Research has discovered that men who carry a common genetic variant are twice as likely to develop dementia in their lifetime compared to women. This groundbreaking study, published in Neurology, used data from the ASPirin in Reducing Events in the Elderly (ASPREE) trial to investigate whether people with variants in the haemochromatosis (HFE) gene might be at increased risk of dementia.

One in three people carry one copy of the H63D variant, while one in 36 carry two copies. Having just one copy of this gene variant does not impact someone’s health or increase their risk of dementia. However, having two copies of the variant more than doubled the risk of dementia in men, but not women.

The researchers emphasize that the genetic variant itself cannot be changed, but the brain pathways affected by it could potentially be treated if we understood more about it. Further research is needed to investigate why this genetic variant increased the risk of dementia for males but not females.

The findings suggest that perhaps testing for the HFE gene could be offered to men more broadly, considering its routine testing in most Western countries, including Australia, when assessing people for haemochromatosis – a disorder that causes the body to absorb too much iron. The study found no direct link between iron levels in the blood and increased dementia risk in affected men.

This points to other mechanisms at play, possibly involving the increased risk of brain injury from inflammation and cell damage in the body. Understanding why men with the double H63D variant are at higher risk could pave the way for more personalized approaches to prevention and treatment.

The ASPREE trial was a groundbreaking study that created a treasure trove of healthy ageing data, which has underpinned a wealth of research studies. This collaboration between Curtin University, Monash University, The University of Melbourne, The Royal Children’s Hospital, Murdoch Children’s Research Institute, and Fiona Stanley Hospital demonstrates the importance of diverse Australian research groups working together to improve health outcomes for people around the world.

The implications of this study are significant, considering that more than 400,000 Australians are currently living with dementia, with around a third of those being men. This discovery could lead to improved outcomes for people at risk of developing dementia and ultimately contribute to a better understanding of these progressive diseases.

The APOE gene is a major genetic risk factor for Alzheimer’s disease, with three different versions: APOE2, APOE3, and APOE4. While APOE4 increases the risk of developing Alzheimer’s, APOE2 is associated with a lower risk. However, how these isoforms lead to strikingly different risk profiles is poorly understood.

A recent study published in Nature Communications offers clues into how APOE isoforms differentially affect human microglia function in Alzheimer’s disease. The study, led by Dr. Sarah Marzi and Dr. Kitty Murphy at the UK Dementia Research Institute at King’s College London and the Department of Basic and Clinical Neuroscience, underscores the need for new targeted interventions based on APOE genotypes.

The researchers developed a human “xenotransplantation model,” where human microglia were grown from stem cells, manipulated to express different APOE versions, then transplanted into the brains of mice that had developed a buildup of amyloid plaques. The microglia were then isolated and analyzed for their gene expression (using transcriptomics) and chromatin accessibility.

The study uncovered widespread changes to the transcriptomic and chromatin landscape of microglia, dependent on the APOE isoform expressed. The largest differences were observed when comparing the APOE2 and APOE4 microglia.

In APOE4 microglia, researchers saw an increase in the production of cytokines, signaling molecules involved in immune regulation. They also observed diminished capacity for the microglia to migrate and shift into protective states. Furthermore, the microglia became less effective in phagocytosis, a process by which they digest and clear up particles such as debris and pathogens.

Conversely, APOE2 microglia showed increased expression of various genes that increase microglia proliferation and migration, and a decreased inflammatory immune response. Additionally, APOE2 microglia showed increased DNA-binding of the vitamin D receptor. Low levels of vitamin D have been associated with a higher incidence of Alzheimer’s.

The study highlights that microglia responses to amyloid pathology differ significantly across APOE versions. This finding underscores that considering the interplay between genetic risk factors and microglial states is critical in disease progression. The study also highlights the potential role of the vitamin D receptor, providing new avenues for therapeutic exploration.

Dr. Sarah Marzi, Senior Lecturer in Neuroscience at King’s College London and lead author of the study, said: “Our findings emphasize that there is a complex interplay between genetic, epigenetic, and environmental factors that influence microglial responses in Alzheimer’s disease. We found remarkable differences when comparing microglia expressing different isoforms of the same gene. Our research suggests that microglia expressing the risk-increasing APOE4 variant are not as effective at mounting protective microglial functions, including cell migration, phagocytosis and anti-inflammatory signaling. This underscores the need for targeted interventions based on APOE genotype.”

A groundbreaking study from the University of Nottingham has successfully proven that multiple sclerosis (MS) can be diagnosed using an MRI scan, eliminating the need for a painful spinal tap. The research, published in Neurology Open Access, demonstrated that by utilizing a new MRI scan technique, experts could accurately diagnose MS in just 8 minutes.

The study’s lead author, Professor Nikos Evangelou, Clinical Professor of Neurology at the University of Nottingham, expressed his excitement about the findings, stating, “More than half of all people diagnosed with MS in the UK have had at least one lumbar puncture, following the suspicion of MS diagnosis. The findings of our research are particularly exciting as we have now shown that we can give the diagnosis of MS without this painful procedure.”

The team used a clinical MRI scanner to carry out a special type of scan called a T2*-weighted MRI, which is able to reveal lesions in the brain’s white matter that are centered on a vein – a known indicator of MS. For a conclusive diagnosis of MS, the researchers developed the ‘rule of six,’ whereby if there were six lesions found with a central vein, this confirmed a diagnosis of MS without having to analyze all lesions.

The team conducted a prospective study in Nottingham, Cardiff, and London with patients who had a suspected but not definite diagnosis of MS. Each patient was given an 8-minute MRI scan and a lumbar puncture, and after 18 months, they were able to find out what the diagnosis was and whether it matched that of their initial scan.

The results show that the use of the T2*-weighted MRI along with the ‘rule of six’ supported the diagnosis of MS as an alternative to a lumbar puncture. As a result of this study and previous research conducted in Nottingham and in the USA, the International Committee for the Diagnosis of MS recently announced that the MRI scan, as first proposed by the Nottingham research team, is enough to diagnose MS. A lumbar puncture is no longer needed.

This breakthrough has huge benefits for patients, as it makes diagnosis safer, faster, and more cost-effective. It also means significant savings for the NHS, which can be reinvested in better services for MS patients. Professor Evangelou estimates that this change could save the NHS up to five million pounds each year, which can be used to improve care for those affected by MS.

In conclusion, this study demonstrates the potential of MRI scans to revolutionize the diagnosis and treatment of multiple sclerosis, making it safer, faster, and more cost-effective. The elimination of painful procedures such as lumbar punctures is a significant step forward in improving patient care and outcomes.