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20 February 2026 - 06:01 PM
Levetiracetam Reduces Amyloid-β Production in the Brain 20 February 2026 - 11:22 AM
The failure of anti-amyloid-β immunotherapies to more than slightly slow the progression of Alzheimer's disease has not much dented the amyloid cascade hypothesis, just clarified that amyloid-β becomes unimportant to disease progression once at the stage of sizable tau aggregration, neuroinflammation, and loss of cognitive function. The consensus continues to be that amyloid aggregation is the originating cause of Alzheimer's disease, the pathology that sets the stage for what comes later. That hypothesis will be confirmed or disproven in the years ahead as anti-amyloid-β immunotherapies are deployed in ever earlier stages of the condition. There may be other approaches to obtaining useful data, however. Here, researchers note that an existing drug, levetiracetam, reduces amyloid-β production in the brain, which will in turn reduce misfolding and aggregation of amyloid-β. This suggests the potential for a trial to directly assess its ability to delay or prevent Alzheimer's disease.
Amyloid-β (Aβ) peptides are a defining feature of Alzheimer's disease (AD). These peptides are produced by the proteolytic processing of the amyloid precursor protein (APP), which can occur through the synaptic vesicle (SV) cycle. However, how amyloidogenic APP processing alters SV composition and presynaptic function is poorly understood. Using App knock-in mouse models of amyloid pathology, we found that proteins with impaired degradation accumulate at presynaptic sites together with Aβ42 in the SV lumen.
Levetiracetam (Lev) is a US Food and Drug Administration-approved antiepileptic that targets SVs and has shown therapeutic potential to reduce AD phenotypes through an undefined mechanism. We found that Lev lowers Aβ42 levels by reducing amyloidogenic APP processing in an SV-dependent manner. Lev modified SV cycling and increased APP cell surface expression, which promoted its preferential processing through the nonamyloidogenic pathway.
Stable isotope labeling combined with mass spectrometry confirmed that Lev prevents Aβ42 production in vivo. In transgenic mice with aggressive amyloid pathology, electrophysiology and immunofluorescence confirmed that Lev restores SV cycling abnormalities and reduces synapse loss. Brains from patients with Down syndrome also displayed presynaptic protein accumulation before the occurrence of substantial Aβ pathology, supporting the hypothesis that protein accumulation is a relevant pathogenic event in amyloid pathology. Together, these findings highlight the potential to prevent Aβ pathology before irreversible damage occurs.
Link: https://doi.org/10.1126/scitranslmed.adp3984
View the full article at FightAging
Aging is Often Overlooked in Mouse Models of Age-Related Conditions 20 February 2026 - 11:11 AM
Academic research is, as a rule, always short of funding. Researchers are consistently strongly motivated to find less costly approaches to animal studies. One aspect of this pressure is that the standard, most widely used animal models of disease tend to be the ones that can be created as rapidly as possible, using various toxic, damaging strategies to reproduce aspects of aging in relatively young mice. Time has its own cost, and budgets don't stretch to waiting around for mice to get old. Thus in this modern era of enthusiasm for targeting the mechanisms of aging, the research community finds itself in the position of knowing too little about how aging interacts with disease processes.
Mouse models of Parkinson's disease (PD) are invaluable for advancing our understanding of the disease, and there is much hope that their use will help develop new therapeutic interventions. PD is a complex multisystem disorder characterized by a spectrum of motor and non-motor symptoms, and numerous mouse models have been developed to study its various aspects. While age is the primary risk factor for PD, the role of biological aging in PD is still unclear, and it is often overlooked in the design and application of these models. This omission risks missing critical insights into disease mechanisms and opportunities for the development and translation of novel interventions, in particular as aging biology is emerging as a therapeutic target.
The International Network for Parkinson's Disease Modelling and AGEing (PD-AGE), funded by the Michael J. Fox Foundation for Parkinson's Research, was established to address critical gaps in our understanding of the role of aging in PD. Its creation was prompted by a workshop that brought together leading experts in PD modeling and aging who collectively highlighted the need for a systematic investigation into how aging contributes to PD.
To achieve its goals, PD-AGE was divided into four working groups, each focusing on different models. Here, we report on the working group that focused on approaches using mouse models and conducted a series of workshops to build consensus on prioritizing models of aging and PD, experimental approaches, and the standardization of protocols for their characterization. The result is a comprehensive roadmap for selecting optimal models, defining relevant measurements, and harmonizing protocols.
Link: https://doi.org/10.1038/s41531-025-01239-x
View the full article at FightAging
IL-6 as a Measure of Peripheral Inflammation is More Often Elevated in Cognitively Impaired Individuals 19 February 2026 - 07:30 PM
The immune system is a very complex array of interacting cell populations, constantly changing over time. The inflammatory response is similarly complex, arising from many different inciting events and cascades of signaling and interaction between various immune cell types. Thus there are no simple measures of inflammation, no matter that the medical community has certainly tried very hard to make that goal a reality. Or perhaps it is better to say that simple measures of, say, one signaling molecule (in practice often C-reactive protein), paint a limited picture of what is actually going on. Sometimes that limited picture is useful, sometimes it is misleading.
Today's open access paper is a good illustration of the limits of what one can learn from a single marker, or two related markers. Circulating C-reactive protein and IL-6 are linked mechanistically in that C-reactive protein rises in response to IL-6. These are also the most commonly used measures of inflammation, so the research and medical communities have a fair grasp on the limitations. Nonetheless because they are commonly assessed markers, there is a tendency to continue to use them, as then at least there is a large body of existing data to compare against.
"Inflammaging" describes chronic low-grade inflammation observed in aging individuals. It may play a major role in neurodegeneration. Interleukin-6 (IL-6) and C-reactive protein (CRP) were assessed in 514 Canadian individuals in COMPASS-ND, a detailed study of cognitive impairment in the elderly. Cumulative link model (CLM) was used to investigate the relationship between inflammation status (low, medium, or high tertiles) and demographic and lifestyle factors along with cognitive function and cognitive diagnoses.
We found that 12% of cognitively normal older adults had IL-6 levels in the highest tertile, but this increased in cognitively impaired cohorts - 36% in Alzheimer's disease, 55% mixed dementia, 30% mild cognitive impairment, and 39% vascular mild cognitive impairment. We found that 36% of cognitively unimpaired older individuals display "elevated" IL-6 (middle and high tertile values), while approximately 70% of those with cognitive impairment also do so. Inflammation markers increased most robustly in association with age, higher body mass index, and higher Fazekas (MRI white matter hyperintensity) score. There were also weaker associations with female sex, nutrition, number of comorbidities, and poor sleep.
In conclusion, peripheral low-grade inflammation was common, particularly in individuals with cognitive impairment; and obesity and age were the main drivers. It remains unclear whether treatment targeting such inflammation might have a therapeutic role in dementia prevention.
View the full article at FightAging
A Circulating Inflammation Suppressor Decreases Mortality 19 February 2026 - 05:16 PM
Researchers publishing in Aging have used Mendelian randomization to conclude that the inflammatory factor IL6 causes increased mortality and that its circulating receptor, IL6R, decreases it.
Looking for a proof of danger
Chronic, age-related inflammation (inflammaging) is very well-known to be closely connected to negative age-related outcomes, to the point that it has been addressed by the Hallmarks of Aging authors [1]. However, as these researchers note, proving causation in this case is particularly difficult; inflammation often comes with a large variety of confounding factors, and reverse causation must also be ruled out [2].
To accomplish that, the researchers turned to Mendelian randomization, a technique that uses large genomic datasets derived from very large groups of people, to discover the effects of various conditions in a way that is far less prone to confounding and reverse causation. They chose the well-studied inflammatory factor IL6, along with its soluble receptor IL6R, which leads this inflammatory factor down a different and possibly contradictory pathway [3].
Ruling out other factors
This study found that increases in IL6R cause increased longevity and protected against a variety of conditions. While Alzheimer’s and kidney diseases were unaffected, increases in IL6R were found to be protective against lung cancer, diabetes, stroke, and coronary artery disease. People with more circulating IL6R had less all-cause mortality.
Similarly, increases in IL6 were found to cause more overall mortality, and genetic propensities for the various conditions that cause mortality, such as heart disease, were not connected to this increase in IL6, meaning that reverse causality was not a factor. C-reactive protein and GDF15, two other inflammation-related compounds frequently studied in aging, were not found to have any effects.
The researchers noted that, because very few genes are associated with increased inflammation, they had to use only those genes that were very significantly and strongly associated in order to avoid creating data from weak instruments. Additionally, by using repeated leave-one-out analyses, the researchers made sure that the associations that they discovered stood on their own. None of the individual genes responsible for the IL6 increase was found to be the cause; instead, the cause was, indeed, the increased IL6.
A cardiovascular focus
The researchers noted that most of the causes of increased mortality linked to IL6 were cardiovascular in nature. They note that IL6R is not abundant in the walls of blood vessels or heart tissue, and therefore, increases in this anti-inflammatory factor throughout the bloodstream bring it to where it is needed. By binding to and taking away IL6, the researchers reason, IL6R prevents this inflammatory compound from worsening various cardiovascular conditions, such as thrombosis and dysfunction of the endothelium, providing a “clear mechanistic pathway” for its beneficial effects.
The researchers sum up their findings simply: “Taken together, the results of the current mendelian randomization study strengthen the rationale for IL6R antagonism as a potential strategy to reduce cardiovascular disease and associated mortality.” Fortunately, an IL6R antagonist already exists in the clinic: tocilizumab is already approved by the FDA and has been found to reduce mortality in both the contexts of COVID-19 [4] and giant cell arteritis [5].
However, this approach still needs to be examined carefully. Experiments will need to be performed in animals and people to determine if artificially increasing circulating IL6R through tocilizumab or other methods is a viable method of reducing overall cardiovascular disease risk.
Literature
[1] López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2023). Hallmarks of aging: An expanding universe. Cell, 186(2), 243-278.
[2] Emerging Risk Factors Collaboration. (2010). C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. The Lancet, 375(9709), 132-140.
[3] Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium. (2012). The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis. The Lancet, 379(9822), 1214-1224.
[4] Rosas, I. O., Bräu, N., Waters, M., Go, R. C., Hunter, B. D., Bhagani, S., … & Malhotra, A. (2021). Tocilizumab in hospitalized patients with severe Covid-19 pneumonia. New England Journal of Medicine, 384(16), 1503-1516.
[5] Stone, J. H., Tuckwell, K., Dimonaco, S., Klearman, M., Aringer, M., Blockmans, D., … & Collinson, N. (2017). Trial of tocilizumab in giant-cell arteritis. New England Journal of Medicine, 377(4), 317-328.
View the article at lifespan.io
