Clinical Potential of Quantitative Susceptibility Mapping MRI to Predict Cognitive Decline

Research has shown that iron overload can drive neurodegeneration by inducing oxidative stress, exacerbating amyloid toxicity, disrupting tau protein function, and promoting neuronal cell death. A recently published prospective study, conducted between January 2015 and November 2022, evaluated how brain iron and amyloid-ß (Aß) levels, measured using quantitative susceptibility mapping (QSM) MRI and PET, help predict mild cognitive impairment (MCI) onset and cognitive decline in participants without cognitive impairment (n = 158).

Led by Xu Li, PhD, a research associate in the F.M. Kirby Research Center for Functional Brain Imaging at Kennedy Krieger Institute, higher baseline entorhinal cortex magnetic susceptibility at MRI was associated with increased risk for onset of mild cognitive impairment both overall (hazard ratio, 2.00; P = .005) and in the PET subgroup (hazard ratio, 3.59; P < .001). In addition, higher baseline entorhinal cortex (β = −0.022; P = .008) and putamen (β = −0.018; P = .04) susceptibility in the PET subgroup was associated with greater global cognitive decline, especially with amyloid pathologic abnormalities.

Following the publication, NeurologyLive caught up with Li to gain extra commentary on the significance of these findings, and the potential of using QSM MRI going forward. Within the discussion, Li gave clinical insights on the role of brain iron levels in cognitive decline, particularly in individuals with amyloid pathology. He also highlighted the need for more targeted research in brain regions sensitive to iron changes, deeper exploration of iron’s interaction with amyloid and tau, and collaborative efforts to standardized QSM for braoder clinical use.

NeurologyLive: What were the motivations and origins for this study?

Xu Li, PhD:We were motivated by the need for earlier and more practical biomarkers of Alzheimer disease. While amyloid-β and tau are well-established markers, they are typically detected by PET scans, which are costly and involve radiation. MRI, by contrast, is widely available and safe, but traditional measures like brain atrophy only capture late-stage neurodegenerative changes. In addition, therapies targeting amyloid have shown only modest effects, highlighting the importance of other co-pathologies. As increasing evidence suggests that abnormal brain iron may play an important role in Alzheimer-related neurodegeneration, we wanted to test whether QSM — an MRI method that can precisely measure brain iron — could serve as an earlier, noninvasive marker of dementia risk, even years before mild cognitive impairment develops.

Among the findings, what were the greatest clinical takeaways?

The key takeaway is that higher brain iron levels in memory-related regions, such as the entorhinal cortex, predict who is more likely to develop mild cognitive impairment (MCI), the transitional stage to dementia. In addition, higher brain iron is also linked to faster overall cognitive decline over time, especially in individuals with amyloid pathology.

Clinically, this reinforces the important role of brain iron in Alzheimer-related neurodegeneration and suggests that QSM could complement PET imaging by offering a safe, MRI-based biomarker for early risk assessment. It also raises the possibility that brain iron itself could be a therapeutic target, though much more work is needed in this area.

Should there be more dedicated research to the entorhinal cortex and putamen? If so, how can we target this in the proper way?

Yes. The entorhinal cortex is one of the earliest sites of Alzheimer pathology, and the putamen appears sensitive to iron-related changes. Our findings highlight the need for more targeted research in these regions, ideally combining QSM with other Alzheimer biomarkers such as amyloid and tau. Longitudinal studies will be essential, as will further technical advances. For example, some groups are already developing higher-resolution QSM for regions like the hippocampus and entorhinal cortex, which could provide more sensitive measures and deeper insights into the pathological changes occurring during Alzheimer disease.

How has the conversation around brain iron and its relationship with neurodegeneration evolved over the years? What questions do we still have left to be answered

Interest in brain iron dates back to the 1950s, when researchers showed that brain iron accumulates naturally with age. Later, elevated iron was found in many neurodegenerative diseases, including Alzheimer. It is known that impaired brain iron homeostasis, particularly iron overload, can lead to oxidative stress, cell damage, and iron-related cell death. What has changed more recently is our ability to measure iron precisely in vivo with techniques such as QSM MRI. Also, emerging evidence shows that iron may interact with amyloid and tau to accelerate neurodegeneration through complex mechanisms.

Major questions remain — especially whether iron is a causal driver of disease or a byproduct of other processes. How exactly iron interacts with amyloid and tau, and whether there are effective treatments that can modify these risks and slow cognitive decline, are still not clear.

Should brain iron be something that is more closely monitored? If so, is this feasible/possible from a societal perspective

Yes, brain iron should be monitored more closely, particularly in at-risk populations. The advantage of QSM is that it can be easily added to a standard MRI exam, making it far more scalable than PET. The current challenge is to standardize the technique across scanners and sites and to make it widely available. Collaborative efforts are already underway to move this forward. With further refinement, monitoring brain iron with QSM could become both feasible and clinically valuable at the population level.