Our lab has developed a highly sensitive and precise mass spectrometry based blood test to detect Alzheimer’s disease amyloid plaques in individuals even before symptom onset. In this project, we aim to determine blood amyloid-beta isoform level relationships to CSF amyloid-beta and amyloid PET, using archived blood samples from cross-sectional and longitudinal studies of cognitively normal, AD, and other neurodegenerative dementias. We are also conducting a cross-sectional clinical study of n=1120 individuals (Study to Evaluate Amyloid in Blood and Imaging Related to Dementia: SEABIRD) recruited from clinics and communities to determine the participant acceptability and validity of the blood Aβ test as a screening test for brain amyloidosis.
Apolipoprotein E (ApoE) is a 34 kDa glycoprotein essential for the transport and metabolism of lipids and cholesterol throughout the body. As the most significant genetic risk factor for the development of late-onset AD, the APOE gene has been the focus of a considerable amount of biomedical research. The gene is polymorphic with three high-frequency alleles. The ε2 allele is generally considered protective and is associated with a decreased risk of AD. The ε4 allele is associated with an increased risk in a dose-dependent manner (~3-fold for heterozygotes and ~12-fold for homozygotes). Despite nearly three decades of intense effort, the complete mechanism by which the APOE alleles modulate AD risk and pathogenesis remains elusive. Current efforts in the Bateman lab for ApoE include the structural characterization of the various glycoforms of ApoE present in human blood, csf, and tissue lysates. In addition, we are also currently assessing the value of adding peripheral ApoE measurements to our already high-performing blood-based Aβ test.
Neurofilament light-chain (NfL), a biomarker of neurodegeneration, is elevated in the cerebrospinal fluid and blood of patients with Alzheimer’s disease (AD) and many other neurodegenerative diseases but is poorly characterized at the protein structure and isoform level. The overall goal of this project is to characterize NfL isoforms in human cerebrospinal fluid and blood using IP-mass spectrometry, quantify total and phosphorylated NfL isoforms in AD and non-AD controls, and compare concentrations and isoforms across multiple disease states.
Neurofibrilary tangles are another hallmark of AD, and made of phosphorylated and aggregated tau proteins. Unlike amyloid beta that forms amyloid plaques outside the cells, tau proteins are associated with stabilizing microtubules and primarily found inside the neurons. But recent studies show that they are secreted outside the neuron under physiological and pathological conditions in regulated manners. Tau proteins have longer half-life than amyloid beta and have multiple isoforms and post translational modifications (PTMs) including phosphorylation that may further contribute to disease. The goal of the tau projects in the lab is to understand the metabolism of tau in the human CNS that may serve as accurate and early biomarker of AD and other tauopathies. We use quantitative and sensitive mass spectrometry methods to understand turnover and phosphorylation of tau in the brain, CSF, and in plasma.
Stable isotope labeling & quantitative mass spectrometry imaging of Alzheimer’s disease pathology in human brain
Our goal is to measure, for the first time in human AD brain, the nanoscale structure and metabolism of neurons, tangles and amyloid plaques, how they are affected by AD, and how this metabolism is related to cognition, function and overall health.