Potential Blood-Based Biomarkers for Predicting Change in Cognitive, Functional and Neuroimaging Parameters over Subsequent Years in Prodromal Alzheimer’s Subjects.

Objectives: To test prognostic value of several potential blood biomarkers in predicting course of decline in prospectively recruited subjects with prodromal Alzheimer’s disease over subsequent two years of follow-up. Methods: This present analysis included levels of 6 constituents of human blood [plasma neurofilament light chain (NfL), creatinine (Cr), arginine (Arg), methionine, asymmetric dimethylarginine and symmetric dimethylarginine (SDMA)] measured in 81 non-demented subjects enrolled in Alzheimer’s Disease Neuroimaging Initiative (ADNI) GO and ADNI 2. Subjects represented a consecutive series of those having clinically documented non-reversible clinical impairment and longitudinal neuroimaging data collected over at least two years as of January 2019. Each constituent was tested for its value in predicting disease progression, as assessed by clinical and functional neuropsychological instruments, as well as neuroimaging parameters indexing amyloid plaque frequency assed with florbetapir-PET, regional metabolic decline assessed with FDG-PET, and cerebral volume loss and T1-hypointensities assessed with structural MRI. Subgroups comprising those subjects falling above or below mean level for each constituent were statistically compared with respect to magnitude of change in cognitive [Mini-Mental State Exam (MMSE) and Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog)], functional [Functional Activities Questionnaire (FAQ)], and neuroimaging [both region-of-interest (ROI) and voxel-based] parameters, and subgroup differences in those parameters were considered significant if p < 0.05 after statistical adjustment for multiple comparisons, by Family Wise Error (FWE, for voxel-based mapping) or Bonferroni-type (B, for clinical or ROI-based parameters) methods of correction. Results: All higher baseline constituents were significant predictors of more profound loss of gray matter volume in left caudal middle frontal gyrus over two years, with Cr being the most predictive (p = 1.87x10^-5, p_B = 0.00251). Higher Cr also predicted greater amyloid accumulation in frontal and association cortex (p_corr.FWE = 0.024), over the ensuing two years. Higher baseline Arg predicted diminishing temporal metabolism (p = 0.0050, p_B = 0.025), as well as greater amyloid accumulation in hippocampus (p = 2.78x10^-4, p_B = 0.0336) and caudate nucleus (p = 2.98x10^-4, p_B = 0.0361). Higher NfL was also associated with more diminished metabolism in anteromedial cerebellum (p_corr.FWE = 0.003). Finally, baseline SDMA was correlated with greater loss of function with respect to instrumental activities of daily living as assessed by FAQ (r= 0.31, p = 0.005, p_B = 0.03), and tended to correlate with greater loss of cognitive ability as assessed by ADAS (r = 0.28, p = 0.012, p_B = 0.14), over the subsequent two years. Conclusions: These analyses support that blood-based constituents, including Cr, Arg, NfL, and SDMA may have utility in subjects with prodromal Alzheimer’s disease for predicting various signs of progression.