Promising New Therapies for Alzheimer's Disease

<blockquote> <h3>Fast Facts</h3> <ul> <li>Currently, there are more than 100 medications either being used or investigated for use in treating Alzheimer's disease. </li> <li>Cholinesterase inhibitors — such as donepezil (Aricept®), rivastigmine (Exelon®), and galantamine (Razadyne®) — are the cornerstone of old Alzheimer's treatments and theoretically slow down the loss of memory and cognitive function.</li> <li>The first Alzheimer's drug considered to be “disease-modifying” was approved by the Food and Drug Administration (FDA) in 2021, called aducanumab (Aduhelm®). It's a monoclonal antibody that works by sticking to the amyloid protein that forms plaques in the brain of people with Alzheimer's. Once the drug is stuck to the plaque, the body's own immune system will recognize it as a foreign invader, which will initiate an immune response to destroy and remove the plaque.</li> </ul> </blockquote> <p>Alzheimer's disease. It's the disease that robs people of their cognitive abilities, and worse, their precious memories. The scarier part is that, while scientists have made major strides in Alzheimer's treatment since its discovery in 1906 — with more than 100 medications either being used or being investigated for use — there is still no cure for the disease. </p> <p>And the truth is, for the past several decades medications used as Alzheimer's treatments focused more on managing symptoms rather than reversing the progression or addressing the underlying cause of the disease. But that's not without trying — the fact of the matter is, many researchers who study Alzheimer's disease have primarily focused their research on determining the cause of the disease, slowing down the progression of cognitive decline, and finding a cure. </p> <figure><img src="https://cdn.storymd.com/optimized/RqVNgLIxqm/original.jpg" alt width="721" height="480" /> <figcaption>The Principal Players of Alzheimer's Disease <em>Source: TheVisualMD</em></figcaption> </figure> <p>But the challenge is that the human brain is extremely complex, and Alzheimer's disease is one of the most complex diseases of the brain. Additionally, research based on theories involving the proteins amyloid-beta (â) and tau may have lead researchers down the wrong path. </p> <p>The good news is that there has been a surge in research and innovation in Alzheimer's research over the past few years, with new theories on the cause of Alzheimer's that hold a lot of promise. Along with that, there are new Alzheimer's treatments based on these new theories that some experts claim may change the course of the disease. </p> <p>But the pressing question is: are these new Alzheimer's treatments more effective than the old ones? </p> <p>Read on to learn more about how Alzheimer's disease is treated, the difference between old and new treatments, and whether these new Alzheimer's treatments are as promising as some claim them to be. </p> <h2>The old guard of Alzheimer's treatments </h2> <p>Historically, the arsenal of Alzheimer's treatments neurologists had available for their patients primarily focused on managing symptoms rather than tackling the root cause, or causes, of the disease. These treatments include: </p> <h3>1. Cholinesterase inhibitors</h3> <p>Examples such as donepezil (Aricept®), rivastigmine (Exelon®), and galantamine (Razadyne®), are the cornerstone of old Alzheimer's treatments. This class of medications target a neurotransmitter called acetylcholine, which plays an important role in transforming thought and experiences into retrievable memories. So, by inhibiting the enzyme that breakdowns down acetylcholine – called cholinesterase – theoretically, these drugs can slow down the loss of memory and cognitive function. </p> <p>However, the effectiveness of these cholinesterase inhibitors is modest at best. While they may provide temporary relief by improving some symptoms and offer a brief respite from the disease's relentless progression, they do not alter the course of the disease. On top of that, this class of drugs also causes a host of unsavory adverse effects, such as: </p> <ul> <li>gastrointestinal problems</li> <li>sleep disruption</li> <li>increased risk of bleeding </li> <li>decreased heart rate</li> <li>disrupted heart rhythm</li> </ul> <h3>2. Memantine – NMDA Receptor Antagonists</h3> <p>Another older Alzheimer's treatment is memantine (Namenda®), a N-methyl-D-aspartate (NMDA) receptor antagonist. Memantine works by binding to NMDA receptors to prevent other molecules from binding but does not have an effect on receptor activity. </p> <p>NMDA receptors are a major part of what is called neuroplasticity. Basically, that means how malleable and adaptable the brain is – how able the brain is to learn new information, which means forming new pathways between brain cells. But that's not all, NMDA receptors are also a receptor for the neurotransmitter, glutamate – which plays a key role in uniting various brain cells that need to come together to form a specific memory. So, when glutamate, or other chemicals (e.g., aspartate, glycine, D-serine) bind to the NMDA receptor, it becomes activated and revs up activity in areas of the brain that help with learning new information and storing new memories. Essentially, these receptors work to stimulate and ‘excite' brain cells. </p> <p>However, if – for some reason – there is too much glutamate or aspartate, the NMDA receptor stays continuously active. As a result, various brain cells will remain in an excited state. When that happens for too long, they can become so overstimulated and overexcited that they start to function poorly, and eventually, die. This can contribute to many neurodegenerative diseases like Alzheimer's disease. </p> <p>And so, by treating Alzheimer's patients with an NMDA, like memantine, it blocks the receptor and prevents neurotransmitters from binding and over activating these receptors. While memantine's side effects are often minimal compared to cholinesterase inhibitors, there are side effects such as enhanced confusion, agitation, severe constipation, and headache. </p> <h2>Old treatments don't stop the needle on Alzheimer's disease progression. </h2> <p>On paper, these old Alzheimer's treatments were promising. For example, on average, the NMDA receptors antagonists were able to slow down disease progression for about six months. Anyone affected by Alzheimer's will tell you that 6 months is better than no months. But when taken into consideration that the effectiveness of these drugs differs from those of placebo by only a few points, it may not be worth suffering through their side effects for minimal, if any, improvement – particularly with cholinesterase inhibitors.</p> <figure><img src="https://cdn.storymd.com/optimized/PqEk45C1o2/original.jpg" alt width="728" height="485" /> <figcaption>Stages of Alzheimer <em>Source: TheVisualMD</em></figcaption> </figure> <p>However, the most significant limitation of the older classes of Alzheimer's treatments is their inability to alter the underlying course of the disease. Meaning that these drugs primarily work by addressing symptoms, they do not act on the fundamental mechanism of the disease – such as the accumulation of amyloid plaques and tau tangles in the brain. Put simply, the effectiveness of these old Alzheimer's medications is modest, at best, at boosting cognitive performance and improving some behavioral symptoms – they do not slow down or halt the relentless progression of Alzheimer's. And so, patients taking these medications may experience a temporary boost in cognitive abilities, but the disease continues to advance unabated. Essentially, these older Alzheimer's treatments are mere band-aids. </p> <h2>New Alzheimer's treatments on the block</h2> <p>While old Alzheimer's treatments were heavily criticized for not addressing the underlying cause of the disease, a new group of medications that have recently been introduced are unlike their predecessors. These new treatments are considered to be “disease-modifying” medications capable of altering the course of Alzheimer's disease progression. These new disease-modifying treatments are considered immunotherapy treatments. They all use monoclonal antibodies, which are designed to help the immune system specifically target and destroy amyloid plaques that are present in the brain. </p> <p>The new immunotherapy Alzheimer's treatments include: </p> <h3>1. Aducanumab (Aduhelm®)</h3> <p>This is the first of its kind in a new class of “disease-modifying” Alzheimer's treatments, which was approved by the Food and Drug Administration (FDA) in 2021. Aducanumab has a completely different mechanism of action that may make an actual difference in the progression of Alzheimer's disease. In fact, the drug received accelerated approval because clinical trials showed that it could reduce the rate of amyloid plaques on scans, which, theoretically, should slow down the cognitive decline in people with Alzheimer's disease.</p> <p>The “amyloid hypothesis” – which is the prevailing Alzheimer's theory – states that Alzheimer's is caused by the formation of plaques, which damages brain cells, causing tau tangles to form inside them, and eventually killing brain cells. So, if there's a way to prevent the formation of plaques or stop the plaques from damaging brain cells, then there may be a cure for the disease – or at the very least, a way to slow progression. </p> <p>Enter Aducanumab, a monoclonal antibody that works by sticking to the amyloid protein that forms plaques in the brain of people with Alzheimer's. Once the drug is stuck to the plaque, the body's own immune system recognizes it as a foreign invader, which will initiate an immune response to destroy and remove the plaque. The hope and expectation are that, once the plaques are removed, the brain cells will not be damaged, preventing it from dying, and thus, thinking, memory function, and behavior will stop deteriorating.</p> <p>Like older Alzheimer's treatments, aducanumab works best for people who have Alzheimer's in its early stages, meaning those with mild cognitive impairment (stage 2) or mild Alzheimer's disease (stage 3).</p> <p>Yes, aducanumab sounds like it may change the lives of people with Alzheimer's disease; however, there are significant downsides to the drug. </p> <ul> <li><strong>First, patients will need an intravenous infusion every four</strong> <strong>weeks</strong> <strong>– forever.</strong> This means that not only does taking aducanumab require a trained specialists to administer the drug, but also, tremendous amount of monitoring after it has been administered. </li> <li><strong>Second, there are risks and adverse effects.</strong> 30% of patients who took the drug had a reversible swelling of the brain, and more than 10% had tiny brain bleeds. </li> <li><strong>Third, it's not cheap.</strong> The estimated cost per year of the drug is $56,000. Worst still, Medicare and Medicaid Services, and private insurance will not cover this medication. </li> <li><strong>Lastly, scientists do not know if the drug works or not</strong> – even though aducanumab has been approved for use. The FDA based aducanumab's approval on two large clinical trials that investigated the effectiveness, side effects, safety, and how long the drug might be used. In one study, the results were positive, meaning that the drug worked to slow down the cognitive deterioration. However, the other larger study was negative, meaning that aducanumab was no more effective than placebo at improving any of the measured outcomes. </li> </ul> <p>So, should you or someone you know suffering with Alzheimer's take aducanumab? This is a question that you need to discuss with your doctor. Yes, findings from studies do show that aducanumab clears away amyloid plaques from the brain. However, and unfortunately, this finding does not translate to any measurable clinical outcome. Meaning that while plaques may be removed from the brain by aducanumab, it's still unclear whether this clearing slows down the progression of Alzheimer's or not.</p> <h3>2. Lecanemab (Leqembi®)</h3> <p>While similar to aducanumab, in that it's also a monoclonal antibody, it's different in that its effectiveness in slowing down cognitive decline is much clearer than the former drug. Lecanemab also received accelerate approval from the FDA in early 2023. </p> <p>Like aducanumab, lecanemab works by sticking to amyloid plaques in the brain, which allows the immune system to target, destroy, and clear them. The difference is that lecanemab binds to a particular form of the amyloid protein as it clumps, called a protofibril. According to other studies, this is the form of amyloid that is most likely to stick and form plaques in the brain that damages brain cells. Whereas other monoclonal antibodies, like aducanumab, might be targeting other forms of the amyloid protein either too early or too late in the clumping process. </p> <p>Additionally, in clinical trials, not only was lecanemab effective at clearling amyloid plaques from the brain, but it also showed symptomatic improvements in Alzheimer's patients, which is still unclear with aducanumab. In a study involving about 1,800 participants with early-stage, symptomatic Alzheimer's, lecanemab slowed clinical decline by 27% after 18 months of treatment compared with those who received a placebo. Meaning that study participants in the lecanemab group not only showed a significant reduction in amyloid plaques in imaging tests, but they also showed a 26% slowing of decline in cognitive function and a 37% slowing of decline in a measure of daily living compared to the no treatment group. </p> <p>Again, while promising, lecanemab is not without disadvantages. Like aducanumab, lecanemab: </p> <ul> <li>is administered by intravenous infusion every two weeks – indefinitely, which, like aducanumab, also requires a trained specialist to administer the drug and monitor progress after administration. </li> <li>comes with severe side effects – 26.4% of lecanemab participants vs. 7.4% in the placebo group experienced infusion-related reactions; 12.6% of participants showed fluid formation in the brain vs. 1.7% in the placebo group; and 17.3% of participants experienced brain bleeding vs. 9% in the placebo group. </li> <li>costs about $26,000 per year, and unfortunately, Medicare and Medicaid Services, and private insurance have yet to commit to paying for the treatment. </li> </ul> <p>Even with similar disadvantages, the main advantage of lecanemab over aducanumab is that there is clear evidence that it is effective at slowing down the progression of Alzheimer's in people with early stages of the disease. However, it's important to note that lecanemab was not studied in and was not approved for those with moderate or severe stages of Alzheimer's disease. </p> <h2>To take or not to take the new Alzheimer's treatment?</h2> <p>In a perfect world, scientists will discover a treatment that is able to completely stop the decline and even restore the cognitive function of those with Alzheimer's. However, science is not there yet. </p> <p>Yes, these new treatments give those suffering with Alzheimer's disease a lot to hope for. And with any fatal disease, people should have options – and that's what these new treatments offer. But they do not come without disadvantages, side effects, and risks. </p> <p>And so, this is a difficult question to answer. For now, the answer can only be Alzheimer's disease is complicated and whether to try these new treatments depends on multiple factors, which will be different for everyone. But more importantly, this is a decision that should be made with the guidance and support of a healthcare professional. </p> <h2>In with the new, out with the old? The role of old treatments today.</h2> <p>While old Alzheimer's treatments may have limitations, they still have a role to play in Alzheimer's care. For some patients, these medications can provide a degree of symptomatic relief and improve their quality of life. They may help individuals and their families navigate the challenges of daily living with Alzheimer's.</p> <p>Additionally, old treatments are often used in combination with other supportive therapies, including behavioral interventions, caregiver support, and lifestyle modifications. These holistic approaches aim to provide comprehensive care that addresses the multifaceted needs of people living with Alzheimer's.</p> <h2>The takeaway</h2> <figure><img src="https://cdn.storymd.com/optimized/Xdbz4Gc0dB/original.jpg" alt width="786" height="382" /> <figcaption>What Can You Do Now? <em>Source: TheVisualMD</em></figcaption> </figure> <p>In the ongoing battle against Alzheimer's disease, the shift from old to new treatments is nothing short of a medical miracle. The transition from primarily symptomatic management to treatments that actually address underlying causes is a major step forward. While the effectiveness of these new treatments continues to be studied and debated, they undeniably offer hope for a brighter future for those suffering with Alzheimer's disease – and their loved ones. </p> <p>And yes, there's still going to be challenges and obstacles – many, in fact – but the promise of effective treatments and, perhaps one day, a cure, seems closer than ever. So, for now, as science continues to march on, keep hope alive that one day soon, hearing the word “Alzheimer's” won't be as scary. </p><h2>More on Alzheimer's Disease</h2><ul><li><a href="https://soulivity.storymd.com/journal/qjo8do91nm-alzheimer-s-disease" target="_blank">Alzheimer's Disease: Risk Factors, Treatment, Prevention</a></li><li><a href="https://soulivity.storymd.com/journal/rjyggektyj-mild-cognitive-impairment" target="_blank">Mild Cognitive Impairment (MCI): Symptoms, Causes, Treatments</a></li><li><a href="https://soulivity.storymd.com/journal/j6yod981zw-cognitive-health-and-older-adults" target="_blank">Cognitive Health and Older Adults: Caring for Your Brain As You Age</a></li></ul>