Prospects For The Next Generation Of Alzheimer's Disease Therapies

For Alzheimer's disease, researchers are looking for drug combinations, vaccines, and gene therapies to develop next-generation treatments. When neuroscientist Reisa Sperling received a lifetime achievement award at an international Alzheimer's disease conference last December, she was more excited about new treatments in the future than celebrating past accomplishments.

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Sperling, who was awarded for her work on clinical trials of Alzheimer's treatments, is gratified by the new hope for Alzheimer's disease. For years, research on Alzheimer's disease has been lackluster. Most of the other attendees felt the same way.

Just months before the meeting, researchers announced that an antibody drug called lecanemab significantly reduced the number of amyloid plaques in the brains of clinical trial participants and slowed their rate of cognitive decline.

Sperling directs a lab at Harvard Medical School in Boston, Massachusetts. When she took the stage to deliver her acceptance speech, she clutched the microphone, exuberantly saying that after more than 30 frustrating years of Alzheimer's research, there was finally evidence that people like them were on the right track. But that's still not enough.

In trials, the treatment slowed the rate of cognitive decline by 25%, enough to give participants several months of life.

In this regard, Sperling pointed out that defeating a devastating disease that affects tens of millions of people around the world is another matter. What's more, lecanemab, sold under the brand name Leqembi in the United States, requires complex and carefully monitored administration: it must be infused intravenously by a nursing professional; at the same time, because the drug can cause life-threatening brain swelling and Bleeding, so people taking this drug must be monitored regularly.

In 2021, the FDA approved a similar antibody, aducanumab, but the decision sparked controversy because clinical trials of the drug did not show clear efficacy.

Despite these twists and turns, the lecanemab findings reinforce the hope that Alzheimer's disease may ultimately be preventable if treated early. This success also raises the possibility that this drug and future drugs could be used in combination to target different stages of the disease, which are often controlled by different molecules.

Few expect a single treatment to solve the problem. Combination therapy trials, however, are expensive and complex because each drug must be tested individually and with partner molecules. Pharmaceutical companies may be wary of pegging their product to another product in case the combination fails and casts a shadow over their drug.

The confidence-boosting mood among industry insiders isn't just due to the success of the anti-amyloid antibody. At present, the pipeline of pharmaceutical companies is full of potential new treatments, and some drug candidates that were originally suspended have also returned to the stage.

Promising combination

Alzheimer's disease had a long, silent beginning. First, plaques -- clumps of sticky amyloid beta -- begin to accumulate in the brain. They were quickly surrounded by immune cells called microglia, which tried and failed to cannibalize them.

The plaques increased in size and number but went unnoticed for years or even decades until they caused another protein called tau to accumulate to toxic levels and spread in the brain in tangles. Scientists are still studying how this sequence of events occurs, but cognitive symptoms only appear when these plaques and tangles are going well. The severity of symptoms correlated with the degree of tau tangles.

So far, individual therapies targeting tau have performed poorly in trials. But scientists think tau-damaging drugs may work better when combined with anti-amyloid therapies.

They know that amyloid somehow drives the accumulation of pathological tau, which then spreads like wildfire in the brain, says neuroscientist Randall Bateman of Washington University in St. Louis, Missouri. So, they thought, while trying to extinguish the flames of tau tangles, it made sense to remove the beta-amyloid that fueled the flames.

Bateman et al. began planning such a trial in 2015, but it was not feasible until recently because amyloid therapy might prove effective. Last year, they launched an international trial called Tau NexGen. They recruited 168 participants, all of whom were at risk of developing Alzheimer's disease at an early age -- usually in their 30s, 40s, or 50s -- because of a mutation in one of their genes that caused them to develop Alzheimer's disease Produce beta-amyloid.

Participants were divided into two groups based on whether they already had symptoms of dementia or expected to develop symptoms within the next decade (these people tended to develop symptoms at the same age as their parents with the same genetic defect).

All participants will receive lecanemab and a tau-reducing antibody but in a different order. Those without symptoms will receive the anti-tau antibody E2814 for a year, followed by lecanemab; the symptomatic group will receive lecanemab for six months, then add E2814. The researchers conducting the trial hope they can use this setup to learn about the best combination of treatments.

More anti-tau drugs will eventually be included in this study, with the first results expected after 2027.

Tau NexGen is the first, and to date only, ongoing clinical trial of the combination drug for the disease. A similar trial is being planned in the United States for sporadic, late-onset Alzheimer's disease, which primarily affects older adults and falls into this category of most Alzheimer's cases. The National Institutes of Health (NIH) is expected to decide in the coming months whether to form a public-private partnership with the drug company to co-fund the effort, called the ATP trial. If so, patient recruitment could begin next year.

Several pharmaceutical and biotech companies are developing anti-tau therapies, some as antibodies, others using other small molecules or new genetic approaches to block the production of pathological forms of tau. Adam Boxer, a neuroscientist at the University of California, San Francisco, who co-leads the ATP trial, notes that several of these companies have already formally expressed interest in participating.

Like Tau NexGen, this will be a precautionary trial. Participants will have few or no detectable symptoms, but there is evidence from blood tests and scans that their brains contain early signs of plaque and tau tangles. Approximately 900 participants will be divided into 6 groups: 1, first tau therapy alone; 2, second tau therapy alone; 3, first tau therapy combined with lecanemab; 4, second tau therapy Therapy was combined with lecanemab; 5, cinema alone; 6, placebo.

The research team hopes that anti-tau therapy will increase the therapeutic benefit of lecanemab, and in a virtuous circle, by reducing plaque burden, cinema will create better conditions for anti-tau therapy to work.

Key to the trial is a set of sensitive new biomarkers -- measurements in the brain or blood that can confirm the disease state. Brain scans monitor the presence and severity of amyloid plaques and tau tangles; tests on blood or cerebrospinal fluid can measure many other molecules in the pathological chain, such as different forms of amyloid and tau.

The researchers anticipate that the wealth of molecular and clinical data they have generated will help reveal more about the mechanisms of Alzheimer's disease. Boxer cautions that, so far, the evidence points to tau as a driver of Alzheimer's symptoms, disability, and ultimately death. But this hypothesis needs to be tested in humans.

Trials of combination therapies have some drawbacks: They are complex and costly to administer. Despite new biomarkers that could improve clinical trial efficiency, the ATP trial will still cost hundreds of millions of dollars, Boxer estimates.

Antibodies are expensive treatments in their own right. Lecanemab will be priced at $26,500 for a one-year course of treatment. Aducanumab (sold under the name Aduhelm in the U.S.) initially cost $56,000 for a year of treatment, but the manufacturer cut the price in half after a public outcry.

These drugs are also inconvenient for patients because they must be infused every few weeks. Neurologist Paul Aisen of the University of Southern California in San Diego, who directs the US Alzheimer's Clinical Trials Consortium, points to data from clinical trials showing that lifelong treatment is needed to control Alzheimer's disease. sick. The disease appears to rebound when the infusion is stopped. Because long-term antibody therapy is impractical, they thought it might make sense to maintain a low-amyloid state with an oral drug that blocks peptide production once the antibodies have removed the plaques.

Such compounds do exist. Beginning around 2010, researchers experimented with a suite of oral drugs designed to reduce amyloid in the brain by modulating the activity of an enzyme called beta-secretase and gamma-secretase key to protein production. But clinical trials of these drugs have failed, and interest in them has dried up, until now they're getting a second chance.

Other drug candidates

In 2018, a group of pharmaceutical companies agreed to do something unusual in their normally secretive industry. They decided to share confidential clinical data from six failed trials with each other and with a group of experts convened by the Alzheimer's Association, a patient rights group based in Chicago, Illinois. lobby groups.

The society hopes to learn as much as possible from the disastrous clinical trials, each of which tested a different beta-secretase inhibitor. None of the drugs have shown a benefit, and worse, many have toxic side effects, including worsening cognition in some cases.

The association wants to discuss the trial data in detail, not have the trial data locked away in a drawer. The society's chief scientific officer, Maria Carrillo, says the goal is "to help the field learn more about the disease-associated organisms that these investigational drugs target."

A review by the group, to be published in 2021, suggests that trial participants may have been too sick for the class of drugs to improve symptoms and that lower doses could avoid side effects. Aisen believes that once existing plaque is cleared by antibodies, it may be possible to use these drugs at low doses to prevent plaque recurrence.

Several clinical trials targeting γ-secretase also failed. But instead of giving up on that goal, researchers have been working on a more subtle approach. They wanted to alter the enzyme's behavior, not completely block it -- which clinical trials have shown can lead to toxic side effects.

A compound developed in academic collaboration with such a function will be tested in early clinical trials this year. The drug, taken orally, causes enzymes to break down amyloid into shorter proteins that are nontoxic and even protective. The trial will be sponsored by Acta Pharmaceuticals, a new startup in Boston, Massachusetts, and funded by the National Institutes of Health.

Most of the drugs being considered for combination trials target amyloid or tau proteins. But some early approaches try to improve the brain's natural immune defenses against Alzheimer's. Again, researchers have learned a lot from families with genetic mutations that predispose them to Alzheimer's.

The mutation in question is in a gene called TREM2, which produces a molecule that sits on the surface of microglia, the brain's immune system fighters. Regulating microglia could make them more efficient at clearing plaque or preventing the spread of amyloid pathology, says neuroscientist Christian Haass of the Ludwig Maximilian University of Munich in Germany. Especially if plaque burden is first reduced by anti-amyloid therapy. He is planning experiments in mice to test how an antibody that binds TREM2 and activates microglia might work if given along with anti-amyloid therapy. A similar antibody is in early clinical trials as a monotherapy.

Vaccines, Genes, and Plasma

More and more treatments for Alzheimer's disease are entering clinical trials. Researchers aim to deliver useful molecules to the brain via vaccines, viral vectors, or blood transfusions.

Like enzyme drugs, vaccines are being reinvented long after the first clinical trials of an anti-amyloid vaccine were halted in 2002 when brain inflammation was observed in some participants.

Several anti-tau and anti-amyloid vaccines are currently in preparation for early clinical trials. They include fragments of tau, or beta-amyloid, that are screened and packaged to avoid severe inflammatory responses. They are designed to stimulate the brain's immune system to recognize and destroy the full version of the protein, primarily to prevent disease or slow the progression of early-stage disease. Scientists have even tried to develop vaccines that attack both tau and beta-amyloid.

Other researchers are betting on gene therapy to overcome Alzheimer's disease caused by genetic mutations.

Different forms of the APOE gene, which encodes a protein involved in fat metabolism, affect Alzheimer's risk in different ways. The APOE4 allele is associated with increased risk, while the APOE2 allele reduces risk.

New York City-based Lexeo Therapeutics enrolled 15 volunteers with mild Alzheimer's disease symptoms in its open-label trial who had two copies of the APOE4 gene. They wanted to test whether passing on the APOE2 gene variant would mitigate the harmful effects of the high-risk gene variant. So they ligated the gene to a viral vector and injected it directly into the volunteers' spinal fluid.

The gene transfer appears to be successful. Lexeo reported last year that the APOE2 gene was detected in the spinal fluid of some participants a year after the injection that no serious side effects have been observed so far, and tau levels have dropped in participants. It is too early to assess whether disease progression has been slowed as a result, but participants will be monitored until 2028.

Gene therapy isn't for everyone because known genetic mutations determine only a small percentage of Alzheimer's cases. But the concept of alternative medicine has been embraced by others. San Carlos, California-based Alkahest has completed a small clinical trial testing whether factors in the blood of young people can replace those lost during aging.

Some researchers have found success with low-tech approaches. For example, a large, well-controlled trial showed that 18 months of aerobic exercise or stretching could suppress cognitive decline in patients with mild cognitive impairment, underpinning the value of staying active during drug treatment.

It's too early to say which, if any, of these potential new treatments will be successful. Most researchers agree that treatment needs to be individualized: individuals at different stages of the disease need different treatments. It's great to see so many plausible approaches being taken, Aisen cautions. But we still have a long way to go.

Still, it's encouraging that so many approaches are making it into clinical trials, Sperling said. A new dawn of success is driving us forward.

How does Cistanche extract treat Alzheimer's disease

There is some research suggesting that Cistanche extract may have a protective effect against Alzheimer's disease. 

One possible mechanism is its ability to increase levels of certain neurotransmitters, such as acetylcholine, in the brain. Acetylcholine is a neurotransmitter that is important for memory and cognition, and levels of this neurotransmitter are often decreased in people with Alzheimer's disease.

Cistanche extract also contains a number of bioactive compounds, including phenylethanoids and iridoids, which have been shown to have neuroprotective and anti-inflammatory effects. These effects may also help to prevent or slow the progression of Alzheimer's disease.

Original search:

Alison Abbott. (2023) Conquering Alzheimer’s: a look at the therapies of the future. Nature: 616, 26-28.