dementia (N = 124). The latter two groups were combined into a cognitively impaired group (N = 272). We used multinomial regression models to estimate discrimination (concordance [C] statistics) among three amyloid PET stages (low, intermediate, high), four tau PET stages (Braak 0, 1-2, 3-4, 5-6), and a combined amyloid and tau PET stage (none/low vs. intermediate/high severity) using plasma biomarkers as predictors separately within unimpaired and impaired individuals. Plasma analytes, p-tau181, Aβ 1-42 and 1-40 (analyzed as the Aβ42/40 ratio), GFAP, and NfL, were measured on the HD-X Simoa Quanterix platform. Plasma p-tau217 was also measured in a subset (N = 355) of CU participants using the Lilly MSD assay.

Models with all Quanterix plasma analytes along with risk factors (age, sex, and APOE) most often provided the best discrimination among amyloid PET stages (C = 0.78 to 0.82). Models with p-tau181 provided similar discrimination of tau PET stages to models with all four plasma analytes (C = 0.72 to 0.85 vs. C = 0.73 to 0.86). Discriminating a PET proxy of intermediate/high from none/low AD neuropathologic change with all four Quanterix plasma analytes was excellent but not better than p-tau181 only (C = 0.88 vs. 0.87 for unimpaired and C = 0.91 vs. 0.90 for impaired). Lilly p-tau217 outperformed the Quanterix p-tau181 assay for discriminating high vs. intermediate amyloid (C = 0.85 vs. 0.74) but did not improve over a model with all Quanterix plasma analytes and risk factors (C = 0.85 vs. 0.83).

Plasma analytes along with risk factors can discriminate between amyloid and tau PET stages and between a PET surrogate for intermediate/high vs none/low neuropathologic change with accuracy in the acceptable to excellent range. Combinations of plasma analytes are better than single analytes for many staging predictions with the exception that Quanterix p-tau181 alone usually performed equivalently to combinations of Quanterix analytes for tau PET discrimination.