| Alzheimer’s clinical trials increasingly require imaging biomarkers that go beyond simply confirming a diagnosis. As drug development becomes more targeted and Alzheimer’s is understood as a biologically complex disease, the right combination of MRI and PET biomarkers can help select and stratify participants, measure different aspects of disease biology, monitor progression and assess treatment effects. This blog explores eight key imaging approaches: 1) structural MRI volumetrics, 2) cerebrovascular imaging, 3) diffusion microstructure imaging, 4) MR spectroscopy (MRS), 5) arterial spin labelling (ASL) perfusion imaging, 6) amyloid PET, 7) tau PET and 8) FDG PET. The key premise is that there is no one-size-fits-all approach: the optimal biomarker strategy should be tailored to the therapy’s mechanism of action, trial phase, target population and the decisions the data need to support. |
We're in the midst of a neuroscience renaissance. The precision medicine approach that has transformed oncology over the past two decades is now beginning to reshape how neurodegenerative diseases are understood, diagnosed and treated. This shift is especially important in Alzheimer’s disease (AD), which accounts for an estimated 60-70% of dementia cases worldwide. With more than 57 million people living with dementia globally, and around 32 million living with AD dementia, there is a clear need for more precise tools to detect disease biology, select the right participants and measure whether new therapies are working.
Despite these challenging figures, advances in diagnostics and drug development offer a more hopeful picture. A key driver is the growing recognition that AD is biologically heterogeneous. Researchers are increasingly unpicking the complex, interconnected mechanisms that contribute to disease pathogenesis, including amyloid-β plaque accumulation, tau-mediated neurofibrillary tangles, synaptic dysfunction, neuroinflammation and mitochondrial impairment. Understanding this complexity is essential for developing targeted therapies and for selecting biomarkers that can measure the right aspect of disease biology in the right trial population.
This more nuanced understanding of AD biology is also reflected in the clinical pipeline. While amyloid-targeted agents remain an important part of development, they represent only one area of therapeutic focus. Inflammation and immune dysfunction, tau pathology and other mechanisms each account for meaningful portions of the current pipeline. In total, at least 17 aspects of Alzheimer’s impact on the brain are being targeted by one or more drugs in clinical trials.
There has also been progress in diagnostics, with four FDA-approved blood-based biomarker tests now available to help diagnose Alzheimer’s disease in people showing signs of cognitive impairment. IXICO was proud to contribute to one of these advances: Fujirebio’s Lumipulse® G pTau 217/β-Amyloid 1-42 Plasma Ratio in-vitro diagnostic (IVD) test.
As neuroscience moves towards more precise diagnosis and targeted treatment, clinical trials need reliable ways to measure what is happening in the brain non-invasively. Imaging biomarkers can help validate emerging biological signals, support exploration of treatment effects on underlying disease mechanisms, and provide robust, regulatory-ready measures for large-scale studies. IXICO’s advanced imaging analytics are designed to help sponsors generate precise, reproducible answers across the biomarker strategy. Below are eight key imaging biomarkers that may be relevant to consider in Alzheimer’s disease clinical development.
1. Structural MRI Volumetric Biomarkers
Structural MRI volumetric biomarkers quantify the size of specific brain regions and how those regions change over time. In AD trials, these measures can provide sensitive and reproducible indicators of neurodegeneration, including regional atrophy patterns that are relevant to disease progression. They can support longitudinal monitoring, contribute to regulatory endpoints and help enrich or stratify participants according to baseline neurodegeneration burden.
In practical terms, structural MRI can act as both a monitoring and prognostic biomarker. It can track neurodegeneration and atrophy progression over time, while baseline volumetric measures can help identify participants with different levels of neurodegeneration burden.
The most appropriate structural MRI measures will depend on the trial design and therapeutic mechanism of action. However, several approaches are commonly valuable in AD clinical development, particularly where sponsors need to quantify regional atrophy, whole-brain change or ventricular enlargement over time.
2. Cerebrovascular Imaging Biomarkers
Cerebrovascular disease (CVD) is detected in a substantial proportion of clinically diagnosed Alzheimer’s disease cases, with estimates ranging from 55-80%, and vascular pathology can independently contribute to cognitive decline. In AD trials, cerebrovascular imaging biomarkers can be used to assess white matter lesions, cerebral microbleeds and other vascular findings on appropriate MRI sequences. Characterising vascular burden may provide useful context for understanding disease progression, interpreting treatment effects, and evaluating potential safety considerations. Incorporating these measures into the imaging strategy may be valuable, particularly in trials investigating vascular contributions to Alzheimer’s disease or therapies targeting multiple disease mechanisms.
3. Diffusion Microstructure Biomarkers
Diffusion MRI is an advanced imaging technique that measures how water molecules move through brain tissue. Because water movement is influenced by tissue structure, diffusion measures can provide insight into white matter microstructure and connectivity. In AD trials, regional diffusion metrics such as free-water imaging, DTI-ALPS, PSMD and structural connectivity may help evaluate vulnerable tracts including the cingulum, fornix, corpus callosum, uncinate fasciculus and posterior thalamic radiations. These measures can support monitoring of AD-relevant microstructural change.
Free-water imaging may provide an indirect exploratory signal of neuroinflammation, particularly in studies of therapies designed to reduce inflammatory processes. DTI-ALPS measures water movement along perivascular spaces and is being explored as a proxy for glymphatic function in AD research, which may be relevant for therapies targeting clearance mechanisms.
4. MR Spectroscopy Biomarkers (MRS)
MR spectroscopy (MRS) is an advanced, non-invasive MRI technique that analyses metabolic signals from a defined three-dimensional volume of tissue, known as a voxel. By measuring chemical and metabolite concentrations such as NAA, myo-inositol, choline, glutamate/Glx and related ratios, MRS provides biopsy-free biochemical insight into tissue integrity and disease processes in AD. It may be particularly valuable in early-phase studies targeting mitochondrial function or other metabolic pathways.
5. Perfusion Biomarkers (ASL)
Arterial spin labelling (ASL) is a non-invasive MRI technique that measures cerebral blood flow by magnetically tagging water protons in arterial blood as an endogenous tracer. ASL-derived biomarkers can quantify regional cerebral blood flow changes linked to neurodegeneration, vascular disease and metabolic dysfunction. This makes ASL particularly relevant for assessing therapies that may influence vascular or metabolic function.
6. Amyloid PET Imaging
Amyloid PET is a molecular imaging biomarker that visualises and quantifies β-amyloid plaque deposition in the brain, one of the hallmark pathologies of Alzheimer’s disease. It plays a critical role in confirming amyloid status, supporting participant selection and monitoring disease progression or target engagement in anti-amyloid therapeutic studies. Quantitative approaches such as SUVR and the Centiloid scale enable standardised assessment across tracers and studies. In clinical trials, amyloid PET can help reduce biological uncertainty, confirm eligibility based on amyloid-positivity, enrich study populations with varying level of amyloid burden, and provide an objective measure of treatment effects on amyloid pathology.
7.Tau PET Imaging
Tau PET is a molecular imaging biomarker that measures the distribution and burden of aggregated tau protein, which accumulates as neurofibrillary tangles in Alzheimer’s disease. Unlike amyloid pathology, tau burden correlates more closely with disease stage and clinical symptoms, making it particularly valuable for characterising disease severity and progression. In clinical trials, tau PET can support participant stratification, disease staging and longitudinal monitoring, while helping identify participants who may be more likely to demonstrate a measurable treatment response. It also provides an important exploratory endpoint for therapies targeting tau pathology directly.
8. FDG PET
FDG PET measures regional cerebral glucose metabolism, providing an indirect assessment of neuronal and synaptic function. Areas of reduced FDG uptake can reflect neurodegeneration and functional impairment associated with Alzheimer’s disease. A key benefit is its ability to detect metabolic changes that may occur before substantial structural atrophy is visible on MRI, offering insight into disease activity and progression. In clinical trials, FDG PET can be used to monitor neurodegenerative change, assess pharmacodynamic effects of novel therapies and provide complementary information alongside amyloid and tau biomarkers to build a more complete picture of disease biology and treatment impact.
Choosing the right combination for your AD trial
Choosing the right biomarker strategy depends on the biology being targeted, the trial phase, the participant population and the decisions the sponsor needs the data to support. For example, a disease-modifying therapy may require biomarkers that confirm underlying pathology, enrich for participants most likely to show progression, and monitor treatment effects over time. A therapy targeting vascular, inflammatory or metabolic mechanisms may benefit from a different combination of MRI and PET measures to provide a more complete view of disease biology and treatment impact.
Our neuroscience and biomarker specialists work consultatively with sponsors to understand trial aims, identify the key scientific and operational risks, and design an imaging and analytics pathway that supports more confident decision-making across treatment or diagnostic development.
Frequently Asked Questions
What do PET scans show in Alzheimer’s disease clinical trials?
PET scans reveal different aspects of Alzheimer’s disease biology depending on the tracer used. Amyloid PET visualises and quantifies β-amyloid plaque deposition, one of the hallmark pathologies of the disease. Tau PET measures the distribution and burden of aggregated tau protein, which correlates closely with disease stage and clinical symptoms. FDG PET measures regional cerebral glucose metabolism, offering an indirect assessment of neuronal and synaptic function. Together, these PET-based imaging biomarkers in clinical trials help sponsors confirm diagnosis, stratify participants and track treatment effects.
What is an amyloid PET scan?
An amyloid PET scan is a molecular imaging technique that visualises and quantifies β-amyloid plaque deposition in the brain, one of the hallmark pathologies of Alzheimer’s disease. It helps confirm amyloid status, support participant selection and monitor disease progression or treatment effects in anti-amyloid clinical trials.
Contact our team to discuss how the right imaging biomarker strategy could support your Alzheimer’s disease trial.
