Key paper in depression genetics disputed

I wanted to draw attention to a new paper in JAMA recently because it reveals a lot about how conditional most of the statements we make in behavioral genetics are. Every time you hear a news article that says, “Gene for depression found,” I want you to think about this case.

Risch et al. performed a meta-analysis on 14 studies that were looking at Serotonin Transporter (5-HTTLPR) genotype and number of stressful life events. These two factors were related to the subsequent risk for developing clinical depression. Their analysis found — contrary to a very well known study, Caspi et al. — that there was no association between genotype for this gene and depression risk and no significant interaction between genotype and number of stressful life events.

I think this case is a good example of why we should be skeptical of behavioral genetics studies reported in the news until they have been replicated repeatedly.

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Evil Genes: Why Rome Fell, Hitler Rose, Enron Failed, and my My Sister Stole My Mother’s Boyfriend

When I was asked to review Evil Genes: Why Rome Fell, Hitler Rose, Enron Failed, and my My Sister Stole My Mother’s Boyfriend, by Barbara Oakley, I was pretty certain that my life as a Science Blogger had reached its peak. I mean, blogging about science AND FREE BOOKS?! You’re not serious. When I got the book in the mail I did a little happy dance of joy. It’s the little things in life, you know.
And then, of course, I realized I would have to review it. Luckily, for this particular book, it turned out to be a very easy task. For another, excellent review, check out Gene Expression’s coverage.

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Complete speculation on the health of John McCain

Some people have been noticing erratic behavior from republican nominee John McCain lately. His most recent seems to be slight, but rather odd. Specifically, he appears to have developed ptosis— a drooping eyelid— which could of course be related to any number of causes, from an autoimmune attack on cholinergic receptors such as that seen in myasthenia gravis, to diabetes.
Ptosis can also be the result of a brain tumor that affects the oculomotor nerve (cranial nerve III). Sudden development of the condition at old age following multiple bouts of melanoma (which has a penchant for metastasizing to the brain) would seem to be cause for concern, so I wonder if any neurologists would like to weigh in?
McCain also seems to be hiring a very expensive makeup artist who may be assisting in the coverup of the condition. I really, really wish he’d release his medical records in full so that people can stop speculating about the ramifications of a chronically ill president with a potentially untreatable brain tumor, and his vice president with all the foreign policy experience and political saavy of a Hun.

Oops! Memantine’s actions really aren’t all that and a bag of chips

Memantine is the most recent weapon in the fight against Alzheimer’s. There’s been a lot of hype surrounding the drug because….

The first-generation of compounds aimed to boost the brain’s acetylcholine levels led to the development of drugs such as Aricept™ (donepezil) and Excelon™ (rivastigmine). Attempts to develop drugs that block the action of glutamate by a considerable number of pharmaceutical companies and researchers were not successful for a long time, since these receptors are also required for normal brain function, learning and memory in particular. It was therefore considered a major breakthrough when a drug called memantine was discovered to have beneficial effects in Alzheimer’s disease, which did not affect the normal function of glutamate signalling, but only the excessive actions leading to cell death.

Sounds awesome, right? Well, things aren’t always what they seem.

In the present study, researchers report that memantine has a much more complex pharmacological profile than originally described. It does in fact work rather similar to the originally introduced drugs that affect acetylcholine-related signalling, in addition to weak actions on glutamate, and has negative effects on neuronal communication at high concentrations. At lower concentrations, memantine was able to enhance signalling between neurones of the hippocampus (the main brain area affected in Alzheimer’s disease) and was indeed able to reverse learning and memory deficits. However, a pharmacological analysis showed that this was not due to its ability to block glutamate signalling, but rather to an additional and more potent action on the acetylcholine system.

The press release mentions that there’s a lot of hope that memantine can be applied to other brain disorders that involve exessive glutamate release, such as following stroke or trauma.
This isn’t to say that memantine doesn’t work. But we do need to be judicious in how we apply these drugs as they have a presumed mechanism of action, but the targeted mechanism may not be the primary one affected in humans.

Alzheimer’s Disease and risky sexual behavior: not quite a false alarm?

Abel over at Terra Sigillata got is writ in a tinger over bad grammar and was concerned that Alzheimer’s Disease had been tied to risky sexual behavior. His conclusion was that he got a poorly worded email notice about two separate problems that were linked inappropriately by a semicolon. So everything’s fine, all clear, right? He’s free to engage in risky sexual behavior without fear of getting Alzheimer’s Disease (AD) later in life!
That’s not entirely true.
We’ve known that inflammation plays a huge role in the Alzheimer’s disease process. Unfortunately, inflammation is caused by a number of sexually transmitted diseases, such as those of the herpes family. What’s more, herpes viruses have a proclivity for neural tissue. Multiple herpes viruses have been found in the brains of AD patients; indeed (note the proper use of a semicolon, Abel), herpes simplex 1 (HSV-1) is a known risk factor for AD. Additionally, other herpes viruses have been studied and it appears that human herpes virus 6 (HHV-6) type B (but not type A) may be another with a strong link to incidence of AD. Cytomegalovirus (CMV) and HSV-2 seems to lack a relationship, and very few control or AD brains are infected with them.
Now now now, I know what you’re thinking. You’re saying “Aha Evil! HSV-2 is the simplex virus commonly associated with sexual activity!” While this is true, HSV-1 infection can and does result from sexual activity, just as HSV-2 is not only transferred via genitogenital contact. CMV is also transmitted sexually.
As I said, thankfully, HSV-2 rates seem to be quite low in AD brain and in elderly control brain. However, that could change in the future. As Tara at Aetiology mentions, the elderly are a population that is at an increasingly high risk for STD transfer, as the geriatric population is largely ignored by educational efforts, and they are less likely to practice safe sex or use condoms . An increase in the incidence of HSV-2 in the elderly could conceivably change that.
To make matters worse, those at risk for AD due to the presence of the apoE4 gene get a double whammy: HSV-1 is present at higher levels in the brains of those with the apoE4 allele, and HSV-1 shifts processing of amyloid precursor protein into Abeta (1-40) and (1-42) overdrive, which is unfortunate since Abeta protein fragments are what aggregate and form one of the pathological hallmarks of AD; the amyloid plaque. Fibrillar Abeta is thought to “gum up” synapses and contribute to neuronal dysfunction and cell death.
On a related note, CMV may also cause problems for the aging noggin– it is transmitted sexually and also increase the risk of vascular dementia.
It is thought that merely having, say, HSV-1 isn’t causative (obviously it isn’t because 85% of people have HSV-1 from a young age and not that many people develop AD), but that HSV-1 “flareups” in the brain, over time, increase the inflammatory processes that contribute to AD, so that the effect is cumulative.
So Abel, you’re sorta right and unfortunately sorta not. We don’t have rock solid evidence that sex=Alzheimer’s by a long shot, but there’s definitely some cause for concern that STDs (or at least viruses that target the brain and can be transmitted sexually) may be contributing to the incidence of AD, and quite possibly to other neurodegenerative diseases.

Depression is all in your head….

…but for those who suffer from it, “in your head” can be more debilitating than other chronic, painful illnesses. A massive WHO survey study of 60 countries reported that 3.2% of people had depression over the course of a year. Interestingly, though…

This was a bit lower than for asthma (3.3 percent), arthritis (4.1 percent), and angina (4.5 percent), and higher than for diabetes (2.0 percent.)
But the results of a quality-of-life index called the “global mean health score” showed that depression was, by a significant margin, the most difficult to bear.

The most difficult to bear, and also quite prevalent.

The study, published in the British journal The Lancet, says that depression accounts for the greatest share of non-fatal disease burden, accounting for almost 12 percent of total years lived with disability worldwide.
The researchers called on doctors around the world to be more alert in the diagnosis and treatment of the condition, noting that it is fairly easy to recognize and treat.
They also note that even if the prevalence of depression is similar to the four other chronic physical diseases, the lifetime risk — the number of people who cycle in and out of depression — is five to 10 times greater.

As the article says, depression is pretty easy to identify. Educating doctors and the public about the warning signs is a simple thing, but getting people to stop looking away isn’t.
I think it’s pretty obvious that we, as a society, need to step up and remove the stigma associated with mental health issues. Not only are they as prevalent as so-called “real” diseases and disorders, more people will experience them at some point in their lives. Every facet of life is affected too, from rearing children to personal health to productivity at work, which may not necessarily be the case with a physical disorder. National health care system, I’m looking at you….

Promising Effects of Statins on Alzheimer’s Pathology

Finally we get some data on changes in AD pathology with statin use! Statins are taken for lowering cholesterol, but they have other beneficial effects such as modulating inflammatory responses. Thus, they could prove beneficial in the treatment of AD given the disease has a significant inflammatory component.
According to the press release

The two changes in the brain that are considered the most definitive hallmarks of Alzheimer’s are brain “plaques” and “tangles.” After controlling for variables including age at death, gender, and strokes in the brain, the researchers found significantly fewer tangles in the brains of people who had taken statins than in those who had not. “These results are exciting, novel, and have important implications for prevention strategies,” said senior co-author Eric Larson, MD, MPH, the leader of the ACT study and executive director of Group Health Center for Health Studies. “But they need to be confirmed, because ACT is not a randomized controlled trial.”

As the press release rightly points out

A randomized controlled trial of statin treatment and brain autopsy findings would be problematic for ethical and practical reasons, said Dr. Larson. But the ACT setting made the study more rigorous than previous observational epidemiological studies, because it uses reliable automated pharmacy records, is based in a community population, and includes autopsies in people both with and without dementia.

so don’t expect any prospective comparisons anytime soon. Or, ever. However, this study appears promising as it backs up the epidemiological data. I’ll have to see if I can get my hands on the actual paper and post about it.


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