rewrite this title Alzheimer’s Update and Late Winter Miscellany

The bit of news that prompted this particular revisiting of the Alzheimer’s disease scene was the promising possibility that a simple laboratory test would reliably predict the onset of Alzheimer’s in advance of the symptoms, and also in advance of detectable amounts of the two main protein structures that have for decades been known as signals of AD. These are, as we have discussed many times, amyloid-beta (αβ) plaques and neurofibrillary tangles.

The amyloid precursor proteins clump together to create the αβ plaques, which tend to have an adverse effect on the function of brain cells. Tau (τ) proteins serve a valuable function in the healthy brain, maintaining the structure of neurons. However, as a person develops AD, these proteins misbehave and form neurofibrillary tangles, as they are called, which also mess with the transportation of information by neurons and therefore impede the normal function of our brains.

That sounds like a fairly simple and straightforward way of diagnosing AD and instituting treatment early enough in the disease process to launch some form of intervention that preserves cognitive function and brain health. Unfortunately, detection of αβ plaques and tau proteins has not been feasible early enough in the progression of symptoms to institute any kind of meaningful intervention.

Historically, most efforts to identify the biomarkers that could predict AD have focused on amyloid beta plaques. However, many individuals who have αβ plaques never develop dementia, so those particular biomarkers are not the most effective predictors of AD.

Neurofibrillary tangles (NFTs) correlate much better with the progression of the actual disease.  Unfortunately, by the time the level of NFTs in the brain can be detected in a brain scan, the patient has already developed definitive Alzheimer’s disease, and cognition (as well as other aspects of the patient’s health) is quickly deteriorating.

A group of scientists therefore focused on the parts – call them “building blocks” – that constitute these NFTs. Very little is known about the nature of these compounds – oligomers and protomers – and how they function. However, there is evidence that the early phase of NFTs’ development is more toxic to brain cells than the fully formed NFTs.

In their multi-pronged study, the researchers first successfully measured soluble tau assemblies in brain samples from people who died with Alzheimer’s. Then, they identified a pivotal stage of NFT development and phosphorylation sites that seem important for forming NFTs.

A study in mouse brains showed that the presence of these phosphorylation sites, called p-tau-262 and p-tau-356, could predict future NFT production, making them potential biomarkers for early disease. The study was conducted by researchers at the University of Pittsburg. (Nature Medicine, 10:1038/s41591-024-03400-0)

Another study focused on a different biomarker, labeled p-tau-217, and found that this specific biomarker was strongly associated with higher levels of the brain-cell damaging tau protein and NFTs. This study was conducted in 912 human patients who were diagnosed with subjective cognitive decline, mild cognitive impairment, or dementia. Researchers took blood samples to check for six biomarkers. They then conducted positron emission tomography (PET) brain imaging on the participants to look for amyloid-beta and tau protein buildup, the hallmark signs of Alzheimer’s disease. (JAMA Neurology. 2024 Mar; 81(3): 255–263.)

Although the results need verification, the findings are a potentially exciting advance in the fight against Alzheimer’s. A simple blood test may eventually help identify which people should go on to have expensive PET imaging or an invasive spinal tap, required to determine whether a person might benefit from drugs that target the toxic neurofibrillary tangles or amyloid plaque.

The development of tests that can predict whether a person will develop the devastating symptoms of AD puts the use of some recent drugs, such as Leqembi (lecanemab), from Biogen, under scrutiny. Lecanemab was granted FDA approval on July 6, 2023. Here is the text of the FDA’s press release announcing their approval:

“Leqembi should be initiated in patients with mild cognitive impairment or mild dementia stage of Alzheimer’s disease, the population in which treatment was studied in clinical trials. The labeling states that there are no safety or effectiveness data on initiating treatment at earlier or later stages of the disease than were studied.”

Lecanemab/Leqembi won FDA approval primarily based on clinical studies that demonstrated conclusively that in patients who were in the early stages of Alzheimer’s disease, the drug delayed the disease process. Here is an excerpt from one of the decisive clinical studies:

“Lecanemab treatment resulted in significant reduction in amyloid plaques and a slowing of clinical decline. Data indicate that rapid and pronounced amyloid reduction correlates with clinical benefit and potential disease-modifying effects, as well as the potential to use plasma biomarkers to monitor for lecanemab treatment effects.” (Eric McDade, Alzheimer’s Res Ther 2022;14,121)

FDA approval at this point is limited to patients who are diagnosed as being in the early stages of AD. However, previous studies in lecanemab as well as in some similar drugs classified as BACE inhibitors point to the ability of these agents to have an effect on the processes that lead to cognitive decline before those processes actually take effect. To put it another way, treating individuals in advance of their developing AD may prevent the onset of the actual condition.

Aducanumab (trade named Aduhelm), the first BACE inhibitor, got FDA approval in on June 7, 2021 and was discontinued in January, 2024. According to aducanumab’s maker, Biogen, aducanumab was discontinued in order for the company “to reprioritize its resources in Alzheimer’s disease.” Clinical trial data showed that aducanumab provided statistically significant benefit in slowing cognitive decline in patients with early AD. Biogen asserted that discontinuing this drug was a business decision based on how it wanted to allocate its resources.

Researchers in AD had hoped that the FDA’s approval of aducanumab/Aduhelm would spur more research on BACE inhibitors. Aduhelm works (to the extent that it does work) by reducing the accumulation of amyloid beta (Aβ), which is one of two substances generally thought to contribute to the cognitive decline in Alzheimer’s patients. BACE is beta (β) secretase, the enzyme that cuts apart amyloid precursor protein (APP), which results in Aβ accumulation in the synaptic space between neurons, and the inhibition of the transmittal of neurotransmitters across this space. Since the transmittal of neurotransmitters from one neuron to another essentially constitutes brain activity, Aβ accumulation impeding this activity has been considered to be, if not the, at least an essential cause of AD.

The mechanism of action of BACE inhibitors is somewhat promising. If we can prevent the formation of amyloid beta, and if BACE inhibitors effectively accomplish this task, it would seem evident that BACE inhibitors would significantly alleviate AD symptoms. But BACE inhibitors are very large molecules, and they have great difficulty in passing through the blood-brain barrier in enough concentration to be at all effective. Several BACE inhibitors have been developed, but up to now they have disappointed all parties – pharmaceutical companies, clinicians, and patients. Patients in particular have been waiting for a drug – something! – that will meaningfully slow the progression of AD. Aduhelm does not appear to be it.

The FDA’s approval of aducanumab was not based on a published study, but on an analysis presented to the FDA that subjects in the EMERGE study taking aducanumab experienced somewhat slower cognitive decline than placebo subjects. The difference attained statistical significance, but the difference between aducanumab and placebo subjects was quite small – a fraction of a point on an 18 point scale. Biogen performed the same analysis on the ENGAGE study, but on this analysis aducanumab demonstrated no benefit at all in terms of cognitive decline.

Biogen’s withdrawal of Aduhelm/aducanumab and shifting of its focus to Leqenbi/lecanemab makes a tiny bit of sense in terms of the relative benefit of the two drugs – aducanumab delivering almost none, and lecanemab delivering some, but not much.

The benefit we have been discussing here is benefit to patients with established Alzheimer’s disease. But what about potential benefit to patients who have the precursors of AD that we discussed above – those neurofibrillary tangles and tau proteins? In my opinion, BACE inhibitors are unlikely candidates for treatment of the early neural changes that predict AD.

The focus of research should be on interventions that target the precursors of Alzheimer’s, now that several of these have been identified. It appears unfortunately evident that once the AD brain changes take place, reversing these changes is extraordinarily difficult. However, reversing those changes is precisely what treatment of established Alzheimer’s disease attempts to accomplish. Any interventions that might prevent the formation of those precursors that lead to Alzheimer’s would present an opportunity to halt the development of this dire disease.

The economics aspect of Alzheimer’s disease treatment

Looking at the economics around the one agent (so far) that appears somewhat to slow the advance of Alzheimer’s does not give us an encouraging picture. The annual price tag for Leqembi/lecanemab, set by Eisai/Biogen, is $26,500. It is projected to cost the Medicare program something in the range of $3.5 billion in 2025. Medicare and Medicaid patients will make up more than 90% of the market for Leqembi. Medicare costs for Leqembi are projected to be $5,300 per patient per year.

In addition to that significant price tag, because of necessary expenses related to treatment with Leqembi, the overall costs of treatment have been estimated to reach $82,500 per patient per year, almost all of which would be borne by taxpayers. These expenses include genetic tests, frequent brain scans, safety monitoring, and other costs. These estimates come from ICER, the Institute for Clinical and Economic Review, which is a Boston-based private organization whose primary focus is on the cost effectiveness of medical interventions.

ICER, by the way, has issued a public statement casting doubt on whether Leqembi/lecanemab should be widely adopted as a treatment for AD.

“Individuals and families dread Alzheimer’s disease, and the first therapy that effectively halts or reverses dementia will warrant a very high price in the US health system,” said David Rind, MD, ICER’s Chief Medical Officer. “Current evidence strongly suggests that lecanemab mildly slows the loss of cognition in patients with early Alzheimer’s disease. However, given the risks of brain swelling and bleeding, particularly when lecanemab is used outside of clinical trials, our report concluded that significant uncertainties remain as to whether the average benefits of lecanemab will exceed its risks. A majority of the California Technology Assessment Forum was clearly unconvinced that the current evidence adequately demonstrates that lecanemab provides a net benefit to patients. In addition, using the best current data from the clinical trials, at its announced list price lecanemab exceeds typical thresholds for cost-effectiveness and, given the large number of patients with Alzheimer’s disease, it is particularly important that therapies for Alzheimer’s disease be priced in line with their value to patients.”

I can’t disagree with the general principle that there needs to be a relationship between the price of a medical intervention, whether a drug or a procedure, and the benefit to patients. However, with regard to Leqembi in particular, I would favor employing this agent in patients with precursor indications in the effort to prevent the development of full-fledged Alzheimer’s disease. If it worked, it would save grief as well as money.

With apologies, a bit of bad news

The wave of federal employee layoffs has affected the Center for Alzheimer’s and Related Dementias (CARD), resulting in the termination of a tenth of the nearly 100 employees at the center. Workers there described a carefully woven web of collaboration that they say could be threatened by the layoffs of just a handful of employees, warning that it could jeopardize progress in answering key questions about dementia. This included the termination of lead researcher Kendall Van Keuren-Jensen, who was announced internally as the organization’s next acting director and was expected to bring significant advancements to the research field.

In addition, there have been 700 terminations at the Centers for Disease Control and 90 at the Food and Drug Administration of individuals who worked on nutrition, food safety and regulating infant formula.

Putting “molecular glues” to work in combating cancer

“Molecular glues” is a term that has been coined to describe small molecules that force two proteins to bind. These proteins would not normally interact, but the particular small molecules described as molecular glue trigger a response in one of the proteins, causing the protein to degrade. The response has been characterized as a “natural garbage disposal system.

Researchers have been exploring the possibility of using these so-called molecular glues to target disease-causing proteins. Until now, many of these interactions went unexploited because of their complexity and the difficulty of precisely locating them. However, recent research unveils a new scaffold and mechanism that can be used to design molecular glues to influence specific protein interactions and functions.

A team of scientists led by Harvard’s Department of Chemistry and Chemical Biology (CCB) has demonstrated how both small molecules and genetic mutations can alter the same critical protein interactions in cancer cells. These studies provide insights into two areas: discovering new molecular glues and understanding the impact of genetic mutations within cancer cells, setting the stage for therapeutic approaches.

Dr Brian Liau said “Our research has centered on understanding how specific mutations in medulloblastoma, a pediatric brain cancer, mimic the action of ‘molecular glues’ to drive oncogenic processes. During the course of these studies, we’ve detailed the convergence of genetic mutations and chemical modalities that alter protein interactions.”

One study explored how molecular glues alter essential protein interaction networks. The researchers showed that a molecule labeled UM171 works as a glue that can trigger the breakdown of an organizing system that controls access to genes known as the CoREST complex. Their findings demonstrate new ways for molecular glues to be used to target proteins traditionally considered not susceptible to being affected by external agents such as drugs, such as the so-called CoREST complex. Targeting these previously “undruggable” proteins may provide new strategies for drug design.

In a companion study, the researchers investigated cancer-causing mutations in the KBTBD4 protein, which is often found with mutations in a type of brain cancer. These mutations can turn normal cell interactions into harmful ones by changing how proteins connect, causing aberrant degradation of the CoREST complex.

The team was able to identify which mutations in KBTBD4 contribute to cancer. They then used cryo-electron microscopy to “see” these mutations at the atomic level. Combining these techniques, the team discovered that cancer mutations alter protein structure and function, mirroring the interaction of UM171 and KBTBD4.

A defining feature of this research was its focus on “convergence,” where a small molecule and a genetic mutation precisely mimic the effects of one another functionally and structurally.

This research presents a new strategy toward understanding and targeting proteins for small molecule drug discovery. The implications of the research go well beyond treating cancer, and could in the future reshape the approach to treating a range of diseases.

It should be evident to denizens of Planet Gumshoe that the research described above is years, if not decades, from generating drugs that are actually used to treat patients with cancer and other diseases. As you certainly know, that’s the normal course in drug development. And there can be detours and dead ends between the early research and the results of that research. But when the researchers push forward past the difficulties and complications, the results in terms of delivering concrete benefits to individual human beings, for whom previously there were no treatment options, can be highly consequential.

We saw that in the development of CAR-T drugs which, in some people with very advanced cancer, can completely eradicate the disease. The FDA approved the first CAR T-cell therapy in 2017 to treat children with acute lymphoblastic leukemia (ALL). Since then, other CAR T-cell therapies have been approved to treat adults with blood cancers like non-Hodgkin lymphoma and multiple myeloma.

My hope/expectation is that “molecular glues” will have similar success.

The FDA approves a new non-opioid pain medication

The drug is Journavx (suzetrigine), from Vertex Pharmaceuticals. It received the FDA’s nod this January 25th. Journavx is the first non-opioid analgesic to gain FDA approval in more than 20 years. It will be sold under prescription only, as a 50 mg pill to be taken every 12 hours. The cost will be $15.50 per tablet, according to Vertex.

The mechanism of action of this new analgesic is also new. It targets a pain-signaling pathway involving sodium channels in the peripheral nervous system, before pain signals reach the brain.

The FDA’s approval of Journavx/suzetrigine is in line with the agency’s policy of prioritizing the development on non-opioid pain medications, for obvious reasons. Vertex Pharmaceuticals has stressed that its new analgesic can be used for many types of moderate-to-severe pain, and in the two clinical trials that led to its approval there was no evidence that the medication was at all addictive.

Jacqueline Corrigan-Curay, acting director of the FDA’s Center for Drug Evaluation and Research, said in a statement “Today’s approval is an important public health milestone in acute pain management. This action and the agency’s designations to expedite the drug’s development and review underscore FDA’s commitment to approving safe and effective alternatives to opioids for pain management.”

Journavx/suzetrigine is primarily intended for treatment of acute rather than chronic pain. Acute pain generally follows an injury or surgery and is often more intense than chronic pain, but usually easier to treat than chronic pain. More than 80 million Americans fill prescriptions to treat acute pain each year, according to Vertex.

Journavx/suzetrigine was evaluated in two randomized double-blind clinical trials enrolling a total of 874 participants who had experienced surgical procedures. As is the rule in these trials, the subjects were not informed as to which arm of the trial they were in. Per the FDA’s approval statement, “Both trials demonstrated a statistically significant superior reduction in pain with Journavx compared to placebo.”

One of the drug trials followed abdominoplasty surgeries – known colloquially as a “tummy tuck” – while the other followed bunionectomies, or an operation on toes. Trial participants were randomly given placebos or the active drug, and all participants were able to use ibuprofen if the pain became too great.

Pain levels were measured using the Numeric Pain Rating Scale (NPRS) and the Sum of Pain-Intensity Difference over 48 hours (SPID48). Higher SPID48 and NPRS values are considered to be indicators of greater pain relief. In the abdominoplasty surgeries, treatment with Journavx resulted in greater pain relief compared with placebo estimated at 48.4 on the SPID scale, and in bunion removal, the difference between Journavx and placebo was 29.3 units. Both of these differences were considered statistically and clinically meaningful. The median time to meaningful pain relief was reported as 2 hours for abdominoplasty and 4 hours for bunion removal compared with 8 hours for placebo.

The most common reactions study participants experienced after receiving Journavx were itching, muscle spasms and rashes, according to the FDA.

According to the NCDAS (National Center for Drug Abuse Statistics) 9.7 million persons in the US misuse or abuse painkillers, and of the individuals who are addicted to prescription drugs, the great majority – 70% – are addicted to painkillers.

Whether the risk of addiction following analgesic treatment for acute pain is comparable to the risk of addiction following treatment for chronic pain is at present not known. At one time it was thought that if a person was prescribed an analgesic for the treatment of pain, he/she was not likely to become addicted, because once the pain diminished, that person would not need to continue taking the drug and would stop taking it. Unfortunately, that has not always turned out to be the case.

In any case, it is abundantly evident that the availability of medications for acute pain that are not opioid-based and are less likely to lead to addiction is a major blessing for the many persons around the globe who need treatment for these episodes of acute pain.

Some recent COVID-19 facts and figures

I agree, it’s a wearying topic. But here are some numbers to cheer you up, I hope! I’ll start with the weekly US death totals since the pandemic first emerged.

Total recorded deaths per week ending:

04/01/20 — 17,20108/01/20 — 8,28501/09/21 — 25,97407/03/21 — 1,54309/03/21 — 15,49311/13/21 — 7,15901/29/22 — 20,96804/23/22 — 1,34601/07/23 — 3,87107/15/23 — 51001/13/24 — 2,58406/03/24 — 31407/31/24 — 1,35302/01/25 — 274

These figures come from CDC data. I picked those dates to show how overall the death rate is decreasing, but there are still big changes in the highs and lows. As perhaps you observed, the death rate in the week ending this past July 31 was higher than the death rate in the week ending April 23, almost three years ago. But the general decrease since the peak in January 2021 is huge. The current death rate is less than 1% of the rate at that point. The trend is good, but we’re not over it.

The level of test positivity for the week ending March 1 is 3.9%, which is a bit down from the positivity level for the previous week. However, the percentage of emergency department visits for COVID is much lower, down 12.5% from the previous week.

The parade of variants continues. CDC is now tracking 35 different variants. The most common variant, now detected in about 32% of cases, is designated XEC. However, I would not call XEC a “dominant” variant. Back in January of 2024, JN1 was a genuinely dominant variant, responsible for 82% of the COVID cases.

What that tells us is that the coronavirus mutates rapidly and constantly, and is going to keep mutating. As it mutates, it will keep on infecting people. Infecting people is what the virus needs to do, in order to reproduce, survive, and mutate.

The encouraging part of this story is that, even as we’re besieged by armies of newly mutated viruses, our resistance to the harms brought by these nasty bugs is robust. Even if we should happen to get infected, the risks of serious harm are much, much lower. Almost all of us are either vaccinated and/or have previously been infected. That doesn’t entirely prevent infection with one of the new variants, but our cellular immunity, which recognizes the essential characteristics of the coronavirus regardless of the variant changes, protects us very effectively against serious illness and death. 

I’m looking forward to abandoning this subject, but in the meantime it’s probably just as well to stay informed.

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I’ll be looking into a treatment area that Doc Gumshoe has previously not paid much attention to – illnesses of the digestive tract. We all have digestive tracts, so it’s worth some attention.

Many, many thanks for all comments! Best to all, Michael Jorrin (aka Doc Gumshoe)

[ed note: Michael Jorrin, who I dubbed “Doc Gumshoe” many years ago, is a longtime medical writer (not a doctor) and shares his commentary with Gumshoe readers once or twice a month. He does not generally write about the investment prospects of topics he covers, but has agreed to our trading restrictions.  Past Doc Gumshoe columns are available here.]