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Tag: Alzheimer

  • Why more women than men have Alzheimer’s

    Why more women than men have Alzheimer’s

    The higher risk of Alzheimer’s disease in women compared to men may be due to a difference between the sexes that manifests as a protein shift in the brain. Specifically, it is found that C3 protein changes occur more often in female dementia patients than in male ones. This immune protein leads to synaptic atrophy when it undergoes a change.

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    Proteins adapt to their new environment in part because estrogen levels diminish after menopause.

    Nearly 4 million women are among the more than 6 million Americans aged 65 and over who have Alzheimer’s disease. About twice as many females as males are afflicted. Nobody knows for sure what causes this neurological illness. The usual plaques in the brain are known to be formed by misfolded amyloid beta proteins. Moreover, tau protein filaments, or fibrils, develop inside the nerve cells. Both are known to increase the risk of brain cell death and subsequent cognitive decline. However, additional systems that are poorly known seem to be implicated in the illness as well.

    Post-translational changes

    Researchers from China’s Changchun University of Chinese Medicine, led by Hongmei Yang, have shifted their focus to other processes that may contribute to Alzheimer’s disease. Post-translational changes were investigated by the team studying the human brain. These are protein extensions that can change how the protein works.

    S-nitrosylation (SNO) is one example of such a change. In this situation, a nitric oxide group serves as the appendage. The potential involvement of this alteration in neurodegenerative illnesses was suggested by previous research. Yang and his colleagues looked into the brains of 10 men and women who had died with and without Alzheimer’s disease to see whether there were any differences between the two groups.

    Distinct variations

    Researchers found a total of 1,450 SNO-modified proteins across all human brain tissues. Despite the fact that Alzheimer’s brains had just slightly more SNO proteins, their composition was very different from brains without Alzheimer’s.

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    They utilized statistical techniques to figure out which proteins were more likely to be S-nitrosylated in Alzheimer’s brains.

    The researchers used this information to create a ranking of proteins that may have a role in Alzheimer’s disease. They discovered alterations in proteins associated with autophagy, a cellular mechanism that eliminates unnecessary or broken pieces. This finding has the potential to shed light on previously unrecognized mechanisms through which Alzheimer’s progresses.

    Alzheimers disease c3 protein
    Alzheimer’s dementia is exacerbated by mutations in the immunological protein C3, which accelerate the aberrant destruction of synapses in the brain. (Credit: Scripps Research Institute)

    The majority of these alterations concern females

    The so-called complement factor C3, a protein with a crucial function in the innate immune system, showed the most dramatic modifications. The investigation revealed that altered C3 proteins were mostly found in the brains of females with Alzheimer’s disease. Female brains with Alzheimer’s disease exhibited a 34-fold increase in SNO-C3 compared to the brains of women without Alzheimer’s disease. Male Alzheimer’s brains increased just 5.6-fold.

    Although C3 has been implicated in the pathogenesis of Alzheimer’s disease, its S-nitrosylation and differential distribution between the sexes were previously unknown. Scientists used human stem cells to show that the altered C3 proteins increase neuronal deterioration by leading immune cells to erroneously attack healthy synapses.

    Beta-estradiol could shield premenopausal women

    The data demonstrated that beta-estradiol, a female sex hormone, may inhibit C3 modification, a process critical to the proper functioning of the immune system. This may explain why postmenopausal women have a higher risk of developing Alzheimer’s than men do.

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    The findings imply that beta-estradiol could shield premenopausal women against S-nitrosylation of C3.

    However, this defense diminishes when estrogen levels decline after menopause. Therefore, C3 proteins in women’s brains undergo greater pathogenic alteration, making women more likely to develop Alzheimer’s disease. Together, these discoveries improve our capacity to comprehend Alzheimer’s disease’s progression and, maybe, to design more effective strategies for early diagnosis and treatment.

  • New Antibody Against Alzheimer’s Disease

    New Antibody Against Alzheimer’s Disease

    There is a reason for optimism for those with dementia. A novel monoclonal antibody has shown positive results in treating Alzheimer’s disease in its earliest stages. Lecanemab was shown to decrease cognitive decline by roughly 27 percent in the phase 3 clinical study, and it also reduced dangerous amyloid plaques in individuals with dementia. There was also a significant decrease in the occurrence of serious adverse events such as brain hemorrhage and edema compared to two other antibody formulations examined for Alzheimer’s disease.

    The gradual death of brain cells, or Alzheimer’s dementia brought on by misfolded amyloid and tau proteins is still incurable and cannot even be halted. Despite the fact that numerous active compounds have shown promise in animal experiments, they have often underwhelmed in testing with humans. Both of these treatments either did not effectively slow the progression of dementia or had unacceptable adverse effects.

    Anti-dementia antibodies

    Histopathology of amyloid plaque in Alzheimer's disease.
    Histopathology of amyloid plaque in Alzheimer’s disease. Image: Wikimedia.

    This has been the case with the most recent therapeutic tool in the arsenal against dementia as well.


    Antibodies. These immune proteins were engineered in a lab to specifically bind with and eliminate the misfolded proteins that are characteristic of Alzheimer’s disease. The amyloid plaques of Alzheimer’s disease patients have responded well to antibody preparations including aducanumab, donanemab, and gantenerumab in early clinical studies.

    The difficulty is that although these antibodies were successful in reducing amyloid plaques in clinical studies, they typically failed to decrease dementia as well. Additionally, all antibody preparations have major and occasionally fatal adverse effects, including cerebral edema and microhemorrhages. The European Medicines Agency (EMA) has rejected the antibody preparation aducanumab on the grounds that the hazards outweighed the benefits.

    Lecanemab antibody study

    However, recent success in a phase 3 clinical study of an antibody created by a team headed by Christopher van Dyck of the Yale School of Medicine offers renewed optimism. Lecanemab is a combination of monoclonal antibodies that are highly selective for amyloid beta protofibrils. There is evidence to suggest that these misfolded proteins, which appear as filaments, play a role in the development of amyloid plaques.

    A total of 1,785 individuals with moderate Alzheimer’s dementia were given lecanemab antibodies through biweekly infusions or a placebo. Researchers used positron emission tomography to regularly scan participants’ brains over the course of 18 months, measuring amyloid deposit density and volume (PET). In addition, at the start of the trial and at regular intervals thereafter, all patients were given a battery of standardized tests measuring different aspects of their cognitive functioning.

    Decreased dementia and plaque formation

    After 18 months of therapy, those who received the antibody had much less amyloid plaque growth in the brain than those in the control group. In addition, their mental deterioration slowed by 0.45 points on the so-called CDR-SB scale of 18 points.


    According to the researchers, this translates to a 27% reduction in dementia and a 37% reduction in ADL impairment (Activities of Daily Living).

    The current trial demonstrates the most convincing evidence of effectiveness for lecanemab among the three antibodies (aducanumab, gantenerumab, and lecanemab). But it’s true that initially, the patient is unlikely to feel this influence particularly strongly in their day-to-day existence.

    However, there is a bigger picture: If the impact continues, the gap will widen over time, making the initial discrepancy much more significant. Throughout the course of the 18-month trial, it became clear that the discrepancies between the treatment and placebo groups grew.


    Antibodies with fewer negative effects

    However, adverse effects may be a deciding factor in the approval process. Exaggerated immunological responses occurred with lecanemab soon after infusion, similar to earlier antibody preparations, although they were often neither severe nor enduring. On the other hand, lecanemab has also been linked to brain swelling and bleeding. Researchers found that 21.3% of the time they occurred. However, the vast majority of them were symptom-free and could only be identified by a brain scan.

    Consequently, it seems that lecanemab results in less cerebral edema and microbleeds than other antibody preparations. When compared to other antibodies, lecanemab has a lower incidence of such ARIA. The researchers found that the benefit-risk ratio of lecanemab improved due to the drug’s relatively low risk.

    But will lecanemab be approved as a treatment for Alzheimer’s disease? The last stage before an application is often a “phase 3” trial. However, van Dyck and his group remain cautious and suggest doing more, longer-term research first. The researchers need to wait for clearance before they can submit an application for this study.

    On the other hand, Schulz is certain that lecanemab will join the approval procedure in the near future since the statistics are so compelling and consistent, and the recorded adverse effects are quite minimal.

    The turning of the tide for antibody treatments to treat Alzheimer’s

    Despite these limitations, the new antibody formulation represents a promising advance in this relatively novel approach to treating Alzheimer’s disease. These findings represent a watershed moment for the reason that they prove that modern antibody treatments are making progress toward their objective of eliminating amyloid plaques and halting the progression of dementia.

    The authors and commentators on the paper agree that lecanemab’s targeting of amyloid protofibrils, rather than amyloid plaques, is a significant step forward. It is believed that the progression of dementia in the brain is related to the presence of these misfolded beta-amyloid filaments, which are especially harmful to cells.

    It’s believed that Alzheimer’s disease begins with the first stages of Alzheimer’s plaques damaging nerve cells. On the other hand, the plaques should be left alone since they are evidence of successful elimination of the harmful early stages.

    (NEJM 2022; 10.1056/NEJMoa2212948).