Is there new hope?
When it comes to Alzheimer’s disease, there hasn’t been much in the way of treating it or preventing it. The lack of information has led to many scientists studying the condition. In recent months, new data has come to light that indicates the disease might not be such a devastating diagnosis in the future. What are these discoveries? What will be their impacts?
Alzheimer’s disease is a neurodegenerative condition that is irreversible and progressive, meaning it slowly destroys the parts of the brain associated with memory, thought, and language. The disease is characterized by changes in the brain, such as the buildup of amyloid plaques and neurofibrillary (tau) tangles. Most researchers believe that the plaques form first and damage brain cells, causing tau tangles to form inside them, killing the cells. These changes result in the loss of neurons and their connections, which affect a person’s ability to remember and think. Symptoms start with mild memory loss and advance to the inability to hold conversations, environmental disorientation, and mood changes. Eventually, the person is unable to care for themselves. As of September 2021, the Centers for Disease Control and Prevention (CDC) estimate that close to 5.8 million people in the United States have the condition.
Previous research suggested that various elements, like age, family history, diet, and environmental factors, influence a person’s risk of Alzheimer’s disease. However, scientists in Australia have recently discovered an additional factor that may be responsible for its development. The study from Curtin Health Innovation Research Institute at Curtin University in Perth used mice to look at the impact of the human amyloid-beta on the structure and function of various body tissues. The researchers found that when the amyloid-beta proteins made in the liver combined with fats and traveled to the brain, they interfered with the proper functioning of the microscopic blood vessels (capillaries). The dysfunction led to the protein-fat complexes leaking from the blood into the brain, causing inflammation. While the inflammation occurred in both the test and control groups, it started at a much younger age in the test group. It was also associated with marked degeneration in the brain cells when examined under a microscope. The neurodegeneration was rarely seen in the control group, and, if present, it was usually at a much older age. Unsurprisingly, during the test for cognitive function, the test group performed approximately half as well as the control group at the retention of learning. The findings suggest explanations for long-standing questions about the role of amyloid-beta in Alzheimer’s disease development. Certain dietary behaviors and medications could potentially reduce the blood concentration of these toxic fat-protein complexes, leading scientists to believe that simple changes could reduce the risk for Alzheimer’s or slow down the disease progression. Despite promising results, further studies, particularly in humans, are necessary. However, this finding was significant.
New Treatment Option
In June 2021, the Food and Drug Administration (FDA) approved Aduhelm (aducanumab) to treat Alzheimer’s. It’s the first new treatment approved for Alzheimer’s since 2003 and is the first therapy that targets the fundamental pathophysiology of the disease. Currently, other available medicines only treat symptoms of the disease.
Aduhelm is a monoclonal antibody engineered to stick to the amyloid molecule that forms plaques in the brains of people with Alzheimer’s. Once the medicine has attached to the plaque, the body’s immune system removes it, thinking it’s a foreign invader. The thought is that once the plaques are removed, the brain cells will stop dying, and thinking, memory, function, and behavior will stop deteriorating. It’s vital to point out that this isn’t a cure. The disease will continue to progress, just at a slower rate.
Aduhelm is recommended for individuals with early-stage Alzheimer’s disease and those with mild cognitive impairment. Typically, these individuals may function normally, or they may need a little bit of help with complicated activities, such as paying bills, grocery shopping, or preparing meals. The drug is given every four weeks via an intravenous infusion. It can’t be stopped; otherwise, the disease will go back to progressing at the rate before taking the medication. About 30%t of those who took the drug during the trials had a reversible brain swelling, and over 10% had tiny brain bleeds. As a result of these side effects, patients need to be monitored by an expert neurology/radiology team during transfusion.
It’s critical to note that not everyone with mild cognitive impairment or dementia has Alzheimer’s disease. To determine if the condition is present, you need to get either an amyloid PET scan or a lumbar puncture to see if you have the amyloid plaques. Presently, most insurance companies will cover the cost of a lumbar puncture, but not an amyloid PET scan, which costs approximately $5,000.
Why is Aduhelm not getting to those who need it?
Aduhelm isn’t reaching many patients for several reasons. The first is that there are still lingering questions about if it actually slows memory loss. While the FDA granted conditional approval, an advisory panel had recommended against allowing the drug on the market. The agency convened a panel of experts to discuss the complicated data set because when submitting the request to the FDA, Biogen (the maker of Aduhelm) submitted two large studies. One found that the drug could delay the loss of memory and thinking, but the other found no apparent benefit. Ten panelists voted against approval, and one abstained. After the FDA approved aducanumab, three committee members quit in protest. The Department of Health and Human Services (HHS) is reviewing the steps that led to the approval and is scheduled to release a report in 2023. Two congressional committees in the US House of Representatives are also investigating the decision. Also, the result has divided the doctors and medical institutions about the drug’s effectiveness, making them hesitant to prescribe it.
Another reason for the slow rollout of Aduhelm is insurers are hesitant to cover the cost of the drug. Medicare, which insures most people with Alzheimer’s, won’t decide whether to pay for it until sometime this year, possibly by mid-April. Health policy experts point out that Medicare almost always pays for FDA-approved drugs, at least for the medical conditions designated on their label, but with Aduhelm, they’ve undertaken a review process that could result in no coverage, full coverage, or limited coverage. If Medicare denies coverage for Aduhelm, it’ll be the first time they’ve declined to pay for a drug that the FDA approved for its on-label indication. Initially, the price of Aduhelm was $56,000 a year. According to Biogen data, in the three months following its approval, it brought in $300,000. Following the weak sales, the company slashed the price to $28,200 a year. Even at this price, Aduhelm would still be one of Medicare’s biggest drug expenses. Private insurers seem to be waiting for the government’s decision before determining their coverage policies. Patients and their families who want Aduhelm would have to pay out of pocket for the time being. Most people can’t afford the drug.
Aduhelm was approved using the accelerated approval pathway, which is used for a drug to treat a serious or life-threatening illness that provides a meaningful therapeutic advantage over existing treatments. The process requires a post-approval trial to verify that the drug delivers the expected clinical benefit. If the trial fails, the FDA can initiate proceedings to withdraw approval of the drug. This additional study will likely take three to four years once it’s started. Biogen has yet to launch that trial, and the FDA gave it nine years to collect the results. Some experts are upset by the length of time, saying that it’s too long to leave the drug on the market without conclusive data regarding its efficacy.
In the meantime, the accelerated approval of Aduhelm established a precedent for others to follow, meaning the FDA can approve Alzheimer’s drugs based on their ability to remove amyloid-β from the brain without clear evidence of cognitive benefit. One thing that could significantly influence this is Medicare’s decision regarding coverage. As of November 2021, Eli Lilly hopes its antibody donanemab, which works similarly to Aduhelm, will have better reception. The company plans to finish submitting its application for FDA approval, hoping for a decision later this year. The first trials of donanemab enrolled 257 people and showed that the cognitive capabilities of people who received the antibody declined more slowly than placebo recipients. If the FDA approves donanemab using the same accelerated approval pathway, Lilly will also have to verify the benefit of its antibody. A 1,500-patient phase III trial is currently being conducted, with results due in the first half of 2023. It’s essential to note that generic medicine that has been used for 25 years, donepezil, used to treat the symptoms of Alzheimer’s, not the cause, outperforms both Aduehlm and donanemab.
Other Treatment Options
Another critical consideration is that Alzheimer’s patients may have different underlying cellular mechanisms that lead to their neurodegeneration. This means the disease can be divided into subgroups that require different treatments.
A significant genetic risk factor for Alzheimer’s disease is having one or more copies of the gene APOE4. Close to 25% of people possess one copy, raising their risk of developing Alzheimer’s by three- to four-fold. About 2% of people have both copies, increasing their risk 12 to 14 times. A group of scientists looked at the brains of Alzheimer’s patients carrying one or more copies of APOE4 and found nearly 2,000 other genes whose expression had been altered compared to individuals without the disease. Many link back to pathways that have nothing to do with beta-amyloid metabolism, such as circadian rhythms, morphine addiction, and GABA — a neurotransmitter that keeps neurons in check, preventing them from firing too often. Next, the team scanned a database of 1,300 medicines to find ones that could flip those altered genes back to a healthy state. One that came up was bumetanide, a potent diuretic used to treat the swelling associated with high blood pressure and heart failure. The first part of the experiment involved testing the drug’s effectiveness on a group of mice engineered to have two copies of the human APOE4 gene. The mice had a significant boost in performance on various cognitive and spatial memory tests. The second portion of the experiment took a different group of mice, who, in addition to APOE4 genes, also carried the human gene for APP (a protein that when broken down becomes beta-amyloid). Furthermore, the study also detailed real-world data collected from millions of patients’ electronic health records showing that people over 65 who regularly took bumetanide were 35% to 75% less likely to be diagnosed with Alzheimer’s. Bumetanide treatments shrank the plaques and restored healthier brain function. Analysis of the results suggests that bumetanide can improve symptoms without specifically targeting plaques. Instead, therapies that target the multitude of molecular changes might be more effective.
Besides new medications to treat Alzheimer’s, there needs to be an easy and cost-effective way to diagnose it. Symptom-based diagnosis of Alzheimer’s disease is only about 70% accurate. The two current tests, lumbar punctures and amyloid PET scans, have logistical and financial challenges. A study published in the journal Brain in June 2021 found that a blood test may help predict an increased risk for Alzheimer’s disease and brings hope to fixing the problem. The study followed 159 people for two years. The individuals were cognitively normal. However, the results showed that higher levels of one blood marker (P-tau) predicted which people were more likely to develop cognitive decline and brain shrinkage. P-tau is associated with Alzheimer’s disease but not with other kinds of dementia. The study findings compared measuring P-tau in the blood to it in spinal fluid, and it was as accurate in predicting risk.
A different blood test, PrecivityAD, uses mass spectrometry to look at the ratio of two amyloid-beta isoforms — Aβ42 and Aβ40 — and the presence of apolipoprotein E (APOE)-specific peptides that reflect a patient’s APOE genotype. The results create a score that indicates the probability of being amyloid-positive on PET imaging. The score correctly identified amyloid status (determined by PET scans) in 86% of 686 older adults with cognitive impairment or dementia. According to C2N Diagnostics, the maker of PrecivityAD, it’s not a stand-alone diagnostic tool. The price of the test is $1,250, but patients who qualify for financial assistance could pay between $25 and $400. Health insurance companies don’t currently pay for the test.
Alzheimer’s is a debilitating condition, so it’s not a surprise that individuals with the illness and their loved ones are hoping to find a way to diagnose it earlier and treatment that can slow or stop its progression. However, companies and regulatory bodies need to ensure that products that come to market are safe and provide positive benefits.