Why so many Alzheimer's drugs fail: two tales of Alzheimer's disease

[00:00:00] Dr. Mia: Welcome to the podcast ask Dr. Mia : conversations on aging well . This is episode number four, but I wanted to share with everyone the exciting milestone of having had a hundred downloads of the podcast. I am super excited that so many of you have listened and have shared with people in your lives. 

[00:00:22] Today I am going to talk about why so many Alzheimer's drugs fail. That really comes down to the divergent definitions of Alzheimer's disease from a clinician's perspective, versus from a scientist perspective. For those of you who don't know. I am a geriatrician and a dementia expert. I work within our memory clinic in addition to working as a researcher within our Alzheimer's disease research center. So I've seen the the evolution of clinical trials for Alzheimer's disease both with my doctor hat on and with my researcher hat on. One question that I commonly get is why there are so few treatments for Alzheimer's disease. Some of you may have heard of a new drug that was approved by the FTA in the summer of 2021. This particular drug is called Aducanumab or the brand name is Aduhelm 

[00:01:31] some of my patients have come to clinic to ask me if this new drug is right for them. I really wanted to share with you the tale of two Alzheimer's through composite stories of two patients who demonstrate these two phenotypes, two presentations of Alzheimer's disease. 

[00:01:52] One patient, her name is Barbara. Barbara is 83 years old. She is a retired librarian. She has high blood pressure, diabetes well controlled, and has had a history of heart attack when she was 70. 

[00:02:11] She came to see me because of some memory problems. She is becoming more repetitive. But her family has also noticed that she almost got into a minor car accident and is needing more help with managing her medications. When we looked at Barbara brain on a head CT scan or brain MRI, 

[00:02:34] she has a lot of what the radiologist called to be white matter ischemic changes. These are just small blood vessel changes that we can see in the brain similar to when we can see plaque buildup in the small blood vessels of the heart. 

[00:02:52] I diagnosed Barbara with what is possibly Alzheimer's disease. But I think also that her, small vessel disease may also be contributing. Barbara is really representative of the majority of patients who have the clinical diagnosis of Alzheimer's disease. Typically people get it in their seventies, eighties, maybe even nineties. And there is a lot of overlap between small vessel disease caused by what we call vascular risk factors: high blood pressure, diabetes, high cholesterol, sedentary activity perhaps and people who smoked or were former smokers. There's a lot of overlap between these vascular risk factors and what doctors call Alzheimer's disease. Outside of the context of specialized memory centers and academic medical centers, Alzheimer's disease is still what's called a diagnosis of exclusion, meaning we have excluded possible reversible causes of memory loss such as low vitamin B12, low thyroid, strokes, which is the major thing that we're looking for on a brain imaging, as well as medications that could potentially be worsening one's memory, such as over the counter medications that contain Benadryl or diphenhydramine. 

[00:04:25] A lot of the sleep aids that says Tylenol PM or Unisom. All of those medications have anti-cholinergic property that are bad to one's memory. Once we have excluded depression, medications, sleep apnea, hearing loss, what is left remaining? Despite addressing all of those other potentially reversible memory loss causes is what doctors commonly call Alzheimer's disease. 

[00:05:02] Most people who get diagnosed with Alzheimer's disease present like Barbara who are older in age and gradual changes also have a lot of other medical problems that contribute to their overall health in addition to memory loss. 

[00:05:19] Now, Steve is an example of the minority of Alzheimer's patients who present much younger. He is only 63. He is actually a family medicine physician. Unfortunately, he had complaints from his coworkers and patients as relates to his work. He has short-term memory problems. And because he is in such a cognitively challenging profession, it was very apparent very early on that he had memory loss. 

[00:05:54] Steve came to see me and was also participating in a clinical trial, that gave him the information of an amyloid pet scan. These are nuclear medicine scans that can look for the protein called amyloid, which some of you may have heard amyloid is a abnormal protein that gets built up in the brain and can cause plaques to build up. Amyloid plaques can also lead to tau proteins. Tau buildup can cause tangles. And that can cause the neurons or the cells in the brain to die and shrink away. 

[00:06:41] Steve represents the minority of Alzheimer's patients who get the disease young and primarily have amyloid as to the cause of their Alzheimer' s disease. Steve is very physically active. Overall healthy has a little bit of high blood pressure that's very well-managed and does not have any other vascular risk factors like Barbara has, has never had a heart attack has, does not have diabetes does not even have high cholesterol. And it was really quite shocking to Steve and his family that his memory loss was so profoundly impactful for his work. 

[00:07:27] I want to show you the case of Barbara and Steve to show that Barbara really represents the majority of what people think of when they think of Alzheimer's disease. It's a diagnosis of exclusion and they generally are happening in folks who are older. However, the research definition of Alzheimer's disease has really focused on Steve and the amyloid protein in terms of clinical trials over the past decade. Amyloid is the target of this new drug that was approved by the FDA in June 2021. Aducanumab Is an antiamyloid antibody, meaning that it binds to the amyloid protein and signals to the body to remove it. 

[00:08:24] I actually have talked about it as part of a NPR interview why so few people are prescribed aducanumab despite the FDA approval. I will link to that NPR episode in the show notes. 

[00:08:44] A lot of the research trials have been focusing on amyloid. However, as I tell my patients, you can also see amyloid buildup as people get older. Having amyloid in your brain is very abnormal when you're 60, but it's really not fairly common if you're 80. A positive amyloid pet scan is really only helpful in terms of diagnosis. 

[00:09:14] Amyloid pet scan is currently a advanced imaging study that can only be obtained within the context of a clinical trial because no insurance company, including Medicare, is covering the cost of amyloid pet scan. This makes the approval of antiamyloid drugs, particularly controversial. Because all of the participants who participate in those clinical trials, for anti-amyloid drugs had to have an amyloid pet scan to become eligible. But one can not financially, logistically get an amyloid pet scan as a patient. The cost is just so prohibitive that essentially the majority of patients could not afford to pay for an amyloid pet scan out of pocket. 

[00:10:11] The research field on Alzheimer's disease has really moved more and more towards the prevention of Alzheimer's disease rather than the treatment of Alzheimer's disease, because many clinical trials have failed to show any difference between those who were receiving the investigational drug versus those who received a placebo or a sugar pill, or if it comes in the form of a fusion, this is just a saline solution that is neutral to the body. Because none of the clinical trials have been able to show, even a smidgeon of improvement for people who already have significant symptoms as a result of Alzheimer's disease. The research side of Alzheimer's trials have really moved towards people who have either very mild symptoms, such as mild cognitive impairment. This is a condition that I talked about in the last episode, which means that someone has some abnormal memory changes that we don't think it's just due to normal aging, but do not have any functional changes, like having difficulty driving, having difficulty managing their medications or their finances. 

[00:11:36] The Alzheimer's research field has also been moving even more preclinical, meaning that even in people who have normal cognition. If they have amyloid protein in their brain, they might be eligible for clinical trials that target that abnormal protein called amyloid. 

[00:11:58] Similar to amyloid clinical trials, there are also now clinical trials looking at the tau tangles. Tau tangles are abnormal proteins in the brain that have gotten somewhat less attention than amyloid. But in contrast to amyloid, which people can have in their brain even if their memory is normal. If you have tau in your brain, most people have symptoms of memory loss. So the presence of tau actually is much more correlated with having symptoms of memory loss compared to the protein amyloid. There was recently a new publication that showed that an anti tau- antibody clinical trial has failed to produce any noticeable improvement compared to people who received placebo .

[00:12:58] Because Aducanumab was approved by the FDA last summer, I think we're also going to see other similar antiamyloid drugs that show that the drug does remove the protein amyloid from the brain, but may not have much real improvement in people's memory, cognitive test, may also have a significant amount of potential side effects, including brain swelling, brain bleed, seizures all of the things that require very careful monitoring, which is why so many of us were very concerned when the FDA approved of Aducanumab because it went against the entire FDA advisory panel, which unanimously voted against the approval of the drug. It really has opened up a Pandora's box in terms of ethical financial and clinical challenges.

[00:14:05] For those of you who are interested in learning more about different clinical trials of Alzheimer's disease, I will include in the show notes, the national Institute on Aging's website, to find clinical trials near you. For people like Barbara who get memory loss in their eighties or for Barbara's family members, such as their children who might be worried about their own risk of developing Alzheimer's disease, the best thing that they can do to lower their risk of developing Alzheimer's disease is actually by controlling their vascular risk factors, meaning getting their blood pressure under control, getting their diabetes under control, being physically active, socially active and cognitively active. There is a lot of interest in people who have mild cognitive impairment, just a smidgen of memory problems to participate in all kinds of investigational studies to see if people could reverse those memory changes or improve them compared to the group who might be receiving placebo. 

[00:15:17] One thing to notice that not everyone who had mild cognitive impairment progresses to have dementia. In fact, half of those who have mild cognitive impairment or MCI do not progress over time. And we still are investigating who are the people who are likely to progress versus those who do not. 

[00:15:43] In contrast to all the publicity and excitement about antiamyloid studies, the study that actually did show improvement in people who develop mild cognitive impairment, was a large study looking at intensive control of blood pressure. The SPRINT trial was originally designed to reduce cardiovascular risk among people who had their systolic blood pressure or their top blood pressure number control below 120 versus those who had the normal blood pressure management, which is less than 140. People are in the high intensive blood pressure control group, were found to have fewer heart attacks, strokes, and other cardiovascular outcomes. In addition, when we looked at the memory changes of those who received intensive blood pressure control, we also found that fewer of those who were in the intensive blood pressure control group ended up developing mild cognitive impairment. 

[00:16:56] I think one reason why the SPRINT study has not made as much headlines is because controlling blood pressure is not as sexy as finding a brand new drug that targets a protein called amyloid. But as I mentioned in Barbara's example, there is huge overlap between what we clinically cause Alzheimer's disease versus small blood vessel changes. It just goes to show that the publicity surrounding clinical trials sometimes has more to do with what is exciting and sexy versus what is less sexy at reducing blood pressure. There is no pharmaceutical company that is interested in necessarily tightly controlling blood pressure because it doesn't really matter what drugs are used to reduce blood pressure. 

[00:17:58] The Alzheimer's trials are treating Barbara and Steve in the same group, when their risk of developing cognitive impairment are very different. 

[00:18:06] so that is a very short primer on the controversies of Alzheimer's disease and why so many Alzheimer's drugs have failed over the years. There are ongoing studies looking at lifestyle interventions, such as aerobic exercise combined with Mediterranean diet. The clinical definition of Alzheimer's disease has really changed from the research definition of Alzheimer's disease. The research participants are usually have very mild symptoms or even no symptoms of memory loss compared to the people that we see in clinic. I think this diversions is causing a lot of confusion among the public, as well as among general health care providers 

[00:18:54] I will continue the discussion about memory loss and reversible causes of memory loss in future episodes. But if you have enjoyed this episode, please share with people in your life and let others know to sign up for the email alerts as when the new episodes are coming out on my website. Thank you so much.