Detection of β-amyloid positivity in Alzheimer's Disease Neuroimaging Initiative participants with demographics, cognition, MRI and plasma biomarkers

In vivo gold standard for the ante-mortem assessment of brain ii-amyloid pathology is currently beta-amyloid positron emission tomography or cerebrospinal fluid measures of beta-amyloid(42) or the beta-amyloid(42)/beta-amyloid(40) ratio. The widespread acceptance of a biomarker classification scheme for the Alzheimer's disease continuum has ignited interest in more affordable and accessible approaches to detect Alzheimer's disease beta-amyloid pathology, a process that often slows down the recruitment into, and adds to the cost of, clinical trials. Recently, there has been considerable excitement concerning the vtilue of blood biomarkers. Leveraging multidisciplinary data from cognitively unimpaired participants and participants with mild cognitive impairment recruited by the multisite biomarker study of Alzheimer's Disease Neuroimaging Initiative, here we assessed to what extent plasma beta-amyloid(42)/beta-arnyloid(40), neurofilament light and phosphorylated-tau at threonine-181 biomarkers detect the presence of beta-amyloid pathology, and to what extent the addition of clinical information such as demographic data, APOE genotype, cognitive assessments and MRI can assist plasma biomarkers in detecting beta-amyloid-positivity. Our results confirm plasma (beta-amyloid(42)/beta-amyloid(40 )as a robust biomarker of brain beta-amyloid-positivity (area under curve, 0.80-0.87). Plasma phosphorylated-tau at threonine-181 detected beta-amyloid-positivity only in the cognitively impaired with a moderate area under curve of 0.67, whereas plasma neurofilament light did not detect beta-amyloid-positivity in either group of participants. Clinical information as well as MRI-score independendy detected positron emission tomography beta-amyloid-positivity in both cognitively unimpaired and impaired (area under curve, 0.69-0.81). Clinical information, particularly APOE epsilon 4 status, enhanced the performance of plasma biomarkers in the detection of positron emission tomography beta-atnyloid-positivity by 0.06-0.14 units of area under curve for cognitively unimpaired, and by 021-025 units for cognitively impaired; and further enhancement of these models with an MRI-score of beta-amyloid-positivity yielded an additional improvement of 0.040.11 units of area under curve for cognitively unimpaired and 0.05-0.09 units for cognitively impaired. Taken together, these multi-disciplinary results suggest that when combined with clinical information, plasma phosphorylated-tau at threonine-181 and neurofilament light biomarkers, and an MRI-score could effectively identify beta-amyloid+ cognitively unimpaired and impaired (area under curve, 0.80-0.90). Yet, when the MRI-score is considered in combination with clinical information, plasma phosphorylated-tau at threonine-181 and plasma neurofilament light have minimal added value for detecting beta-amyloid-positivity. Our systematic comparison of ii-amyloid-positivity detection models identified effective combinations of demographics, APOE, global cognition, MRI and plasma biomarkers. Promising minimally invasive and low-cost predictors such as plasma biomarkers of beta-amyloid(42)/beta-amyloid(40) may be improved by age and APOE genotype.

Automated summary

The study evaluated various plasma biomarkers in relation to beta-amyloid pathology, finding that plasma beta-amyloid(42)/beta-amyloid(40) is a robust biomarker for brain beta-amyloid positivity, while plasma phosphorylated-tau at threonine-181 only has moderate diagnostic value in cognitively impaired individuals. Clinical information, APOE genotype, and MRI scores improve the performance of plasma biomarkers in detecting beta-amyloid positivity.