Key Advances in Tau PET Imaging

This year, we saw an increased focus on improving tau PET imaging as a marker for disease progression and a potential surrogate outcome measure in clinical trials. In fact, a team from the McGill University Research Centre for Studies in Aging (MCSA) is exploring how quantifying the spatial extent of tauopathy (SEOT) might be more useful than the standard uptake value ratio (SUVR), particularly in early Alzheimer’s disease (AD). SEOT, which measures the percentage of brain with abnormal tau load, was shown to correlate more closely with disease severity markers like the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB), hippocampal atrophy, and cerebrospinal fluid (CSF) p-tau217 in regions with low tau burden. This suggests that SEOT captures the initial spreading phase tau pathology, which precedes the tau accumulation phase measured by the SUVR.

The CenTauR (CTR) scale was also discussed, which was developed to harmonize tau PET scans performed with different tracers, similar to the centiloid scale for amyloid. This could allow for the integration of data from multiple tracers, potentially enhancing the utility of measures like SEOT.

Blood-Based Tau Biomarkers for Staging

The conference highlighted the rapid progress in developing blood-based biomarkers for AD diagnosis and staging. While plasma p-tau217 is proving highly accurate in identifying AD pathology, scientists are working on markers that can specifically stage tauopathy.

Kanta Horie, Ph.D., from Washington University presented data on plasma eMTBR-243 tau, a fragment of the microtubule-binding region of tau. This marker appears highly specific for tau tangles and continues to rise as tangle burden increases — unlike p-tau217 and p-tau205, which plateau with tau burden. The data suggests that eMTBR-243 tau could be used in the future to stage AD tauopathy or to link tau tangles with a patient’s observed symptoms.

Henrik Zetterberg, M.D., Ph.D., from the University of Gothenburg discussed using panels of blood biomarkers for tau staging. Using the Nulisa CNS immunoassay panel, his team identified a combination of biomarkers that distinguished people with high and low tangle loads with high accuracy. This suggests that a panel approach could improve tau staging beyond what is possible with single markers. Altogether, there is a growing possibility of using a fluid marker staging system for AD, which may provide a more affordable option than brain imaging in research studies and, ultimately, in everyday clinical practice.

Tau-Directed Therapeutics

The conference also provided updates on therapeutic strategies targeting tau. Of note, Johnson & Johnson scientists described their Phase 2 trial of JNJ-64042056 (NCT06544616), an active tau vaccine designed to induce antibodies specific for phosphorylated tau. The trial will evaluate whether the vaccine prevents tangles from spreading into new brain regions, measured by the appearance of tau signal on PET scans.

This approach aligns with the understanding that preventing tau spread is a key therapeutic goal. Last year, the therapy was granted FDA Fast Track Designation for AD. Preclinical data showed that antibodies induced by the vaccine inhibited cellular uptake of tau aggregates in vitro.

α-Synuclein PET Tracers

Considerable progress was reported in the long-standing effort to develop reliable PET tracers for α-synuclein, the protein that aggregates in Parkinson’s disease (PD) and other synucleinopathies. While these tracers are not yet ideal, they represent a significant step forward in imaging α-synuclein pathology in living individuals. Highlights include:

• Merck presented data on MK-7337, a tracer that showed binding in the substantia nigra of sporadic PD patients. However, the tracer also exhibited off-target binding, leading Merck to focus on a follow-up candidate with improved properties.
• Harvard researchers showcased their candidate SY08, which bound to the brainstem of sporadic PD patients and showed a trend for uptake in the parietal cortices of PD and DLB patients, although it also had off-target binding.
• MODAG presented data on MODAG-005, a tracer specific to α-synuclein that showed expected binding patterns in a multiple system atrophy (MSA) patient and a PD patient.

TREM2 and Microglial Function

TREM2 (Triggering Receptor Expressed on Myeloid cells-2) is a protein primarily found on the surface of microglia, the brain’s primary resident immune cells. It plays a crucial role in regulating microglial function, including their activation, survival, proliferation, phagocytosis (the engulfment and removal of cellular debris), and inflammatory responses. There were multiple presentations exploring its complex role in neurodegeneration and the challenges of therapeutic targeting. Research shows that microglia near amyloid plaques, which express high levels of TREM2, may become resistant to stimulation by TREM2 agonist antibodies. This complicates therapeutic strategies aiming to boost microglial function via TREM2 agonism. Interestingly, these microglia still responded to anti-Aβ antibodies, suggesting a specific resistance to TREM2 agonism.

Updates on first-in-human trials of new TREM2 agonists from Novartis (VHB937, an antibody) and Vigil Neurosciences (VG-3927, a small molecule) were presented. These drugs target TREM2 in different ways and showed opposite effects on CSF soluble TREM2 levels in early trials. While neither raised immediate safety concerns, their clinical efficacy remains to be determined.

Artificial Intelligence in Research and Treatment

Artificial intelligence (AI) is increasingly being integrated into tauopathy research and clinical practice. The Artificial Intelligence Biomedical Research Scientist Initiative was presented, aiming to build a platform of AI tools to accelerate scientific discovery by leveraging large datasets and assisting with hypothesis generation, experimental design, and data interpretation. Prototypes like Alzassistant.org and PaperQA2 demonstrated the potential for AI-powered literature search and synthesis.