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FOR the first time in nearly two decades, a new treatment for Alzheimer鈥檚 disease was approved by the US Food and Drug Administration in June. But instead of joy and relief, the announcement was largely met with frustration and even anger. Some experts pointed out that the clinical trial that was the basis of approval for Biogen鈥檚 drug aducanumab . Instead, the FDA based its unprecedented decision on evidence that the drug treats the underlying cause of Alzheimer鈥檚.

The trouble is, it is far from clear that the target of this drug 鈥� clumps of beta-amyloid protein 鈥� is truly the cause. Drugs aimed at beta-amyloid have failed time and time again. ; some experimental medicines even seemed to make cognition worse.

With this new drug, there were also concerns about the FDA approval process. Ultimately, the agency鈥檚 acting commissioner Janet Woodcock requested an investigation into her own agency鈥檚 decision-making.

But the controversy isn鈥檛 limited to this decision. The big worry is that the continued focus on beta-amyloid is a dangerous distraction, that it may actually obscure the complex nature of the disease and waste precious time. The growing consensus is that there is no single cause of Alzheimer鈥檚, but a complex web of contributing factors. That may not seem like good news, but there is a silver lining: many different factors can provide many paths for treatment.

The only way is amyloid

Worldwide, there are 10 million new cases of dementia every year 鈥� and roughly two-thirds of these are Alzheimer鈥檚 disease. Staggering sums of money have been invested to try to understand the underlying cause, with much of the focus on one explanation.

Initially, there was good reason for that. The amyloid hypothesis . Having one of these . Since beta-amyloid plaques in the brain are a hallmark of the disease, it seemed likely this was the culprit. Other contributing factors were acknowledged, but the idea was that these followed the initial problem with amyloid, in what is known as the 鈥渁myloid cascade鈥� hypothesis.

So far, amyloid-busting drugs have failed to actually improve symptoms of the disease. But some experts hope they might yet be effective, if they are given before symptoms appear 鈥� and other .

Rudolph Tanzi, who studies the molecular genetics of Alzheimer鈥檚 at Harvard University, says the thinking now is that the role of amyloid in Alzheimer鈥檚 is similar to the role of cholesterol in heart disease, in that levels are elevated for decades before the onset of symptoms. If doctors can spot high cholesterol levels early, they can prescribe medications to lower them and prevent heart damage. But once a person has severe congestive heart failure, these drugs will be insufficient. It isn鈥檛 routine for doctors to measure beta-amyloid levels in people, so by the time someone has symptoms of Alzheimer鈥檚, clearing up plaques won鈥檛 undo the damage. Many people are searching for biomarkers to help us detect the disease years before symptoms appear, and so give these preventive treatments a fighting chance.

Tangled up in tau

Beyond beta-amyloid, another major hallmark of Alzheimer鈥檚 in the brain is accumulation of a protein called tau. In healthy brains, , but certain changes can cause it to clump together inside axons (the arms connecting the main body of a neuron to other cells), interfering with a neuron鈥檚 ability to communicate.

Once people develop Alzheimer鈥檚, the amount of tau build-up actually correlates better with dementia severity than the amount of beta-amyloid, which suggests it plays an important role in the progression of the disease once symptoms have begun, says Einar Sigurdsson at New York University. 鈥淭argeting tau is probably a more feasible approach in the later stages of the disease,鈥� he says.

Unfortunately, here too, we don鈥檛 yet have any successful drugs. As the vast majority of tau build-up is inside neurons, targeting it is tricky. Tau can also take many , and it is unclear which are the best to target. A few trials of , but other therapies are in development.

In the meantime, there are things we can do to reduce our risk of accumulating harmful tau tangles. Sigurdsson says there has been relatively little research on how lifestyle factors affect tau pathology, but that in general 鈥渨hat鈥檚 good for your heart is good for your brain鈥�.

Clues in our genes

Genes clearly play a part in Alzheimer鈥檚 disease, because a small proportion of cases occur earlier in life, as a result of specific genetic mutations. These are exceedingly rare 鈥� about . But there are many more common gene mutations loosely connected with late-onset Alzheimer鈥檚 disease. .

Researchers are studying the roles of APOE. The e4 variant seems to promote formation of beta-amyloid plaques and may also increase neuroinflammation that affects the function of the blood-brain barrier, the protective layer that controls the movement of molecules and cells between the brain and the bloodstream.

While some strategies targeting APOE seem promising in animals with Alzheimer鈥檚-like illness, very few have been tested on humans. One especially interesting early stage trial is now testing whether a .

Unfortunately, for now, there is nothing you can do about your genes, and genetic testing for APOE variants isn鈥檛 generally advised. That is because it doesn鈥檛 definitively determine whether you will get the disease 鈥� plenty of people with the protective form still get Alzheimer鈥檚 and plenty with the risk-enhancing form never do.

Outside invaders

Infections may also play a role in the likelihood of someone developing Alzheimer鈥檚. Although there have been conflicting findings over the years, evidence is building that certain viruses and bacteria increase risk.

In particular, research has implicated bacteria that cause gum disease. A . In 2019, researchers at US biopharmaceutical company Cortexyme . They found this microbe 鈥� as well as the toxic enzymes it produces 鈥� in the brains of people with Alzheimer鈥檚 after they had died. In mice, they showed that this bacterium could migrate from the mouth to the brain. Giving the mice a drug that blocks the activity of the toxic enzymes reduced inflammation in the brain and lowered levels of one type of beta-amyloid. The company has now . Results are expected by the end of 2021.

As for how to reduce your risk: there isn鈥檛 yet a direct link between dental hygiene and Alzheimer鈥檚 risk, but it is probably a good idea to brush, floss and see your dentist regularly.

Friendly fire?

It may not be the microbes themselves causing Alzheimer鈥檚, but rather how our bodies respond to them and other perceived threats. Multiple , for example. Initially at least, this response may protect the brain: Tanzi, along with colleagues Robert Moir and Richard Lathe, has . At first, amyloid triggers an immune response 鈥� inflammation 鈥� which helps to clear the infection. But if inflammation persists, it can cause harm. One aspect of this inflammatory response is that brain cells known as microglia and astrocytes become activated into a neuron-damaging state, 鈥渉ousekeepers turned killers鈥�, says Tanzi.

He and others are trying to find a way to flip the switch back. 鈥淲e鈥檝e been screening every approved drug, every natural product, for the ability to tell microglial cells and astrocytes to stop killing and go back to work as nurturers and housekeepers for the neurons,鈥� he says. So far, they have about 35 promising substances. The next step is to test these in animals.

But taming microglia is just one way to reduce inflammation, which can be triggered in many ways. We know, for instance, that people with autoimmune disorders such as rheumatoid arthritis or Crohn鈥檚 disease have higher levels of a pro-inflammatory protein called tumour necrosis factor (TNF). Mal煤 Tansey, director of the Center for Translational Research in Neurodegenerative Disease at the University of Florida, says that people with long-term elevated levels of TNF have a higher risk of developing neurodegenerative disease, but that anti-TNF therapies can reduce this. In mouse models of Alzheimer鈥檚, Tansey and her colleagues have shown that .

Tansey says build-up of proteins like beta-amyloid is important for Alzheimer鈥檚, but doesn鈥檛 believe it is the initiating factor. 鈥淲e need to think about protein aggregation not as triggering the inflammatory immune dysfunction, but resulting from it,鈥� she says. By identifying and treating immune dysfunction, we may be able to prevent the disease.

But what kicks off inflammation and TNF production in the first place? While genes are one factor, Tansey鈥檚 , including in the brain. Blocking TNF can prevent many of these effects, she says.

It remains to be seen if these findings can be translated into treatments. Until then, there may be other ways to reduce inflammation. While there are some exceptions, research generally shows that and , saturated fat and sugar support healthy brain function as we age.

Off to sleep

and , studies have linked Alzheimer鈥檚 disease and sleep problems, but the nature of this relationship isn鈥檛 fully understood 鈥� and probably . While we sleep, potentially harmful proteins are flushed away by the brain鈥檚 waste-removal apparatus, . Even a . But lack of sleep can also promote and . Additionally, the mechanisms controlling our body clock may play a role in the development of neurodegenerative disease, says Erik Musiek at Washington University in St Louis, Missouri, by regulating sleep patterns and inflammation.

Drugs currently used to treat sleep disorders such as insomnia could be useful against Alzheimer鈥檚 as well, says Musiek. Mouse studies have shown that . A .

Musiek says that working out how sleep and our body clock protect our brains is important for finding new treatments. 鈥淚f we knew that when we sleep it activates this particular pathway in this particular kind of cell, and that鈥檚 why [sleep] is protective, then you could just make a drug that does that.鈥�

In the meantime, there is plenty we can do to improve the quality of our sleep, which, unlike prescription drugs, has no negative side effects. The American Academy of Sleep Medicine recommends .

A blow to the head

We now know that brain injury can increase the risk of developing dementia later in life: . While Alzheimer鈥檚 is the most common form of dementia, there isn鈥檛 conclusive evidence that head injury leads to it specifically, says , a neuropsychologist and specialist in brain injury at Mount Sinai Hospital in New York. There is overlap between Alzheimer鈥檚 symptoms and those experienced after traumatic brain injury 鈥渨hich can make it difficult to disentangle them鈥�, she says.

It is important to stress that brain injuries are just one of many risk factors, and even if people who have had a traumatic brain injury (TBI) are, on average, at a greater risk for neurodegenerative disease, 鈥渕ost TBI survivors will not develop dementia鈥�, says Dams-O鈥機onnor. 鈥淪tudying those [who don鈥檛] is just as important as studying those who decline, as it can begin to point us toward resilience factors 鈥� some of which may lead to additional treatment targets.鈥�

Effective treatments for long-term brain injury symptoms are limited, but Dams-O鈥機onnor says we can help safeguard brain health after a head injury with healthy diet, good sleeping practices, exercising, keeping socially active and pursuing cognitively demanding activities. She also stresses the importance of regular medical visits.

鈥淎lzheimer鈥檚, as currently understood, is really not a single disease鈥�

, especially for older adults. Using a seatbelt, wearing a helmet while on a motorbike or bicycle and getting your vision checked regularly to prevent falls can all help.

Pulling it together

The vast majority of researchers studying Alzheimer鈥檚 now acknowledge that the disease has multiple contributing factors that involve cascades of cellular and molecular processes that we don鈥檛 yet understand. 鈥淎lzheimer鈥檚 disease, as it is currently understood, is really not a single disease,鈥� says neurologist Costantino Iadecola at Weill Cornell Medical College in New York. 鈥淚t鈥檚 a number of pathologies that all result in cognitive impairment.鈥�

George Perry at the University of Texas, San Antonio, says that the past obsession with a single cause 鈥� amyloid 鈥� hindered progress. For heart disease, we have more comprehensive treatment programmes involving medicines and surgeries, but also lifestyle factors like diet and exercise. 鈥淲e haven鈥檛 developed that for Alzheimer鈥檚 disease 鈥� why? For the last 30 years we focused on removing amyloid because it was going to cure everything,鈥� he says.

Turning to a different single cause is no better. 鈥淵ou would have the same problems, because it doesn鈥檛 explain the full picture of what鈥檚 going on. All these things fit together,鈥漵ays Perry.

This new way of thinking is finally starting to change how we study the disease and share data. Initiatives such as the Global Alzheimer鈥檚 Association Interactive Netw , Neuronet 鈥� which was launched in 2019 by the European Union鈥檚 Innovative Medicines Initiative 鈥� and the , aim to drive collaboration and data sharing to promote a fuller understanding of neurodegenerative disease. Given its incredible complexity, addressing Alzheimer鈥檚 from multiple angles may be the only way to truly understand and treat it.

Thankfully, many researchers are striving to figure out how all these factors come together, and how each provides a different opportunity to fight the disease. Drawing on even our existing knowledge can have a powerful impact. As Iadecola says, 鈥淚f you could control all the risk factors that we know of, you could reduce Alzheimer鈥檚 by about 30 per cent.鈥�