Mind Matter

In October 2019, US biotech Biogen announced it would apply for marketing approval for its Alzheimer’s drug aducanumab. The news stunned scientists because the company, headquartered in Cambridge, Massachusetts, had previously announced that trials would be halted. No new drugs for Alzheimer’s have been approved since 2003, and there are no disease-modifying treatments.

Aducanumab is a monoclonal antibody that selectively snags the protein amyloid-beta in the brain, marking it for removal. It had looked destined to join a long list of monoclonal antibodies that tripped up in trials – including antibodies that successfully cleared troublesome amyloid plaques, yet without any improvements in patients. After analysing more data, Biogen said high doses of aducanumab slowed cognitive decline. The US Food and Drug Administration (FDA) must now decide on market approval.

Until now, all anti-amyloid therapies have failed, notes John Hardy, an Alzheimer’s disease researcher at University College London, UK, who describes himself as ‘cautiously optimistic’ about aducanumab. If it gets a green light, ‘it tells us that we have been right in our reading of the biology of the disease,’ he says.

Understanding of Alzheimer’s has been founded on what’s called ‘the amyloid-cascade hypothesis’ since the 1980s, when patients with early life Alzheimer’s were found to have mutations in genes that led to insoluble clumps of amyloid-beta protein. The same plaques were seen post-mortem in patients with the late-onset condition, who make up the vast majority of Alzheimer’s cases.

One strategy adopted was to cleanse the brain of these toxic clumps, but clearance did nothing for patients. ‘Even if you modify plaques in the brain by removing them with antibodies, which you can measure using PET imaging, you don’t really improve the symptoms,’ says Thomas Sakmar, a neuroscientist at Rockefeller University, New York, US.

Alzheimer’s is progressive, marked by the death of neurons. Some researchers believe that trial patients had suffered too much damage and that earlier detection could allow the same interventions to work. ‘By the time you get symptoms that are clearly measurable there is a tremendous amount of synaptic function already lost,’ says Sakmar.

Others agree. ‘It could be that they were perfectly good compounds, but were given too late,’ agrees Michel Goedert, a University of Cambridge neurobiologist.

There is growing consensus that identifying patients early will be key. PET imaging using ligands that attach to amyloid is one way to monitor Alzheimer’s, and early detection is now a holy grail since plaques seem to first start 15 to 20 years prior to a clinical diagnosis. Earlier detection could mean prompt action in removing plaques. ‘There is a movement towards treating mild patients including those still cognitively normal, but who already have [aberrant] protein in the brain,’ says Jeffrey Cummings, a neuroscientist at Cleveland Clinic in Las Vegas, Nevada, US, ‘with more emphasis on biomarkers as part of treatment strategies’.

But there is a second reason why clearance of plaques may not deal with symptoms. As the disease progresses, another protein called tau becomes chemically altered, and forms tangles within brain cells. Tau proteins sit inside nerve cells or neurons and naturally contain phosphate molecules. But in Alzheimer’s patients, these proteins become hyperphosphorylated, causing the tau proteins to twist around one another and form insoluble tangles that disrupt neuron signal transmission.

Amyloid plaques seem to encourage tau tangles, which Goedert believes then self-propagate like disordered prion proteins. In space and time, tau tangles more strongly match brain cell death and cognitive impairment than do amyloid plaques. When the tau signal on PET scans increases, cognitive performance falls in normal individuals and in patients with clinical Alzheimer’s.

It seems that when the brain is stressed, including through traumatic injury, tau becomes hyperphosphorylated and changes shape. ‘We now know that Alzheimer’s is a tauopathy,’ says Matt Campbell, a molecular biologist at Trinity College Dublin, Ireland. ‘In patients where antibody cleared amyloid from their brain, they still had an abundance of tau tangles.’

Amyloid plaques are thought to be a stressor that contribute to tangle formation. The long axons of nerve cells deform due to tangles. ‘At some point, it could be that the formation of tau tangles becomes self-sustaining, with prion-like spreading, so that even if you remove the amyloid, you have no improvement in symptoms,’ says Campbell.

Pharma companies know how to develop and deploy monoclonal antibodies. No surprise then that there are now also antibodies against tau in clinical trial, with one agent (LMTX) from TauRx Therapeutics in a Phase 3 trial scheduled to end in June 2020. Overall, 61% of drug candidates in Phase 3 trials for Alzheimer’s look to modify the disease, with 32% of total therapies being anti-amyloid; 4% being anti-tau; and 4% being anti-amyloid and anti-tau. It is possible that a combination of drugs that remove tau tangles and amyloid plaques could help patients in future.

Amyloid plaques seem to encourage the development of tau protein tangles, which more strongly match brain cell death and cognitive impairment than do amyloid plaques. When the tau signal on PET scans increases, cognitive performance falls in normal individuals and in patients with clinical Alzheimer’s.

Shifts in strategy are apparent further down the drug pipeline, with a broader array of therapies and mechanisms being evaluated in Phase 2 trials for Alzheimer’s. Amyloid reduction still dominates as a goal, with 12 small molecules and eight biologics targeting amyloid reduction, and making up 38% of disease-modifying therapies, according to a 2019 paper reviewing the Alzheimer’s drug pipeline (Alzheimer’s and Dementia, 2019, 5, 272). In Phase 2 though, 19% of disease-modifying therapies take aim at tau: four small molecules and six biologics. AbbVie, Biogen and Eli Lilly all have monoclonal antibody candidates targeting tau.

In the US, BioMedX is collaborating with AbbVie to develop a research tool that can detect modification of altered tau proteins in the brains and spinal fluid of sporadic Alzheimer’s patients. This could generate an early biomarker of the disease and allow patients to be treated early.

Campbell foresees targeting tau protein further upstream as a superior strategy. Recent research implicated NLRP3 inflammasomes – a complex of proteins that help trigger an innate immune response – in tau tangle generation. Loss of this inflammasome complex in mice protected them against tau pathology. It has long been thought that neuroinflammation plays a prominent role in Alzheimer’s, with brain protector cells known as microglia facilitating tau seeding and spreading. ‘We really need to start looking upstream and seeing what causes the end-stage disease states, such as phosphorylated tau and amyloid-beta plaques, to develop,’ says Campbell. ‘The NLRP3 inflammasome is a promising target, and there are lots of small molecules that are available to inhibit it.’ Once formed, plaques and tangles seem to stoke inflammation, accelerating cognitive decline.

There are also some researchers who view inflammation as the prime mover in Alzheimer’s clinical manifestations. ‘Neuroinflammation causes the bulk of cell death that leads to dementia,’ according to Rudy Tanzi, an Alzheimer’s researcher at Harvard Medical School. He believes that if the innate immune system ignores tau tangles and plaques, then dementia will not develop. Tanzi is investigating ways to curb the brain’s innate immune response to initial plaques and tangles. ‘The amyloid clinical trials failed because you are hitting the amyloid too late,’ he explains. He believes amyloid, rather than just junk, serves an antimicrobial role. He reported that herpes viruses can seed the production of amyloid in the brain within 24 to 48 hours, aggregating and trapping whichever pathogen is present. Tanzi also suspects that tau tangles may perform a similar function within cells.

Tanzi says the key to unlock therapies for Alzheimer’s lies in the immune system. When patrolling microglia cells encounter amyloid-beta, they react. ‘These are cues for microglial cells to induce neuroinflammation and basically wipe out that area of the grid,’ says Tanzi. Evolutionarily, the immune response to destroy sick neurons and pathogens was a sensible precaution in young people, but today the same immune response is reacting to age-related amyloid plaque formation.

‘A person with full-blown Alzheimer’s symptoms has massive neuroinflammation in response to plaques, tangles and cell death. That began 20 years previously and now we are trying to put out that forest fire by putting out a match, which is the amyloid itself,’ Tanzi explains. ‘Now we know that we have to hit the amyloid very early, which means you are going to do it in a 10 to 15 year prevention trial.’ As long as the drug is shown to be safe, the FDA is moving towards permitting such trials.

For patients with symptoms now, one approach could be to tune down microglia activation. Boston-based company FM Therapeutics, recently acquired by Novartis, developed candidate drugs to stop the formation of inflammasomes, which sound the initial alarm for microglial cells. Paris-based AB Science has an anti-inflammatory compound in Phase 3 masitinib trials which inhibits mast cells that play a role in neuroinflammation. Microglia are pressed into action by p38 mitogen-activated protein kinase (MAPK), which responds to various signs of stress. Netflamapimod (EIP Pharma, Boston, US) is also an inhibitor of this enzyme and has been evaluated as a treatment, with mixed results recently reported from a Phase 2 trial.

There is also increasing evidence implicating cholesterol metabolism. Amyloid-beta was recently found to stick well to lipid cell membranes containing cholesterol, and that this action increased the likelihood of amyloid clumping together (Nature Chemistry, 2018, 10, 673). Cholesterol is a waxy substance that can stick to artery walls and result in cardiovascular problems. Its presence caused amyloid clusters to develop 20 times faster than they would otherwise.

Population-wide studies suggest that cholesterol-lowering statins modestly reduce the risk of Alzheimer’s, and they have reduced amyloid production and tau pathology in mouse models of familial Alzheimer’s. Recent studies suggest plasma cholesterol levels are about 10% higher in Alzheimer’s patients; however, statins have failed to slow cognitive decline in Alzheimer’s patients. Still, there is an ongoing trial of simvastatin on patients with mild cognitive impairment – this is one of the more brain-penetrant statins.

What is more certain is that robust cardiovascular health benefits brain health too. ‘One thing you can do to reduce your risk of Alzheimer’s is to improve your cardiovascular health. If blood vessels in your brain are healthy, then your risks are decreased,’ explains Sakmar. A further issue is that in 80% of sporadic, late-onset Alzheimer’s cases, amyloid plaque gets deposited around small blood vessels and can starve them of oxygen, causing the death of neurons. Campbell says that healthier brain blood vessels bolster stress resistance.

His research focuses on the blood brain barrier, which can be leaky and varies through time. ‘We believe it is [centrally involved] in amyloid-beta deposition around blood vessels,’ says Campbell. He hypothesises that critical cells that line this barrier fail to allow enough amyloid to leak out into the bloodstream in patients with Alzheimer’s; the answer is to tweak them to allow the amyloid to defuse out. He envisages a therapeutic strategy of periodically stimulating leakiness in the blood-brain barrier, to suppress plaque build-up and arrest cognitive decline.

Many monoclonal antibodies that target amyloid for clearance find it difficult to traverse the blood-brain barrier. ‘About one in a thousand administered monoclonal antibody molecules enter the brain. The rest reside in the blood,’ says Cummings: ‘Nearly all monoclonal antibodies have had a four or five-fold increase in the dose administered, since the first trials. Companies realised they were getting far too little in the brain.’ Denali Therapeutics in San Francisco, California, US, is engineering molecules to cross the blood-brain barrier and has some candidates targeting Alzheimer’s.

After many clinical failures, Big Pharma has become more wary of investing in neurodegenerative diseases. A success, even a moderate success, could attract renewed interest. ‘I think people will be getting Biogen’s antibody next year,’ says Hardy, ‘but it will probably be only moderately effective and only for rich people in the US.’ Nonetheless, this will be an important achievement in his view. ‘Once you show it is possible, it brings other people in and things will move quicker,’ says Hardy.

Overall, experts say there will be no magic bullet for Alzheimer’s. Instead, all going well, there will be a plethora of therapeutics. It might also be necessary to target different therapeutics to different patient populations. ‘The overriding symptoms of memory loss in dementia patients might look the same,’ says Sakmar, ‘but each patient doesn’t necessarily go through the same pathogenic pathway, especially at the early stages.’ The trick will be to diagnose patients early, or identify those most at risk, and then have various options for treatment. Another plausible approach will be to combine therapies, perhaps simultaneously targeting plaques, tangles and inflammation.

A bright spot is that a delay would offer significant benefits to patients. Most patients begin to suffer from Alzheimer’s in their 70s. ‘If you could delay onset of the disease, even by on average five years, that would lead to a large reduction in the number of cases,’ says Hardy.

This seems like a low bar, but until now nothing has been proven to arrest or fix the symptoms. This is why the research community will closely monitor what happens with the Biogen antibody and whether finally a disease-modifying therapy makes it to market.

Image: JUAN GAERTNER / SCIENCE PHOTO LIBRARY