A lot of things about getting older can seem kinda fun — like senior discounts, butterscotch candies, and argyle sweaters. But
Even though they’re sometimes used interchangeably, Alzheimer’s disease and dementia are two different things — and neither is an inevitable result of ageing, even though age is the biggest risk factor for both. Dementia is a broad term for a group of symptoms, as opposed to one, specific disease. People with dementia can have a wide variety of cognitive and memory issues, like problems with language, comprehension, learning, and executive and social functioning. It’s generally progressive and often advances to the point where patients can’t live on their own. And it can be caused by a lot of things. One version is vascular dementia, where these symptoms come from problems with blood flow in the brain, like from a stroke, or from much smaller capillary blockages. Another common kind is caused by buildups of a protein called alpha-synuclein in patients’ brains. It’s known as Lewy body dementia and can overlap with Parkinson’s disease. There’s also frontotemporal dementia, where the frontal and temporal lobes of the brain
It also seems to have more of a genetic component, although it’s been tough to pin down. But most cases of dementia — around 50 to 80% of them — are caused by Alzheimer’s disease, which was first described over 100 years ago. Like with dementia in general, Alzheimer’s symptoms get worse over time. They start with things like mild forgetfulness and difficulty concentrating, which a close friend or family member might not even notice at first. Then, the symptoms progress and include more intense forgetfulness, along with personality and mood changes. Eventually, the person can’t carry out most tasks, isn’t aware of their surroundings, doesn’t recognize their family, and needs round-the-clock care.
For now, we’ll just keep researching. Because even if a trial or treatment doesn’t work out, that’s still progress. And in the meantime, doctors and caregivers are focusing on making sure patients’ lives and their families are as comfortable as possible, whether that means getting them the right medicines or just the right daily routines.
Which is why scientists are working so hard to try and understand it. After their symptoms become noticeable, patients live an average of eight more years. The cause of death varies, but often, as the disease starts to affect more basic functions like swallowing and heart rhythm, they become vulnerable to infections or heart attacks. So far, scientists don’t know exactly what causes Alzheimer’s, but they do know that patients develop two major features in their brains. One is plaques, or deposits mostly made of a protein called amyloid beta. The other is tangles of another protein, called tau, that form inside of neurons.
When the immune system tries to clear those out, it can contribute to harmful inflammation. But even if the amyloid hypothesis is right, that protein isn’t the only thing causing problems. There are also those tangles of tau protein, which seem to form after amyloid plaques, and they lead to even more damage. Normally, tau’s job is to stabilize microtubules, structures neurons use as tiny highways to shuttle nutrients and neurotransmitters inside the cell. But when tau abandons its responsibilities and forms tangles instead, it disrupts the molecular highways. So not only is there an 18-car pileup, but the road itself has been washed out by a landslide.
Most people develop some plaques and tangles as they get older, but patients with Alzheimer’s have a lot more of them, and they spread through the brain as their illness gets worse. So doctors think they must have something to do with the disease’s symptoms. Our best idea right now is called the amyloid hypothesis, and it suggests that a build-up of amyloid beta is mainly responsible for Alzheimer’s. Scientists aren’t sure how, but the plaques might disrupt communication between brain cells. And besides clumping together to form plaques, amyloid beta can also join together in bundles that dissolve in the fluid in the brain.
As amyloid, inflammation, and tangles progress, they disrupt all kinds of systems in the brain, and a patient’s memory and cognition get progressively worse. And, unfortunately, there’s no way we know of to reverse all this. We’re also not sure what causes someone to develop these plaques and tangles in the first place. Many researchers think Alzheimer’s disease is caused by interactions between a bunch of factors, including genetics, overall health, and the environment.
Still, we do know of at least one case where genetics alone definitely causes Alzheimer’s. In about 1% of cases, the disease is caused by mutations in the amyloid-related genesPSEN1 or PSEN2, or in APP, a protein that gets processed into amyloid beta. If someone inherits just one copy of a mutated gene, they’ll develop Familial Alzheimer’s disease. And these cases show up earlier in life — in the person’s 40s or 50s instead of their60s or later.
Although we can’t cure either Alzheimer’s or dementia in general — no matter what causes it — we at least have some treatment options on the market right now that can slow its progression. Today, there are two types of drugs used for treating Alzheimer’s specifically: acetylcholinesterase inhibitors and an NMDA antagonist. The inhibitors increase levels of the neurotransmitter acetylcholine in the brain by blocking the enzyme that normally breaks it down, which can ease the cognitive symptoms of Alzheimer’s. Researchers think the enzyme might also help form plaques and tangles, so blocking it might slow that process down, too. And the antagonist decreases the activity of the neurotransmitter glutamate, which tends to excite the brain. Lowering glutamate levels stops over-excited nerves from firing as often, which also seems to ease symptoms. Now, these drugs might slow the progression of Alzheimer’s, but they don’t stop or reverse it — we don’t know how to do that yet. And, unfortunately, we also don’t have specific medicines for dementias not caused by Alzheimer’s, like vascular dementia.
Those patients can take medicine for Alzheimer’s, but they don’t seem to work as well, and doctors are looking for other options. So far, there are some clinical trials to develop new drugs or test existing ones for-Alzheimer’s dementia, and those focus on their specific characteristics — like treating blood flow in the brain for vascular dementia. At least one of these appeared to slow cognitive decline in more patients compared to a placebo, but results overall have been mixed. Most research today focuses on developing new drugs for Alzheimer’s disease — and then getting them approved to treat other dementias, too.
Many of the drugs in the Alzheimer’s pipeline focus on amyloid beta. One of the hottest tools in drug development right now is antibodies, those Y-shaped molecules your immune system makes to target foreign proteins. Since a build-up of amyloid beta proteins is a problem with Alzheimer’s, researchers are trying to design antibodies to target and flush them out. You might hear these drugs referred to as biologics, because they’re biological molecules, and they’re also being tested to treat other diseases like cancer.
One antibody scientists are testing is aducanumab, which binds to small clumps of amyloid beta before they’re deposited in plaques. Right now, it’s in the last phase of clinical trials before it could become publicly available. A study from 2016 claimed that, according to brain scans, the antibody actually reduced amyloid buildup in trial participants — which would be awesome if it works in these last tests. Ongoing studies are expected to be published in 2019.
Unfortunately, a few biologics have already crashed and burned, which is normal for clinical trials. Not everything makes it through or works in people as it does in a Petri dish. So besides biologics, scientists are testing a bunch of other strategies. One is to block an enzyme that helps produce amyloid beta fragments, called beta-secretase, by using a so-called small molecule. Most small molecule drugs are actually fairly big — they’re just tiny compared to things like proteins. Several of these are in early human trials, but they’re not close to being ready for the general public.
There are also drugs in development that go after tau, rather than amyloid. One is a vaccine called AADvac1. A trial testing it with 185 people began in 2015 and will end in February 2019. A vaccine might be an odd-sounding idea, but it’s similar to the biologic approach. With a biologic, you give the patient antibodies to attack a certain protein. But with a vaccine, you stimulate their body to make its own antibodies, instead. And it’s an interesting idea, but it’s nowhere near ready until these studies show some results.
Besides just looking for cures, scientists are also researching ways to better diagnose Alzheimer’s, since those plaques and tangles can only be diagnosed for sure with an autopsy– although we can see the symptoms of the disease long before then. Finding biomarkers — some kind of molecule doctors can easily spot to confirm someone has the disease — is also a major goal. That would help recruit reliable patients for other studies, too. But the thing about clinical trials is that, no matter how quickly we make discoveries, it takes a long time to get them approved and completed. Even if a medicine works in a lab, we want to be sure it will help. And we definitely want to make sure it won’t do more harm than good. That takes a while, which is why you don’t hear about new treatments coming on the market every week.
Also, even though scientists are doing a ton of research, they’ve still been struggling to come up with anything that works really well. A lot of drugs have failed in clinical trials — more than you’d normally expect — and there are a bunch of possible reasons why. For one, drugs that affect the central nervous system are notoriously hard to develop because brains are so complicated. Also, treatments that looked promising in small trials often fail to scale up to larger ones. And recruiting enough people for Alzheimer’s trials has proven to be extremely difficult, too.
But the most troubling possible reason for all this failure is that researchers could be barking up the wrong tree. There’s good evidence to support the amyloid hypothesis, but all those failed drugs could be evidence against it. At least one major expert in the field has argued that Alzheimer’s is actually caused by problems related to ageing, not amyloid, including accumulation of DNA damage in the brain, problems with the cell cycle, or loss of the fatty sheaths surrounding parts of neurons. But we’ll need more evidence to be sure. Most researchers aren’t ready to abandon the amyloid hypothesis just yet, but it maybe worth considering down the road.
For now, we’ll just keep researching. Because even if a trial or treatment doesn’t work out, that’s still progress. And in the meantime, doctors and caregivers are focusing on making sure patients’ lives and their families are as comfortable as possible, whether that means getting them the right medicines or just the right daily routines. Because at the end of the day, every person with Alzheimer’s and dementia should get the attention they need. And hopefully, one day, we’ll find a cure for both of them.