Beta-Amyloid and tau accumulation in Alzheimer’s disease

Drug development for Alzheimer’s disease (AD) continues to face significant challenges, largely due to the limited availability of reliable biomarkers and the high risk of trial failure. To improve outcomes, researchers need better tools to identify patients who might benefit from treatment and to monitor how the disease progresses over time.

AD is characterised by the build-up of two key proteins: beta-amyloid (Aβ) and misfolded tau inside neurons.

The role of PET imaging

Positron Emission Tomography (PET) is a powerful imaging method that helps visualise these protein accumulations in the brain. It’s now part of the diagnostic / staging criteria for AD and used in clinical trials. PET scans can be interpreted visually by neuroradiologists or analysed quantitatively, helping researchers include participants who haven’t yet shown clinical symptoms.

Standardising PET imaging analysis

Quantitative PET analysis has become more standardized in recent years. A common method is the Standardised Uptake Value Ratio (SUVR), which compares tracer uptake in a region of interest to a reference region. However, SUVR values can vary between tracers, making comparisons tricky.

To address this, the Centiloid scale was developed. It allows amyloid PET data from different tracers (such as Flutemetamol, Florbetaben, and Florbetapir) to be mapped onto a single scale from 0 (young, healthy controls) to 100 (mild to moderate AD) (https://pubmed.ncbi.nlm.nih.gov/25443857). This makes it easier to compare results across studies.

The Centiloid scale has proven robust across scanners, tracers, and analysis methodology. The European Medicines Agency (EMA) recently endorsed it for use in clinical trials, following validation in two AMYPAD studies (Link).

Progress in Tau PET standardisation

Efforts are also underway to standardise tau PET imaging. A promising approach called ‘CenTauR’ uses brain masks to focus on specific regions, enabling data pooling across tracers like 18F-flortaucipir, 18F-MK6240, 18F-PI2620, 18F-PM-PBB3, 18F-GTP1, and 18F-RO948. This method aims to create a ‘Centiloid-like’ scale for tau imaging, which is a hot topic in current research (Link 1, Link 2).

Applications in cutting-edge studies

Recent studies are leveraging these advances in PET imaging. The Global Alzheimer’s Platform Foundation’s Bio-Hermes-001 study collected data from over 1,000 volunteers, comparing amyloid PET scans with blood-based biomarkers, digital tools, and cognitive tests. The goal was to better understand how different types of data relate to each other and to PET imaging.

The follow-up study, Bio-Hermes-002, is expanding this work by including participants with and without memory concerns and adding MRI and tau PET imaging.

A new tool: Blood tests for AD diagnosis

Amyloid PET data has also supported the development of new diagnostic tools. The FDA recently cleared the first blood test to aid in AD diagnosis: the Lumipulse G pTau217/β-Amyloid 1-42 Plasma Ratio from Fujirebio (Link). This test detects two key proteins in the blood and was validated against an amyloid measure from PET or CSF. It adds a valuable, less invasive option alongside spinal fluid tests and PET imaging — potentially speeding up diagnosis, improving trial design, and accelerating drug development.

As our understanding of Alzheimer’s deepens, so does our ability to detect and track it. With advanced imaging tools, standardised biomarkers, and now blood-based diagnostics, we’re moving closer to earlier detection, better trials, and ultimately, more effective treatments

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