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 Broad Institute has made a groundbreaking discovery in treating Huntington’s disease and Friedreich’s ataxia by developing a novel approach to edit the genetic sequences responsible for these conditions. These severe neurological disorders are caused by repeated three-letter stretches of DNA that grow uncontrollably, leading to brain cell death or nerve fiber breakdown. The researchers have successfully disrupted this repeat sequence using base editing, a technique that introduces single-letter changes into the middle of the repeated stretch of DNA.

The study, published in Nature Genetics, was led by David Liu, the Richard Merkin Professor and director of the Merkin Institute of Transformative Technologies in Healthcare at the Broad. The research team included postdoctoral researcher Mandana Arbab, graduate student Zaneta Matuszek, and associate scientist Ricardo Mouro Pinto.

The breakthrough comes from the realization that some individuals with the same disease can inherit different numbers of DNA repeats, with more repeats generally leading to faster symptom progression. However, patients who have naturally occurring single-letter interruptions within these repeats often experience milder symptoms and are less likely to pass their disease along to their children. This observation inspired the researchers to develop a gene-editing therapy that could install an interruption mimicking those that occur naturally.

Using base editing, developed by Liu’s lab in 2016 for making single-letter changes in DNA, the team introduced interruptions into the repeat sequences of patient cells and mouse models of Huntington’s disease and Friedreich’s ataxia. The results showed that the edited DNA tracts stayed the same or even became shorter over time.

The researchers caution that more work is needed to catalog potential side effects of installing these edits in the genome, but the approach could be a valuable tool for understanding diseases caused by repeated three-letter sequences. “A lot more studies would be needed before we can know if disrupting these repeats with a base editor could be a viable therapeutic strategy to treat patients,” said Liu.

The team’s findings suggest that this gene-editing therapy could help treat Huntington’s, Friedreich’s ataxia, and other trinucleotide repeat disorders. “Not only does this study show for the first time that inducing interruptions has a profound stabilizing effect on repeats, but that the base-editing approach we’ve used can also be applied to study any of over a dozen repeat disorders,” said Arbab.

The research was supported by various organizations, including the Chan Zuckerberg Initiative, Lodish Family Foundation, National Institutes of Health, and Howard Hughes Medical Institute. The team is now developing a different approach using prime editing to replace disease-causing repeat tracts with a shorter, stable number of repeats all at once.

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.”