High hopes dashed for Alzheimer’s drug

Pharmaceutical company Eli Lilly has announced that its clinical trial of a key Alzheimer’s drug, solanezumab, has failed. The drug, said the firm, didn’t slow down cognitive decline in patients with Alzheimer’s compared to those who took placebo. Solanezumab is an antibody designed to bind to and promote the clearance of the β-amyloid protein, which forms plaques in the brains of people with Alzheimer’s, in the hope that this would lessen the symptoms and slow the progress of the disease. The trial was a repeat of an earlier trial conducted in 2015, which showed promising signs. In the more recent trial, solanezumab was tested in patients with early-stage Alzheimer’s disease. Dr Bryce Vissel, professor of neuroscience and regenerative medicine at the University of Technology Sydney and the Garvan Institute of Medical Research, said: “The results were highly anticipated, not only because of hope for people with dementia, but also because, if the drug had succeeded, it would have demonstrated that β-amyloid contributes to the cause of Alzheimer’s disease, a major but recently controversial theory in the field. This is disappointing news for families who are watching Alzheimer’s rob their loved ones of their memories and emotions – it consumes and absorbs families. Importantly, this isn’t the end for β-amyloid theory. There’s a trial of another important drug for Alzheimer’s, aducanumab, being run by Biogen, which has shown interesting and encouraging signs. And there are numerous other trials in the pipeline of drugs that act in a variety of different ways to try to slow or reverse Alzheimer’s.

Alcohol stroke risk depends on type of stroke

Researchers from Sweden and the UK have found that light and moderate alcohol consumption of up to two drinks per day was associated with a lower risk of ischaemic stroke, but seemed to have no effect on a person’s risk of haemorrhagic stroke, according to a study published in the open access journal BMC Medicine. High-to-heavy drinking was found to be associated with increased risk of all stroke types. The researchers conducted a systematic review and meta-analysis of 25 prospective studies with data on ischaemic stroke, intracerebral haemorrhage and subarachnoid haemorrhage. They also included data from the Cohort of Swedish Men and the Swedish Mammography Cohort, for a total sample of 18 289 ischaemic stroke cases, 2299 intracerebral haemorrhage cases and 1164 subarachnoid haemorrhage cases. Alcohol consumption across all studies was assessed with a questionnaire or by interview and standardised to drinks of alcohol. Exposure categories were light (< 1 drink per day), moderate (1–2 drinks per day), high (2–4 drinks per day) and heavy (> 4 drinks per day). “Our results showed that heavy drinkers were about 1.6 times more likely to suffer from intracerebral haemorrhage and 1.8 times more likely to suffer from subarachnoid haemorrhage. The association between heavy alcohol consumption and these two types of stroke was stronger than that for ischaemic stroke. Previous research has found an association between alcohol consumption and lower levels of fibrinogen – a protein in the body that helps the formation of blood clots. While this may explain the association between light-to-moderate alcohol consumption and lower ischaemic stroke risk, the adverse effect of alcohol consumption on blood pressure – a major risk factor for stroke – may increase the risk of haemorrhagic stroke and outweigh any potential benefit,” the researchers wrote.

Link found between jet lag, obesity and liver cancer

US researchers using mice models have explored how jet lag can increase the risk of liver cancer through the same process seen in obese humans with liver cancer, in a study published in Cancer Cell. The authors wrote: “In human studies, we’ve now seen a clear link that shows patients progressing from fatty liver disease to liver cancer without any middle steps such as cirrhosis. We knew we needed an animal model to examine this connection, and the studies … found that the chronically jet-lagged mice developed liver cancer in a very similar way as that described for obese humans.” Exposure to light resets the body’s central circadian clock in the brain. However, other organs rely on neuronal and hormonal signals from the central clock in response to external light to keep time. This can lead to desynchronisation of the circadian rhythm of the liver during the clock resetting period. When we constantly travel through different time zones, work night shifts, or push ourselves to stay awake, the central clock is being chronically disrupted. By changing the times the lights went on and off during the night each week, the researchers modelled the effects of chronic jet lag in normal mice that were fed a healthy diet. In addition to activation of cancer genes frequently found in human liver cancer, jet-lagged mice lost normal control of liver metabolism. This included the build-up of fat and increased production of bile acids, which progressed to chronic inflammation and eventually liver cancer in some cases. Earlier studies have also linked high bile acid levels to liver cancer, not only in mice, but also in humans. The researchers found that the circadian clock activated two nuclear receptors that help regulate liver bile acid metabolism. Jet-lagged mice lacking a receptor called farnesoid X receptor (FXR), which keeps bile acid level in the liver within a normal physiological range, had very high bile acid levels and much more liver cancer. Mice lacking a receptor called constitutive androstane receptor (CAR) that regulates bile acid breakdown, and is also known to promote liver cancer, did not get any liver tumours. Although the researchers didn’t directly study jet lag in humans, they said that in humans, the FXR and CAR receptors work in a similar manner, and they hypothesised that lifestyle changes that generate chronic jet lag could also disrupt the body’s internal homeostasis and increase liver cancer risk in humans.

 

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