Neurodegeneration: Are We Closer to a Cure, or Still a World Apart?
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“This is all sounding pretty bleak.”
George Perry isn’t wrong. As the editor-in-chief of the Journal of Alzheimer’s Disease, Perry, also the Semmes Foundation Distinguished University Chair in Neurobiology at the University of Texas at San Antonio, has amassed over 1,000 publications in a 40-year career studying the leading cause of dementia. But speaking with Technology Networks about the direction of travel in the field, Perry’s view on our progress toward treating Alzheimer’s disease, which killed over 120,000 Americans in 2019, is profoundly pessimistic.
A schism in neurodegeneration
The landscape of neurodegenerative research has fractured into two camps in recent years – those wedded to the elimination of pathogenic proteins and those pursuing other avenues of research. First, some background. The major neurodegenerative diseases – Alzheimer’s, Parkinson’s and amyotrophic lateral sclerosis (ALS) – proved inscrutable in the decades after clinicians identified their key symptoms. When Alois Alzheimer presented what he called a “peculiar severe disease process of the cerebral cortex” to a group of German psychiatrists in 1906, he was able to detail his patients’ paranoia, memory loss and confusion. But examination of their brains gave little information away about what caused their symptoms, except that it might have something to do with protein deposits – what we now know as amyloid plaques and tau tangles – scarring their cerebrums.
Much neurodegenerative research has followed this thread ever since. The seductive promise underlying this work was that if we could identify and map these proteins, before clearing them from the brain, perhaps cognition and memory would be restored, or at least be spared any further decline.
Our knowledge of how these pathological proteins spread and become deposited throughout the brain in many major neurodegenerative diseases is now extensive. We’ve found genetic clues, which tie mutations that increase levels of these proteins to rare, severe dementias. Alzheimer’s disease research has attracted more funding than any other neurodegenerative condition – seeing over $3.3 billion of investment from the U.S. National Institutes of Health (NIH) in 2022 alone. Nevertheless, our improved understanding of Alzheimer’s molecular mechanisms has yet to bridge over to effective treatments that reverse disease progress.
This lack of development is only part of the reason for Perry’s gloomy outlook on Alzheimer’s research. The future of the field’s funding also gives him cause for concern. He participated in an all-too-rare academic debate session at the American Academy of Neurology meeting in 2017 – one emblematic of the opposing directions in the research field. His opponent: Dr. Reisa Sperling, a neurologist at Harvard University. Perry pitched moving the field beyond protein-centered studies by switching funds to other avenues of research. Sperling pushed back – using the argument that existing therapies had simply targeted the disease at too late a stage.
“Tenuous” results
A show of hands suggested that, on the day, Perry convinced more of the audience than Sperling. But if a rematch was scheduled in 2023, the outcome might be different. In the last six years, a trio of Alzheimer’s drugs have notched up results that amyloid advocates tout as a vindication for their arguments. Aducanumab, lecanemab and donanemab – each an immunotherapy targeting a different stage of the amyloid plaque formation process – all showed statistically significant effects in slowing cognitive decline. Perry tells Technology Networks that these results are likely sufficient to ensure the focus on the field remains on amyloid and a related protein, tau, for the foreseeable future. He does, however, view these effects as “really tenuous”, and he’s not alone.
Why are amyloids so important in neurodegeneration?
Amyloids are groups of proteins that adopt a fibril-like appearance and a complex secondary structure. The formation of thick amyloid plaques is a process that appears to underlie many neurodegenerative conditions. The most notorious amyloid is amyloid-beta (Aβ), which is the dominant target of therapeutic interest within Alzheimer’s disease and is believed to play a key role in the disease’s progress. It has been afforded this lofty status based on decades of research that began with genetic analysis of a gene called APP, which codes for the amyloid precursor protein. Mutations in this gene were found to be causative in genetic forms of Alzheimer's disease.
Further analysis has revealed that the APP protein is cleaved by enzymes called secretases in a process that releases downstream proteins like Aβ. The release of Aβ is a normal physiological process – it is thought to have many roles in the healthy brain that may include controlling how synapses work and repairing leaks in the blood-brain barrier. But in Alzheimer’s disease, an increase in the amount of APP present is followed by a so-called proteinopathy, where levels of Aβ spiral out of control in the brain. This prompts various monomeric forms of Aβ, such as Aβ40 and Aβ42, to aggregate into oligomers and then fibrils, before eventually forming dense plaques that disrupt normal brain physiology. This same kind of amyloid proteinopathy is seen in other neurodegenerative conditions, like Parkinson’s disease – where the amyloid protein involved is called alpha-synuclein – and Huntington’s disease – where Huntingtin protein plays a key role.
Aducanumab, the first compound out of the regulatory hurdles, skipped deftly to an accelerated approval by the US Food and Drug Administration, only to painfully collide with a wall built by unconvinced academics and insurers. These skeptics, Perry included, pointed to the highly unusual statistical techniques used by developers to squeeze significance out of their data and a real-world clinical effect that seemed minor at best. Lecanemab, approved using the same pathway, showed less shaky data, but still had a “placebo-like” effect size, says Perry. The latest kid on the block, donanemab, has, on paper, the best results of all – although at the time of writing only preliminary data has been released on its efficacy – which suggests a 40% reduced decline in a major scale of activities affected by dementia. Even if the final data from this latest compound show significant clinical benefit, there remain two substantial stumbling blocks. One is the disconnect between how these compounds affect protein levels in the brain – dodanemab cleared amyloid from nearly three-quarters of patients after 18 months – and how they affect clinical outcomes – less than half of the group showed no decline in cognition over the same period. Reports of side effects associated with the drug have also proved a cause for concern.
Serious side effects
Investigative reports published in Science and STAT have detailed three fatalities in the extension phase of the lecanemab trial. The fatalities were linked to brain swelling and bleeding events, milder versions of which have been noted as a common feature of anti-amyloid immunotherapies. These mild events, called amyloid-related imaging abnormalities (ARIA), are just that – clinical signs detected by neuroimaging techniques that normally have no functional impact. But the concerning case reports from the lecanemab trial include that of a 65-year-old woman who suffered a stroke and presented with signs of ARIA. After being given a common anti-clotting drug, the woman reportedly suffered a massive brain bleed and died. The drug’s developer claimed in response that the deaths were unrelated to lecanemab’s action. Recently, three additional deaths related to dodanemab-induced ARIA in a Phase III trial were disclosed. While this only corresponds to a 1.6% incidence across the entire trial, 31% of trial participants, versus 13% given placebo, showed sub-clinical microbleeds in the brain.
Are these potential side effects worth it, weighed up against the ceaseless and cruel effects of dementia? Perry points out is that “none of these drugs are being prescribed for the end phase of this disease.” By design, all three immunotherapies target early-stage disease. But it’s in this phase that the timing of disease progression remains uncertain. Some patients, Perry suggests, could have decades of relatively independent life ahead of them. Up to half of cases of mild cognitive impairment (MCI) – a dementia precursor – in people 65 or older recover after 4 years. This makes the risk–reward ratio of the immunotherapies much more uncertain, as do other unsuccessful efforts in the field. After her debate with Perry, Sperling received funding to trial the Alzheimer’s drug solanezumab – which had previously failed to treat advanced Alzheimer’s – in patients with pre-clinical disease. These patients were treated with the drug before any cognitive impact was seen. The trial took ten years and enrolled 1100 people. The drug failed once again.
Moving the focus for neurodegeneration
What remains clear is that the solution to dementia is unlikely to involve a single point of contact. One believer in a multi-pronged approach to treating neurodegeneration is Sara Imarisio, head of strategic initiatives at Alzheimer’s Research UK (ARUK). A major funder of research, Imarisio says the charity works around three major goals – diagnosis of people living with dementia, treatments for this same group and risk reduction and prevention. “We are keen to support innovative research,” she explains. With so much money pouring into pathological protein research from major drug companies, ARUK has “less focus” on amyloid with its new grants, says Imarisio.
Other areas of Alzheimer’s research are currently at a less advanced stage than amyloid, but in Imarisio’s eyes, that picture is changing: “Neuroinflammation is kind of exploding at the moment,” she says. Genomic studies into Alzheimer’s have always pointed a finger in the direction of immune contributions to the disease: in particular, genes coding for the molecule TREM2, which is found on the brain’s in-home immune cells, microglia. This first genetic research, published in 2013, was led by ARUK-funded scientists. Just a decade later, a clinical trial targeting TREM2 is underway. While this dynamic approach to funding might be practiced by bodies like ARUK, Alzheimer’s researchers still believe there is a price to not focusing on amyloid. Axel Montagne, a Chancellor’s Fellow and UK Dementia Research Institute group leader at the University of Edinburgh, researches the vascular contribution to neurodegeneration. This field explores how blood flow to the brain sustains brain health and how impairments to this supply might precede other signs of neural damage. Montagne recognizes the importance of studying amyloid and tau to dementia research, but says vascular work is “underestimated and underfunded.”
“There's growing evidence in both humans and mice using imaging biomarkers that [vascular changes] are happening very early, and we can detect that, and we need to understand the biology,” he says.
Going with the flow
Montagne, like Imarisio, views strategies targeting amyloid as insufficient. A “cocktail” of drugs might be required, he suggests. He points to work that has revealed how transporter molecules called RAGE and LRP-1 act to shuttle amyloid proteins across the barrier between the brain and the general circulation. “These are disrupted very early in Alzheimer’s disease,” says Montagne. “If you fix this, you can at least fix the balance and make sure that amyloid excess is cleared out.”
The contribution of vascular factors is clearer in other forms of neurodegeneration. Cerebral small vessel disease (CSVD) refers to a group of conditions that affect the vast networks of veins, capillaries and arterioles that funnel blood to and from the deep brain. CSVDs are thought to contribute to 45% of dementia cases. Montagne mentions research his lab is conducting that suggests the shared symptoms between Alzheimer’s and CSVDs, including cognitive decline, are accelerated in initially healthy people who have poor vascular health. The challenge for Montagne and his fellow researchers is that this kind of longitudinal research is expensive and by definition doesn’t produce quick results – there’s no guarantee that study participants will come to be affected by neurodegeneration. But this broader focus could help to capture vascular problems that underlie a broader range of neurodegenerative conditions – with a potentially greater payoff.
Beyond the brain
Other neurodegenerative research has cast an even wider net, looking beyond the brain entirely. Dr. Caroline Williams-Gray, a group leader at the University of Cambridge’s Department of Clinical Neurosciences, studies PD, with a focus on the peripheral immune system – the constantly changing mixture of cells and chemicals that flow around our body, guarding us from biological threats. The body’s immune system is activated PD – immune cells in both brain and body fire out chemical stimulants and messengers. Neuroimmunologists think that this process may drive the neurodegeneration that ultimately leads to the loss of control over movement that defines the condition. Immune molecules are activated by the presence of alpha-synuclein, a protein that builds up in the Parkinson’s-affected brain much like amyloid and tau do in Alzheimer’s. Williams-Gray explains that alpha-synuclein, leaking from the brain via the lymphatic system or by nerve cells in the gut, may fire up immune cells, which then migrate to the brain, causing cellular mayhem as they damage the very cells they are trying to protect from this intruding protein.
But with so much activation throughout the body, Williams-Gray says, “the challenge is knowing which aspect of this over-activation to target therapeutically.” A new trial she is leading involves the rheumatoid arthritis drug azathioprine. This drug’s broad immunosuppressing action should allow the trial team to work out if limiting the ability of immune cells to infiltrate the brain can slow Parkinson’s progression. Like Montagne’s vascular work, this exploration is at an early stage – azathioprine has a broad and blunt effect on immune cells that will act as a crowbar, opening up an area of research that can be followed with the delicate stylus of cell-targeting treatments later. “As our knowledge of the precise mechanisms underlying immune activation in PD unfolds, we will be able to move towards more targeted therapies with less 'off-target effects',” says Williams-Gray.
A complex mechanism
The ultimate goal of Williams-Gray’s research, she says, is to design personalized treatments – modular medicines that can be tailored to address the full range of disease courses and stages that people with Parkinson’s present with. This vision has now come into focus in cancer research – a field that has benefited from far higher funding than that received for neurodegenerative conditions. But more money, as Perry points out, will have to be wisely spent, recognizing that the degenerating brain isn’t an incomplete jigsaw missing a stray piece fallen through a crack in the table. Rather, it’s a complex piece of machinery that still ticks largely like it used to, but is now subject to wild and unexpected deviation requiring complex and careful repair.
That fix might involve a realization that certain gears and pistons can’t be put back in place, can’t be set to chug and whirr in the way they once did. But that they might instead be helped to function as well as possible in their new configuration. In the battle to find therapies for the future of neurodegeneration, the fight to help those coping with these diseases now should still be recognized. “Maybe there isn’t a cure, with current technology,” says Perry. “But there’s certainly better ways to live with it.”