Author: Subir Sarkar, Emeritus Professor, Department of Physics, University of Oxford

 

According to our best understanding, the universe is expanding – and is doing so at an accelerating rate. This is believed to be caused by something called the “cosmological constant”, which was first proposed by Albert Einstein in his theory of general relativity. In recent decades, it has become better known as dark energy, which is believed to make up about 70% of the universe.

Crucial to this realisation were studies of Type Ia supernovae – exploding white dwarf stars. These are thought to emit a specific amount of light, which allows astronomers to determine their distances very accurately and thereby track the expansion of the universe. This work was awarded the 2011 Nobel prize in physics.

The accelerating expansion of the universe is thought to be due to negative pressure, an unusual property of dark energy that allows it to overcome the attractive force of gravity. Yet the exact nature of dark energy remains a puzzle. It cannot be explained by our best theory for the fundamental building blocks of the universe – known as the standard model of particle physics.

However, it is an integral part of another theory, devised to explain how the large-scale universe came to be. This is the standard model of cosmology, also called the lambda cold dark matter (ΛCDM) model.

Other observational evidence supporting the existence of dark energy includes fluctuations in the temperature of the cosmic microwave background (CMB) – the “afterglow of the Big Bang” – and the imprint of baryon acoustic oscillations (BAO) – sound waves from the early universe – in the distribution of galaxies.

But the ΛCDM model has come under increasing scrutiny as new data has emerged. A conference hosted by the UK’s Royal Society debated emerging cracks in the standard cosmological model. It has been noted that the model’s past successes may partly be due to “confirmation bias” – the unconscious tendency to favour information that supports our existing beliefs while giving less attention to information that challenges them.

Flawed framework?

Most cosmologists remain unconvinced by such criticism and are instead persuaded by the multiple lines of evidence that the universe’s expansion is accelerating.

However, all such analyses, for example of the CMB or BAO, are conducted using a special solution of Einstein’s equations called the FLRW (Friedmann-Lemaitre-Robertson-Walker) framework. This is a description of space-time that assumes the “cosmological principle”, namely that the universe is, on average, homogeneous and isotropic (looks the same in all directions).

However, our recent study found evidence to falsify the FLRW framework, presenting results showing that the universe is asymmetric, or lopsided. We believe this presents a fundamental challenge to dark energy by undermining the very basis for standard analyses of cosmological data.

The observation that the universe may be lopsided is known as the cosmic dipole anomaly. This anomaly cannot be fixed by tweaking parameters in the ΛCDM model. It requires starting again from scratch to build a model of the universe based on observations, rather than on a philosophical principle.

The Nobel prize winning astrophysicist Jim Peebles has said that the cosmic dipole anomaly is about as well established as another cosmological irregularity known as the Hubble tension. However, he notes, the cosmic dipole anomaly has received only a fraction of the interest heaped on the Hubble tension.

With my collaborators, Mohamed Rameez and his PhD student Animesh Sah at the Tata Institute of Fundamental Research, Mumbai, we have also shown that the acceleration of the expansion of the universe inferred from Type Ia supernovae is not the same in all directions.

The signal from supernovae is mainly aligned with a temperature difference in the afterglow of the Big Bang – the cosmic microwave background. This temperature difference, called the CMB dipole anisotropy, is believed to be due to the local motion of the solar system.

‘Tilted observers’

The acceleration inferred from supernovae cannot therefore be due to dark energy. Rather, it is probably an illusion, because we are “tilted observers”. This is because of Earth’s specific location in the cosmos, where our neighbouring galaxies are participating in a large-scale but localised streaming motion called the bulk flow.

The relationship between the intrinsic brightness of Type Ia supernovae and their distance has been crucial to the idea of dark energy. However, this relationship may not be as robust as was first assumed.

Astronomers in South Korea found evidence that the ages of the white dwarf stars that produce Type Ia supernovae (their progenitors) affect their brightness. However, this has been challenged by another team.

When we corrected for the dependence of the intrinsic brightness on the progenitor age, the indication is that the universe is decelerating, rather than accelerating.

This is just as is expected for a universe without dark energy. But it will come as a surprise to most cosmologists who believe that there is compelling independent evidence for ΛCDM, in particular from studies of the CMB. But CMB temperature fluctuations are not influenced by dark energy. Rather, they are related to the spatial curvature of the universe, the baryon density, and the dark matter density.

Whether dark energy is still a valid inference thus depends on whether the distribution of matter in the universe is indeed isotropic – exactly the same in all directions. Observations suggest otherwise. If these findings are confirmed, they could signal a paradigm shift in cosmology.

 

This article is republished from The Conversation under a Creative Commons license. Read the Original article.

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Author: José R. Pineda got his Ph.D. from University of Barcelona in 2006. Since 2007 he has worked for Institut Curie and The French Alternative Energies and Atomic Energy Commission. Currently he is a researcher of the EHU. He investigates the role of stem cells in physiologic and pathologic conditions.

For decades, Alzheimer’s research has been dominated by a seemingly intuitive idea: the disease is largely explained by the accumulation of abnormal proteins in the brain, primarily beta-amyloid and tau. However, while this view has been useful, it has fallen short in explaining certain fundamental aspects. One of the most striking is that Alzheimer’s affects women far more than men. This is not a minor difference: roughly two-thirds of cases occur in women, and the clinical progression tends to be faster and more severe. The work by López-López and colleagues addresses this imbalance from a different angle. Instead of focusing exclusively on protein accumulation, it shifts attention to the brain’s immune system—specifically to a molecular pathway known as interferon signaling. What the study proposes is that the brain’s immune response, far from being a mere bystander, could be a central driver of the disease, and one that operates differently in men and women ¹.

To understand the importance of this idea, it helps to briefly consider what interferons are. They are molecules that form part of the body’s first line of defense against infections, especially viruses. They activate genetic programs that help cells detect and neutralize threats. Under normal conditions, this system is essential for survival. The problem arises when it becomes chronically or inappropriately activated, as is the case in several inflammatory diseases ². So, the study begins with an analysis of human brain tissue from Alzheimer’s patients. Using transcriptomics (techniques that measure the activity of thousands of genes at once) the authors identified a clear pattern: in the brains of women with Alzheimer’s, genes associated with the interferon response were much more strongly activated than in men (Figure 1). This pattern was not explained by differences in disease severity, since both groups showed comparable levels of neuropathological damage. Instead, it points to an intrinsic difference in how the brain responds to the disease. This finding is significant because it suggests that women not only develop Alzheimer’s more often, but may do so through a partially distinct biological pathway. In other words, the same clinical diagnosis may conceal different underlying mechanisms depending on sex.

To move beyond correlation and explore causality, the researchers turned to animal models. They used genetically modified mice (APP/PS1), widely employed in Alzheimer’s research because they develop amyloid plaques similar to those seen in patients. Once again, the same pattern emerged: female mice showed much stronger activation of the interferon pathway, along with increased brain inflammation, neuronal damage, and functional impairment. An especially interesting point is that these differences were not limited to amyloid plaque levels. Indeed, female mice did have more plaques, but the study shows that neuronal damage and inflammation cannot be explained solely by amyloid accumulation. This supports a growing idea in the field: that Alzheimer’s toxicity depends not only on protein buildup, but also on how the brain responds to it. In this context, microglia (the brain’s resident immune cells) become key players. Cell-level analyses revealed that these cells are the main drivers of interferon activation. In essence, microglia detect signals of damage or stress and launch an inflammatory response which, if sustained over time, can ultimately harm neuronal tissue. To test whether this pathway is not only associated with disease but actually contributes to it, the authors performed direct manipulation experiments acutely activating interferon signaling in healthy animals using an immune stimulus. To do that, they did intraperitoneal administration of polyinosinic:polycytidylic acid (poly(I:C)) to induce inflammation, but also they performed crossings between the APP/PS1 mice and a microglia-specific Rela conditional knockout line (AD hiIFN). The result was striking: within hours to days, the brains of these animals began to show changes resembling Alzheimer’s pathology, including altered neuronal activity, synaptic disruption, and markers of axonal damage. This results suggest that activation of this pathway is not a secondary phenomenon, but may be sufficient to induce key features of the disease. In parallel, the researchers performed the inverse experiment: they chronically enhanced interferon signaling in microglia within APP/PS1 mice (an Alzheimer’s disease model). This led to a worsening of neurodegenerative features, even though, paradoxically, amyloid plaque levels did not increase—and in some cases even decreased. This last finding is particularly revealing because it challenges a widespread assumption: that fewer plaques necessarily means a healthier brain. Here, the opposite happens!! The animals had less amyloid burden, yet more neuronal damage and worse function. This points to inflammation, and specifically interferon signaling, as an independent driver of degeneration.

Next, the key question is whether this pathway can be targeted therapeutically. To address this, the study explores a pharmacological intervention aimed at the cGAS–STING pathway (a molecular system that senses cellular damage and triggers interferon production). Using a specific inhibitor (STING inhibitor C-176), the researchers demonstrated by RNA-seq and immunohistochemistry that the treatment was able to reduce interferon signaling in the brain. The results were consistent: inflammation decreased, neuronal integrity was better preserved, and cognitive performance improved in memory tests (very important from the therapeutic and functional perspective). More importantly, these effects were far more pronounced in females, which aligns with the idea that this pathway is more active in them and therefore more impactful when blocked. Notably, these improvements occurred without significant changes in amyloid plaque levels. Once again, the conclusion is clear: modulating the immune response may be as important as, or even more important than, targeting protein aggregates. Taken together, this work proposes a shift in how Alzheimer’s is understood. Rather than viewing it solely as a disease of protein accumulation, it suggests it is also—critically—a disorder of immune dysregulation. More specifically, one in which excessive interferon signaling plays a central role, particularly in women.

The practical implications are twofold. First, it opens the door to therapies that modulate immune pathways in the brain, something already feasible in other diseases using drugs that target similar mechanisms. Second, it highlights the importance of incorporating sex as a biological variable in both research and treatment design. What works in men may not work the same way in women, and vice versa. As with any preclinical study conducted in mice we must be cautious when extrapolating to humans: results in animal models do not always translate directly, and manipulating the immune system carries inherent risks, given its essential role in protecting against infections. However, the value of this work lies not only in its potential clinical applications, but in the conceptual framework it offers.

By identifying interferon signaling as a key factor in sex-specific vulnerability to Alzheimer’s, the study provides a mechanistic explanation for a long-observed but poorly understood phenomenon. Perhaps more importantly, it suggests that intervening in this pathway could alter disease progression even without changing classical amyloid pathology. In a field where many clinical trials have failed by focusing solely on plaque removal, this perspective is not just novel, it may be necessary to explore it in the future.

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