My lower risk for Alzheimer's may be the silver lining
to being e2/e2 at APOE.
Image courtesy of ImUnicke

When last I left you in my personal genomic journey, I had just discovered that I was e2/e2 at the APOE gene. I was quietly giddy* about this as it meant I was at a lower risk for getting Alzheimer’s. And even more importantly, it meant I didn’t have e4 which would have significantly increased my chances of getting this form of dementia.

Digging a bit deeper I found some more good news. People with e2/e2 usually have lower levels of LDL, the bad cholesterol that increases the risk for a heart attack. This is consistent with my low levels of LDL. Two good effects from one allele!

But there are no free lunches in genetics. For example, having two copies of the delta32 version of the CCR5 gene makes you pretty resistant to HIV infection. But it makes you more susceptible to the West Nile Virus. Having one copy of the sickle cell version of the hemoglobin gene makes you resistant to malaria. But your kids might end up with full blown sickle cell anemia. And so on.

The e2 version of the APOE gene is no different. It makes me less likely to get Alzheimer’s and, most of the time, to have a heart attack. But it means that I can end up with higher triglycerides from what I eat. This is consistent with what I have seen at the doctor’s.

Triglycerides are actually an independent predictor of heart attack risk. So even though my LDL is low, I need to watch my diet to keep the triglycerides down. If I am not careful, my increased triglycerides might cancel out my decreased LDL and so change my reduced heart attack risk to an increased one.

Being e2/e2 also puts me at risk for a relatively rare disease called hyperlipoproteinemia type III (HLP type 3). One reason this disease is rare is because being e2/e2 is rare. For example, only around 0.4% of people of European background have this genetic combination.

But HLP type 3 is obviously more common for me since I am in that 0.4% group already. Still, only 2% of e2/e2 people end up with HLP type 3 so it is a low risk for me. I decided to look into it anyway.

This disease has various symptoms but the most worrisome ones for me are increased risk of heart attack and abnormal glucose tolerance. My fasting glucose levels are stubbornly high whenever I take my yearly blood test. Which makes me wonder if this genetic difference is affecting my glucose tolerance and I am on my way to HLP type 3.

Of course, lots of genetic differences are involved in establishing someone’s glucose tolerance. And the environment plays a role too. So my glucose tolerance might have nothing to do with me starting to get HLP type 3.

Still, I am definitely going to ask my doctor about it at my next visit. It is rare but there are specific blood tests I can ask for that can tell me if I have this condition. Who’d have thought that a lowered risk of Alzheimer’s would only be a silver lining…

*Well, more of a measured giddiness. I know this is just one of the many genes involved in Alzheimer’s but still, it was good news.

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Many genetic tests just uncover one small bit of
your disease risk formula.
Image courtesy of Tungsten

Since 23andMe is offering data on Alzheimer’s risk but only with an upgrade, I decided to get that upgrade. I got the new results last week and opened it right up. There was a new Alzheimer’s link with a little lock on it.

The lock is to keep me out until I feel ready to deal with the news. Well, I’m ready…

When I opened the lock, I was given information about one gene, APOE. This was pretty disappointing. In my case, I was able to guess my APOE status with the old information.

I understand that for people who couldn’t guess their APOE status before that these new results might be useful. But I expected more. Lots of genes all impact our risk of getting Alzheimer’s and scientists are making real progress figuring these out.

What I was hoping to see was a compilation of all the information out there. See, my APOE data suggests that I am at a lower risk. But what if all my other genes are of the wrong type and put me at a higher risk? Then I might be at a higher risk than I think I am.

And my situation is better than people who have APOE gene versions that put them at a higher risk. What if all of their other genes put them at a lower risk? Now they are worried for no reason.

This points to one of the big issues with genetic tests and complex genetic diseases. Right now we know a bit about some of the genes involved but we don’t yet know the whole story.

It is kind of like having a whiteboard with a vast, awful, Jimmy Neutronesque formula scrawled across it. This is our genetic risk for getting something like Alzheimer’s.

Unfortunately, a blanket of ignorance hides most of the formula from us. We can only get a glimpse of one small part of it. What we then try to do is figure out our risk from that glimpse.

So let’s say we manage to uncover a bit of the blanket in the corner and we see a 0.5X. Does that mean that I am half as likely to get Alzheimer’s? Hardly. We have managed to see a piece of the whole formula but the rest remains hidden.

My APOE status is really just a bit of the formula for my Alzheimer’s risk peeking out from under the blanket. I don’t know the rest of the formula and so don’t know the rest of the risk.

APOE status is a well-studied risk that we know a lot about. We have completely uncovered it on our whiteboard. Some studies are staring to reveal other parts of the board but they aren’t completely clear yet. This is probably why 23andMe left them out.

I decided to look at the hazy parts of my equation using good old SNPedia. Remember, they have lots of information about DNA variants and disease that isn’t as filtered as is 23andMe’s.

Here is what I found when I put my data from 23andMe through SNPedia. I have listed the SNP, what I have at the SNP (the allele), and my risk for Alzheimer’s for those that give me a higher or lower chance for Alzheimer’s. I haven’t put in the ones that have normal risk.

I came out very well here. I am at a much lower risk for getting Alzheimer’s when I look at these SNPs. Yay!

But what if I just had s4934 data? I would come out thinking I was at a higher risk when I am actually at a lower one. Lots of needless worry over nothing…

Now I shouldn’t get complacent, this is still only a bit of my risk for Alzheimer’s. There may be some killer SNP lurking in my DNA, ready to spring Alzheimer’s on me. Or a long list of small, not-yet-discovered SNPs that will eat away at my supposed lower risk for Alzheimer’s. We just don’t know yet.

And I haven’t even begun to talk about environmental impacts. We know so little about that one with Alzheimer’s that we haven’t even found the whiteboard yet!

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I might be better off NOT knowing some things about my genes.

Last blog I talked about how I was able to wrest information about my APOE gene from my 23andMe data. I wanted to know because of this gene’s link to late onset Alzheimer’s disease.

APOE comes in three versions: e2, e3, and e4. People with two e4 versions are around 15 times more likely to end up with Alzheimer’s than are people with two e3 versions. And if these e4 folks do get the disease, it tends to come at an earlier age.

I found out that I actually have two e2 versions which protects me somewhat from getting late onset Alzheimer’s. Good news? I guess…

In all of this, I didn’t ask whether this information is worth knowing. Being e2/e2 doesn’t mean I won’t get Alzheimer’s…it just means I am at a lower risk. But at least I didn’t find out I was e4/e4. Then I’d know I was more likely to get Alzheimer’s but not be able to do anything medically useful with that information.

Being e4/e4 would not have meant that I would for sure end up with Alzheimer’s. So it wouldn’t be like having two copies of the delta-508 marker of the CFTR gene. In that case, I would almost certainly have developed cystic fibrosis. No, two copies of e4 would just mean that I was at a higher risk.

And knowing this wouldn’t be able to help me medically at all. There aren’t any good preventative measures I could take to stave off Alzheimer’s.

Now this isn’t always true with these kinds of increased risk genetic markers—some are definitely worth knowing. Women who have certain BRCA1/BRCA2 markers are at an increased risk for getting breast or ovarian cancer. They can choose to screen early (and often) in the hope of catching the cancer early when it is more treatable. Or, more drastically, they can choose to have their breasts and/or ovaries removed. Neither is really an option for Alzheimer’s.

So knowing my APOE status isn’t really that useful medically (at least not yet). I can’t do anything useful with the information other than wait and see if I end up with Alzheimer’s. Which is pretty much what I would have done without the test.

I’m bringing all of this up because 23andMe is now offering people their APOE information (with an upgrade to their new chip, of course). People can now find out their particular combination of e2, e3, and e4 markers*.

In the past, the question was whether or not direct to consumer (DTC) genetic testing companies should offer such a test. That ship has either sailed or is getting ready to leave the harbor. The test will be made available to people who really want the information.

So now the key question is whether knowing your APOE status is worth it. The answer to this question will be different for different people. Given this, the most important thing is for people to have the information they need to make the right choice about whether they want to know their APOE status or not.

One way to figure this out is with a genetic counselor but most DTC tests don’t mandate that you need to talk to one before you are tested. This means it is absolutely critical that the online information provided by DTC companies are presented in an easy to understand way that does not oversell the genetic test. The DTC companies need to be upfront in the fact that this test is not predictive and that there are no proven preventative measures that can keep Alzheimer’s at bay.

I’ll let you all judge how well 23andMe has done at letting people know about what you can learn from the APOE test and what you can do with that knowledge. Click here to read what they have to say.

* You have always been able to get your APOE status with a more expensive genetic test from deCODEme.

Learn more about how genes and the environment work together to cause Alzheimer's.

I put this video in the last blog but it probably should have gone in this one. It shows the unintended consequences of finding out you are e4/e4.

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I was having lunch with a colleague the other day and we got to talking about genetic testing (yes, we are that geeky). I told him about how my 23andMe test had missed my being prediabetic. This says a lot about what 23andMe’s test can tell me about my risk for diabetes. Not much.

Now as I have said before, the fact that 23andMe can’t tell me that I’m likely to become diabetic from their DNA test isn’t their fault (other than, perhaps, some overselling on their part). Diabetes research just isn’t far enough along to be able to accurately predict whether someone will get diabetes or not. Or to make any really meaningful prediction about diabetes at all.

We then got to talking about Alzheimer’s. Turns out his family tree is littered with Alzheimer’s on both his mother’s and father’s side. He ran into a similar problem–23andMe doesn’t report anything for Alzheimer’s.

But here the situation is a bit different than for diabetes. There are a couple of DNA markers that can tell us a lot about our future risk for late onset Alzheimer’s. It just so happens that 23andMe doesn’t report on them.

These markers deal with the APOE gene. This gene comes in three common versions: e2, e3, and e4. People with two copies of the e4 version are 15 times more likely to develop Alzheimer’s and if they do end up with the disease, it tends to come earlier. (One copy of e4 increases your risk about 3 times.)

With a little help from my colleague, I decided to dig a bit deeper into Alzheimer’s and see what I could figure out from what 23andMe did provide. Turns out I can figure out a whole lot about my APOE status. And that I can help other people figure out more from their results too.

The two markers (also called SNPs) that deal with APOE and Alzheimer's are rs429358 and rs7412. Here, according to SNPedia, are the combinations of these markers that tell you your APOE status:

To my surprise, 23andMe gives information on one of them, rs7412. Even though this isn’t usually enough to tell whether you have the dreaded e4 version or not, in my case it was. I almost certainly do not have any versions of e4 (yay!).

See, my results at rs7412 are TT*. If I am interpreting these results correctly, this means I almost certainly have two copies of the e2 version of the APOE gene. In terms of my Alzheimer's risk this is great news as being e2/e2 actually lowers your risk for getting the disease. (There is a chance I could be e1 but this doesn’t seem to be a very common version at all.)

Of course this doesn’t mean I won’t get Alzheimer’s…I still might. After all, the risk for someone over 85 getting Alzheimer’s is almost 50%. Even though this number lumps e4 and e2 folks together, e2 people do not have a 0% risk for Alzheimer's nor do e4 people have a 100% chance. People with e4 are just more likely to have Alzheimer's than e2 people.

It might help to think about getting Alzheimer's like drawing an inside straight in poker. Everyone might do it but people who are playing with wildcards are more likely to get it. These are the e4 folks. But it isn’t a for sure thing…you still may not draw the straight even with deuces wild.

Same thing with not having e4. Now I am less likely to draw that inside straight because there are no wild cards but it can still happen.

Because I was TT at rs7412, my case was pretty easy to figure out. Next blog I’ll try to help people out who are TC or CC at rs7412.

*Remember, we have two copies of each of our genes. So I have a T at rs7412 in one copy and a T at rs7412 in my other copy.

A video showing why knowing your APOE status isn't necessarily a good thing.

Learn more about current Bay Area genetic research from KQED's Forum.

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Writer Irwin Silber appeared in a QUEST TV segment on Alzheimer's. We filmed him having lunch at a Brazilian restaurant in Berkeley in Nov. 2007. Credit: Jenny Oh.

The New York Times reported that writer Irwin Silber, former editor of the influential folk music magazine Sing Out!, died on Sept. 8 in Oakland from complications of Alzheimer’s disease. He was 84.

QUEST featured Silber and his wife, singer Barbara Dane, in a television segment about Alzheimer’s disease that aired in 2008. The story looks at a gene associated with the disease.

Silber was famous for taking Bob Dylan to task in an open letter in Sing Out!, after the 1965 concert at the Newport Folk Festival in Rhode Island in which Dylan shifted his sound from acoustic to electric.

Silber and Dane let us film them as they each attended support groups for patients and caregivers at Alzheimer’s Services of the East Bay, in Berkeley. Silber also led us on a lively tour of his library at their Oakland house, where he kept copies of the books he had written. His interests ranged from folk music to socialist politics to health – after knee and hip replacement surgery, he wrote a guide for people undergoing the procedure. At the end of the day, they sat down for an interview during which they discussed candidly the challenges of dealing with Silber’s Alzheimer’s.

“He always was the smartest guy in the room, always. Everyone knew it,” said Dane. “Many times I’ve been in a meeting with some brilliant people debating different issues, and they all kind of wait for the end for him to come up with a summation that would take it a step higher. He was a specialist at that. And then bit by bit you could see that the ability to do that was ebbing away.”

Silber kept an upbeat outlook. “I’ve lived my life,” he said. “The more I can enjoy it, the better. But I’ll be satisfied when I’m done no matter what because I feel that I did something and I feel good about it.”

We at QUEST are very grateful to Silber and Dane for the openness with which they talked about Alzheimer's and its impact on families.

Video: Watch QUEST's story about Alzheimer's disease featuring Irwin Silber.

QUEST on KQED Public Media.

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This is the second of two stories born out of an afternoon at UCSF's Memory and Aging Center, where a team of scientists, led by Dr. Bruce Miller, is trying to tease out the differences between as many as 200 dementias that affect aging brains.

The two stories have a lot in common: Both introduce us to people who have lived with extremely difficult degenerative diseases: ALS in "Decoding the Emotional Brain," and frontotemporal dementia in this week's story. Both open up provocative questions about human nature. And neither would have happened without the generosity of a Northern California family – in this case, Cassandra Shafer, who drove down from Forestville with her daughter, Columbia, to tell me about Cassandra's husband and Columbia's father, Keith Jordan.

In these video clips, you meet Keith Jordan in the second half of his disease, after doctors at UC Davis and UCSF diagnosed him with frontotemporal dementia. The videos were taken at UCSF over the course of many hours doctors spent studying Keith and his symptoms. In them, we glimpse of two of Keith's FTD-caused obsessions: joke telling and music. (We also see one of the first symptoms to have emerged: his Jerry Garcia hairdo.)

At first glance, Keith's behavior might strike you as more eccentric than brain-damaged, which is precisely why FTD can take so long to diagnose. If you're a doctor with a 15-minute appointment slot, frontotemporal dementia might just look like a midlife crisis. What we don't see in the video clips are the five heartbreaking years that Cassandra spent trying to figure out what was happening to her husband – a search that included marriage and career counseling, the full gamut of conventional western specialists, yoga, meditation, chelation therapy, replacing every household cleaning product, every pot and pan, all the way to shamanic soul retrieval and exorcism – all while his behavior grew more erratic and difficult to be around. It's impossible to overstate the drain – both emotional and financial — that this search brought on Keith's family.

Keith died in May and Cassandra is still, she says, "inching her way" out of the "foreign land" that FTD plunged her into. As unlikely as it sounds, I think she takes some comfort in the fact that Keith's illness also gave doctors a chance to explore profound questions about human nature and the extent to which the structure of our brains determines who we are.

FTD can turn Democrats into Republicans, and vice versa. People with no interest in art begin to paint obsessively. As the neurons in Keith's right frontotemporal lobe (just behind the right eyebrow) died, his taste in music, his sense of humor, his relationships with his family members and friends changed completely. Our self, in other words, may owe much more to the way our brains are built than we'd care to acknowledge.

And what to make of the fact that this same part of the brain that shapes personality is also responsible for reading other people's reactions? People with some forms of FTD can't empathize with others (hear more about this in our slide show about FTD and art) or read the emotion on another person's face. Not only do they experience radical personality changes, but they lose the ability to sense others' reactions to them. In other words, how we define ourselves – whether we consider ourselves funny, smart, ambitious — seems to have everything to do with how others define us. We are all, in other words, people people.

Which begs the question: What about people raised in isolation, without the critical feedback loop of social interaction? What does FTD tell us, for example, about children who have been deeply neglected in orphanages? Or – taking another angle entirely — autistic people, who have trouble empathizing with others? What does self-perception look like in those who can’t perceive those around them?

If all this is giving you a headache, you might spend some time exploring the web extras we've produced for these two stories. Here, Bruce Miller explains why frontotemporal dementia can bring with it an artistic renaissance. And here, we introduce you to Matt Cheney and find out what his compulsive laughing and crying jags might reveal about emotion and the human brain.

Then use our blog, below, to let us know what you think.

Listen to the Beyond Alzheimer's radio report online, and watch our Web Extra: Dementia and Artistic Renaissance slideshow.

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There are many others also working in the field. The Alzheimer's Association has information about current treatments available. The National Institute on Aging gives a good overview of what avenues of research are being pursued to better diagnose the disease and find a cure. A team of health professionals at the UC Davis Alzheimer's Disease Center can provide a diagnostic work-up, as well as enroll patients in several ongoing clinical trials.

Watch the "Alzheimer's: Is the Cure in the Genes?" TV Story online, as well as find additional links and resources.

Gabriela Quirós is a Segment Producer for KQED-TV, and is the producer for this story.

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