Neurofibrillary tau tangles (NFTs) are a hallmark pathology of Alzheimer’s disease (AD) that forms inside neurons. Although misfolded tau is the primary pathology in a number of diseases (primary tauopathies), in Alzheimer’s disease, neocortical tau aggregates typically develop after amyloid beta pathology, and its structure and location in the brain are highly disease specific. In AD, tau pathology first emerges in the brain’s temporal lobes and then spreads in a very consistent pattern that generally correlates very well with clinical symptoms. This predictable propagation is described by Braak stages, named for the scientists who first characterized them from autopsied brains. Scientists hypothesize that the pattern of NFT appearance and accumulation may reflect propagation via connected neurons within circumscribed brain networks, which can have axons that extend from one brain region to another.
The initial development of AD tau PET brain imaging enabled scientists to confirm the close temporal relationship among Braak stages of tau pathology, neurodegeneration, and clinical symptoms. Improvements in PET imaging resolution and tracers have revealed deeper nuances in the spread of NFTs than originally captured by neuropathological Braak staging. For example, four distinct patterns of AD tau deposition (AD tau PET subtypes) have been identified by Hansson, Ossenkoppele, and colleagues (Vogel et al., 2021) in a study published in Nature Medicine. They envision that knowing or even predicting where pathological AD tau aggregates accumulate in the brain, and why they deposit in those locations, could eventually lead to better individualized treatments.
CureAlz researchers Oskar Hansson and Rik Ossenkoppele are truly at the forefront of PET imaging to study tau propagation through the Swedish BioFINDER-2 project, which they lead with Drs. Erik Stomrud, Sebastian Palmqvist, and Niklas Mattsson-Carlgren. BioFINDER-2 is among the largest AD studies worldwide, enrolling over 2,000 participants since 2017. The study features repeated MRI and PET imaging with comprehensive analyses of genetic, cognitive, CSF, and blood plasma data, collected every two years. In their last funding cycle, Hansson, Ossenkoppele, and their team used the BioFINDER-2 dataset to test their hypothesis that there are four AD tau PET subtypes. Each subtype has distinct genetic associations and changes in fluid biomarkers and brain structure and function. They found that the brain regions with the highest burden of AD tau also had the most significant loss of brain tissue (atrophy). They also found distinct patterns of brain activity (detected with functional MRI) specific to each subtype. Most APOE4 carriers aligned with one subtype, suggesting that genetic variations can indeed influence the path of AD tau progression in the brain. Finally, and crucially, they found that the different subtypes had different clinical paths and timelines, establishing the critical relevance of their findings.
Building on their important findings from their prior funding cycle, the team seeks to further characterize the molecular and genetic factors associated with distinct AD tau PET subtypes. Notably, they will extend their previous analyses to participants at earlier disease stages. They have three experimental aims. In the first aim, they will use state-of-the-art MRI techniques to determine if changes in brain microstructure or function drive AD tau deposition and spread. They predict that brain regions physically or functionally connected to regions with high tau levels will be more likely to accumulate tau over time. The second aim focuses on the deep characterization of the genetic and molecular signatures unique to each subtype. They will look for gene variants that distinguish the AD tau PET subtypes (beyond APOE4). They will also analyze and compare the levels of 3,000 proteins in cerebrospinal fluid (CSF), using proteomics, as a first step to developing biomarkers specific to each subtype. Since PET imaging is expensive and tau PET imaging is unavailable in most clinical settings, biomarkers that can be measured in CSF or blood are important for clinical translation. In the third aim, they will determine if AD tau PET subtypes emerge at early disease stages. This effort involves expanding tau PET subtyping to preclinical AD patients (who may still have low levels of tau) and creating a platform for others to use in clinical research settings. The team will take advantage of a wealth of biological and imaging data collected from BioFINDER-2, the A4 clinical trial (Anti-Amyloid Treatment in Asymptomatic Alzheimer’s with an early anti-amyloid immunotherapy, i.e., solanezumab), and other cohorts.
