Longitudinal multicenter head-to-head harmonization of tau PET tracers
Principal Investigator: Tharick Pascoal
Funding agency: National Institute on Aging
Period: July 2021 – June 2026
Tau PET imaging is an important tool to study aging and Alzheimer’s disease in research and to test the impact of therapeutics in clinical trials. However, different tau PET tracers have different affinities for tau aggregates and off-target signal profiles, making it difficult to compare results across studies using distinct tau tracers. In this study, we will compare cross-sectional and longitudinal tau measures obtained with the two most widely used tau PET tracers, [18F]Flortaucipir and [18F]MK6240, head-to-head in the same volunteers to elucidate the advantages and caveats of their use in research cohorts, clinical trials, and clinical practice.
Head-to-head comparisons of high-performance plasma phospho-tau epitopes for the detection of Alzheimer’s disease
Principal Investigator: Tharick Pascoal
Funding agency: National Institute on Aging
Period: March 2022 – February 2027
Three plasma phosphorylated tau epitopes (p-tau231, p-tau181, p-tau217) have recently emerged as important tools to study Alzheimer’s disease (AD) pathophysiology. However, the difference in performance between these epitopes to identify the AD continuum is poorly understood, making it difficult for the field to choose the plasma p-tau epitope or combination of epitopes that will advance for widespread use in clinical trials and practice. We will measure the p-tau231, p-tau181, p-tau217 assays in longitudinally collected plasma samples, with associated positron emission tomography tau and amyloid-beta, from individuals across the AD spectrum to elucidate the performance of each p-tau epitope to use in research and clinical settings.
High-performance plasma phosphor-tau predicts dementia, tau and amyloid PET (AACSF)
Principal Investigator: Tharick Pascoal
Funding agency: Alzheimer’s Association
Period: July 2020 – June 2023
In this project, we will test whether a newly developed blood test can provide the first rapid, cost-effective, and scalable diagnostic test for Alzheimer’s disease (AD). Currently, the diagnosis of AD is based primarily on the clinical examination of the patient, which is only about 70% accurate. Thus, assessing the presence of AD pathology in patients using a simple blood test can completely change the landscape of AD research and patient care, allowing accurate and cost-effective diagnosis of AD. The preliminary results presented here suggest an unprecedented advance for diagnosing AD with more than 90% accuracy using a blood test, bypassing the need for any complementary testing. The present research proposal seeks to extend these preliminary results in a large human population of AD patients and controls, aiming to validate this new blood test for use in clinical practice.
Glial signatures of tau propagation in Alzheimer’s disease (AARF-D)
Principal Investigator: Bruna Bellaver
Funding agency: Alzheimer’s Association
Period: October 2022 – October 2026
The trigger for tau propagation is commonly attributed to amyloid-β (Aβ). However, the low concentration of Aβ in the mesial temporal regions and the existence of individuals tau-positive but Aβ-negative suggests Aβ-independent tau spreading pathways. The neurocentric focus of dementia research has delayed understanding the complex roles of other cell types in AD pathology, such as the glial cells. We hypothesize that glial cells are directly involved in Aβ-independent tau spreading and that measuring proteins released from these cells would allow identifying tau spreading patterns throughout the brain. The goal of this study is to identify glial cell signatures associated with amyloid-β (A)-dependent and A-independent tau propagation in AD.
Racial and ethnic effects on plasma p-tau epitopes across AD spectrum (AARF-D)
Principal Investigator: Pamela Lukasewicz Ferreira
Funding agency: Alzheimer’s Association
Period: June 2022 – August 2026
Blood-based methods measuring phosphorylated tau epitopes (p-tau) are currently the most promising blood-based biomarkers for Alzheimer’s disease (AD)-related tau pathology. However, several lines of evidence suggest that the measures obtained with different plasma p-tau epitopes may not be equivalent and may vary greatly depending on the disease stage. In addition, the generalizability of findings investigating plasma p-tau biomarkers may be limited since the analyzes were performed almost exclusively in Caucasian cohorts. Therefore, there is an urgent need to better characterize the p-tau biomarkers in people from different races and ethnic groups. This project aims to test the effects of race and ethnic groups in the cross-sectional and longitudinal concentrations of these plasma p-tau epitopes in different cohorts.
A deep learning tool to generalize Tau PET to predict AD progression
Principal Investigator: Guilherme Bauer Negrini
Funding agency: Alzheimer’s Association
Period: September 2023 – August 2026
This study aims to develop a user-friendly tool for predicting Alzheimer’s disease (AD) progression using 3D tau positron emission tomography (PET) images, irrespective of tau tracers. We have three primary objectives: train Deep Learning models on large-scale datasets of Flortaucipir and MK-6240 tau PET tracers to predict clinical progression; enhance model performance with transfer learning on head-to-head acquired tau PET scans; and generalize to other tau tracers. By leveraging datasets with longitudinal data, including Flortaucipir and MK-6240 tau PET imaging, clinical, cognitive, and complementary fluid biomarker data, we intend to build robust models for AD prediction.
Harmonization of tau PET tracers to a common scale using head-to-head data
Principal Investigator: Guilherme Povala
Funding agency: Alzheimer’s Association
Period: July 2024 – June 2027
Alzheimer’s disease is associated with the abnormal presence of proteins in the brain. One of these proteins is tau, which its abnormal deposition leads to brain cell death. Hence, measuring tau protein in the brain is key to the study of Alzheimer’s disease. It is possible to know the location of tau protein accumulation in the brain using an imaging exam. This is accomplished by injecting very small doses of a radioactive compound into the blood of patients. This compound binds to these abnormal tau proteins and makes them visible on brain images. To date, two types of tau radioactive markers are widely available in research. However, researchers and physicians find it difficult to compare these markers because their results are slightly different, limiting their utility. Therefore, creating a common scale to convert and harmonize these two markers is necessary, making them more similar. This will allow a patient in a clinical setting to perform exams with different markers and compare them. This will enable us to compare clinical trial results testing drug effects on reducing tau pathology that use these compounds. To achieve this, we aim to develop a tool that uses artificial intelligence to harmonize tau images obtained with different radioactive markers. In artificial intelligence, computers learn from data to get the most accurate results. By harmonizing the different images, we can facilitate their future use in research, clinical trials, and practice.
Astrocyte Biomarkers in Alzheimer’s Disease: Bridging Plasma and Brain
Principal Investigator: Andreia Silva da Rocha
Funding agency: Alzheimer’s Association
Period: October 2024 – September 2027
Alzheimer’s disease is a complex brain disorder that presents abnormalities in various brain cell types, including neurons, microglia, and astrocytes. Astrocytes are star-shaped brain cells that play an important role in supporting brain normal function. When the brain is not working as it should, astrocytes typically respond by altering their structure and protein content. Studies have suggested that the blood levels of certain proteins present in these cells (GFAP, S100B, and YKL-40) can be used for supporting the diagnosis of Alzheimer’s Disease. The idea behind this is that in Alzheimer’s Disease, the levels of these proteins change within astrocytes and can then leak from the brain into the bloodstream, therefore, their levels in blood directly correspond to changes in brain astrocytes. However, this correlation is not as straightforward as it seems. These proteins can be found in other cells in the brain and throughout the body, and there are various biological factors that can influence how they make their way from astrocytes in the brain into the bloodstream. Therefore, in this study we will investigate whether blood levels of astrocyte-related proteins are actually a good measure of astrocyte reactivity in the brain. We have blood samples collected from Alzheimer’s Disease patients before they passed away. In these samples, we will measure the levels of GFAP, S100B, and YKL-40 and then compare them to their levels in brain samples from the same patients, collected after their passing. This will help us see if these blood tests are a good way to track Alzheimer’s-related astrocyte changes in the brain. These findings could have crucial implications for the diagnosis and treatment of Alzheimer’s, as well as provide valuable insights into the role of astrocytes in this disease.
The role of astrocyte reactivity in Aβ negative individuals
Principal Investigator: Pampa Saha
Funding agency: Alzheimer’s Association
Period: April 2025 – March 2028
Role of astrocytes in early Alzheimer’s disease progression Astrocytes are the most abundant non neuronal cell types in brain that provide vital nutrients, mechanical supports to neurons for their proper functioning. In AD, nerve cells die due to abnormal aggregation of toxic proteins called amyloid beta and phosphorylated tau. Astrocytes also respond in a different manner, and they get reactivated in exposure to amyloid beta and tau toxic protein aggregates. These proteins can cross the blood brain barrier and be available in the blood and therefore can be served as AD biomarker. A great deal of research has already been done on identifying AD specific biomarkers and in this regard, amyloid beta proteins, phosphorylated tau proteins have been found to be elevated in individuals having amyloid beta senile plaques. AD is a very slow and progressive disease, the pathology starts inside the brain 10-15 years prior to the onsets of prominent symptoms. So, it is very important to understand the early sequence of events at very early stages of disease progression. In this context, we hypothesize that astrocytes play critical roles in the early disease stages as they are the early sensors of any abnormal situation inside the brain. And therefore, astrocyte derived secreted factors can be of high importance as AD early biomarker. In the present study, we are proposing that astrocyte derived biomarker, GFAP might have high predictive efficacy for AD specific early biomarkers such as phosphorylated tau, neurodegeneration etc. in individuals who have not developed amyloid beta senile plaque yet. We will perform cross sectional and time dependent studies in 7 different cohorts across continents. This will give us vital information about early AD biomarkers, and it will help move the field forward in advancing the specific diagnosis, prognosis, treatment and designing the preclinical trials.
Role of cholesterol metabolism to microglia reactivity and tau spreading
Principal Investigator: Matheus Rodrigues
Funding agency: Alzheimer’s Association
Period: September 2024 – August 2028
Alzheimer’s disease (AD) is associated with the deposition of two proteins in the brain: amyloid-beta and tau. The way these proteins propagate in the brains of AD patients is heterogeneous impacting disease symptoms. Many risk factors have been proposed to explain such differences, including the impact of cholesterol metabolism on AD pathology. However, scientists still don’t know exactly how these events are connected. Cholesterol synthesis and metabolism in the brain are mainly regulated by a group of cells called glial cells (i.e. microglia and astrocytes). Microglia are constantly moving throughout the brain, actively seeking, and addressing challenges to brain homeostasis, including abnormal cholesterol metabolism. Thus, we aim to study the role of changes in cholesterol metabolism to microglia reactivity in the postmortem brain of individuals with distinct patterns of disease progression to identify whether abnormalities in these cells are related to AD heterogeneity. Additionally, we also want to test if proteins possibly released from microglia in response to abnormal cholesterol metabolism will be found in patient’s cerebrospinal fluid. Therefore, identifying specific microglia abnormalities across the different disease stages can provide the blueprint for developing novel personalized therapeutic approaches aiming to mitigate AD progression.