Ovod, Vitaliy

AbstractBackgroundRecent advances in the development of novel Alzheimer’s disease (AD) measures of amyloid, tau, and neurodegeneration in cerebrospinal fluid (CSF) and blood have enabled a better understanding of the links between amyloid‐beta (Aβ), tau species and neurodegeneration in the brain, CSF, and blood. The discoveries of novel tau species in CSF and blood, including specific phospho‐tau (p‐tau) and truncated species containing the microtubule binding region of tau (MTBR‐tau) which aggregates in tau tangles, have greatly expanded our understanding of tau biology and tau target development. The longitudinal Aβ, tau, and neurofilament light chain (NfL) changes previously measured in CSF are now being measured accurately in blood, enabling interpretation and understanding of AD progression in much larger and more robust populations.MethodWe analyzed longitudinal CSF and/or blood plasma mass spectrometry measures of Aβ42/Aβ40, multiple p‐tau species (including p‐tau217, 231, 181, 205, etc.), total tau, MTBR‐tau (e.g., MTBR‐tau243, MTBR‐tau299, and MTBR‐tau354), and NfL in sporadic AD and dominantly inherited AD cohorts. Mass spectrometry results were compared to amyloid and tau aggregation measures by Positron Emission Tomography (PET) scans and clinical and cognitive measures in local and international clinical cohorts including ADNI, AIBL, BioFINDER, Mayo Clinic, the Knight ADRC, and the DIAN.ResultThe longitudinal results indicate that a pathophysiological cascade of events begin with altered CSF and blood plasma Aβ42/Aβ40 ratio, followed by increases in amyloid plaques as measured by amyloid PET, associated with increased phosphorylation of specific CSF tau species (e.g., p‐tau217, p‐tau181, etc.), before increases in p‐tau205, NfL, total tau concentrations, hypometabolism, and atrophy. Finally, some species of MTBR‐tau increase before or with tau aggregation by tau PET and onset of clinical symptoms and correlate with longitudinal tau aggregation and clinical progression.ConclusionThese findings indicate that CSF and blood plasma Aβ, p‐tau, MTBR‐tau and NfL measures are highly precise biomarkers of brain amyloidosis, tauopathy, and neurodegeneration and can accurately identify stages of preclinical and clinical AD.

Abstract In vivo gold standard for the ante-mortem assessment of brain β-amyloid pathology is currently β-amyloid positron emission tomography or cerebrospinal fluid measures of β-amyloid42 or the β-amyloid42/β-amyloid40 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 β-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 value 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 β-amyloid42/β-amyloid40, neurofilament light and phosphorylated-tau at threonine-181 biomarkers detect the presence of β-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 β-amyloid-positivity. Our results confirm plasma β-amyloid42/β-amyloid40 as a robust biomarker of brain β-amyloid-positivity (area under curve, 0.80–0.87). Plasma phosphorylated-tau at threonine-181 detected β-amyloid-positivity only in the cognitively impaired with a moderate area under curve of 0.67, whereas plasma neurofilament light did not detect β-amyloid-positivity in either group of participants. Clinical information as well as MRI-score independently detected positron emission tomography β-amyloid-positivity in both cognitively unimpaired and impaired (area under curve, 0.69–0.81). Clinical information, particularly APOE ε4 status, enhanced the performance of plasma biomarkers in the detection of positron emission tomography β-amyloid-positivity by 0.06–0.14 units of area under curve for cognitively unimpaired, and by 0.21–0.25 units for cognitively impaired; and further enhancement of these models with an MRI-score of β-amyloid-positivity yielded an additional improvement of 0.04–0.11 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 β-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 β-amyloid-positivity. Our systematic comparison of β-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 β-amyloid42/β-amyloid40 may be improved by age and APOE genotype.