Not so long ago, Alzheimer’s could only be confirmed after death, by autopsy, when pathologists would see the disease’s hallmark plaques and tangles in the brain. Later came spinal taps in living patients. Then positron emission tomography (PET) scans.

Now, simple blood tests can detect the biological signs of Alzheimer’s with about 90 per cent accuracy. These tests look for beta amyloid or tau – two proteins associated with the disease. Although the tests are not currently covered by public insurers like OHIP, a person who has reason to be concerned can get a prescription from their doctor and pay between about $300 and $800 to find out whether they are likely to have Alzheimer’s, says Carmela Tartaglia, a neurologist and a professor at U of T’s Tanz Centre for Research in Neurodegenerative Diseases.

As more people learn they have – or are at high risk of developing – Alzheimer’s, pressure will grow to slow, stop or prevent it. Alas, what actually causes Alzheimer’s remains a mystery. Our ability to detect the disease has far outpaced our ability to treat it.

For reasons not well understood, some people later in life start losing the ability to form new memories and to think clearly. They forget what they just did or said. They easily misplace items and get lost in neighbourhoods they used to recognize. At some point, they can no longer go on with their old lives.

It’s not for lack of effort that we find ourselves without answers about the disease. Tens of billions of dollars and some of the world’s best minds have been applied to figuring it out. More than 140 clinical trials have come and gone, yet still we have no drug that can meaningfully alter its course.

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The leading theory of Alzheimer’s over the past few decades has focused on beta amyloid, a protein found clumped together in the brains of Alzheimer’s patients. Many lines of research implicate it: amyloid has been shown to be toxic to neurons; and genes that cause an overproduction of amyloid are associated with a rare, inherited form of early-onset Alzheimer’s. Animal studies have provided further evidence.

So, what if we removed amyloid from the human brain?

Two drugs that do this are now available. Like the blood tests, they are not yet covered, and the out-of-pocket cost for using the drugs is steep: about $40,000 a year. Both drugs involve infusions of antibodies that work to clear clumps of amyloid from the brain. Even though only about one in a thousand antibodies reaches the brain, says Martin Ingelsson, a senior scientist at the Krembil Research Institute, clinical trials show that after about a year there is almost no amyloid left. “It’s enormously effective in removing amyloid,” he says. In fact, PET scans would no longer even classify the majority of patients as having Alzheimer’s.

Our ability to detect the disease has far outpaced our ability to treat it

Yet even though almost all the amyloid disappears, the symptoms do not. Progression slows by only about 30 per cent. Put another way, after four years, a patient will be only three years worse.

It’s still an improvement. It might mean a person can live independently for longer. But it’s not a cure. “It tells us that the amyloid plaques are not the only disease-causing form of amyloid in the brain,” says Ingelsson. Rather, he says, the plaques could be viewed more as inert deposits left behind once the disease is already in motion.

Ingelsson, who is also a clinician scientist at the University Health Network and works at the Tanz Centre, believes that the toxic effects in the brain are caused by smaller forms of the protein that can’t be visualized on PET scans. While the drugs are likely removing some of these “oligomers” as well, they may not remove enough to stop the disease. Other processes, involving neuroinflammation and the tau protein, may also continue to drive the disease, even in the absence of toxic amyloid beta. As for restoring the brain to its former health, that’s probably not possible, at least not with this strategy, he says: “The nerve cells cannot easily regenerate in the brain. The best we can hope for is to bring the disease to a halt.”

These drugs are not without risk. Several people have died and many more have been seriously harmed by brain bleeds and inflammation. Because of this, patients now receive regular MRIs in their first year of treatment to check whether there are serious side effects brewing. And if there are, the patient may have to pause or discontinue treatment.

Currently, more than 100 people in Ontario are being treated with these drugs, says Ingelsson. To qualify, their cognitive impairment must be mild and they must have the biomarker for Alzheimer’s. But there are indications that intervening earlier – before any symptoms at all – would be even better. A new version of these drugs, now in clinical trials, looks promising, notes Ingelsson. Preliminary findings indicate that it might remove amyloid plaques from the brain even more efficiently and, importantly, with less serious side effects. “If this holds up,” he says, “I think that for the first time we will have something that we can consider giving to pre-symptomatic people who are healthy, but who we have reason to believe are en route to developing Alzheimer’s disease.”

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There is now widespread agreement among researchers that Alzheimer’s disease is set in motion long before symptoms become obvious. Nobody knows exactly how long before, but it’s probably in the order of decades, says Graham Collingridge, director of the Tanz Centre and a U of T professor of physiology. “If you really want to treat the disease,” he says, “you want to intervene as early as possible.”

But what, exactly, is the beginning? Colling­ridge believes that one of the earliest stages of Alzheimer’s involves problems with our synapses – structures in the brain that allow neurons to communicate with each other and that store memories. Long before amyloid plaques and tau tangles develop in the brain, something may be damaging our synapses and triggering a cascade of events that leads to synaptic loss. “Too much synaptic weakening can lead to synaptic loss, and that is believed by many scientists, me inclu­ded, to be what is causing the dementia,” says Collingridge.

Identifying what’s causing this dysfunction will be essential. But strengthening the synapses that remain is also important, he says. Prevention is now seen as a crucial strategy in fighting Alzheimer’s, “particularly in the early stages, through the adoption of lifestyle changes,” says Collingridge. Exercising regularly, eating a Mediterranean or anti-hypertension diet, and staying mentally active have all been associated with a reduced likelihood of developing the disease.

In fact, almost half the risk of developing dementia may be within our control, according to a 2024 paper in The Lancet. Education early in life appears protective, while factors such as high cholesterol, brain injury, hearing loss and social isolation later in life increase risk. Genes also play a role, but especially in later-onset Alzheimer’s, they seldom have the final word. A healthy lifestyle, says Collingridge, could tip the balance.

Most people on track to get Alzheimer’s, or even experiencing its mild early stages, do not know they have it. Part of the reason is that they are being overlooked by health-care providers who chalk their symptoms up to old age, says Tartaglia. Another part is shame and dread. “There’s so much stigma with dementia that they don’t even want to bring it up. They don’t realize that at mild stages you can really have a good quality of life,” she says. “Some patients are working – some patients are on the boards of big corporations.”

One day, routine Alzheimer’s screening may become as common as other midlife health tests

Due to this stigma and lack of awareness, most patients are only diagnosed when it’s too late to intervene. It’s like diagnosing cancer at stage four, she says. “We have treatments, but many of the people who could benefit have not sought care yet, or were misdiagnosed with normal aging,” says Tartaglia.

Once there’s greater awareness of reasonably safe drugs that prevent progression from mild to more severe symptoms, that’s likely to change. And, once we develop drugs that can prevent progression to even mild symptoms, there’s a greater imperative to intervene early, and therefore screen early, says Tartaglia.

One day, routine Alzheimer’s screening may become as common as other midlife health tests. With luck, many cases of dementia will be nipped in the bud. “We are at the first steps,” says Tartaglia, “just where cancer was over a decade ago.” 

Rethinking the Amyloid Theory of Alzheimer’s

Donald Weaver, a U of T professor of medicine, chemistry and pharmaceutical sciences, has spent much of his career examining the role of beta amyloid in Alzheimer’s. He was an early proponent of the amyloid theory but now believes the protein is supposed to be in our brains. Rather than being the primary cause of the illness, he contends that beta amyloid is part of the body’s immune system.

“It has antibacterial effects that can kill bacteria,” he says, “and it has antiviral effects that can prevent viruses from entering into neurons.” Brain cells experimentally exposed to bacteria will synthesize beta amyloid of their own, he says. “Anything that turns on the immune system within your brain – be it an infection, or head trauma, or exposure to air pollution – will stimulate the release of beta amyloid,” Weaver notes.

But sometimes, for whatever reason, he speculates, beta amyloid “goes rogue.” It mistakes neurons for bacteria and tries to kill them. He says his lab is alone in pursuing this idea.

Unlikely as that theory may sound, Weaver says his lab has used computer modelling to compare the surfaces of neurons and bacteria and found striking similarities. “What we have demonstrated is that the surface of neurons, particularly at the synapse, has the exact same shape as the surface of bacteria,” he says. Beta amyloid may mistake the surface of a neuron for that of a bacterial membrane, triggering an attack on healthy brain cells.

“We’re suggesting that beta amyloid may even be good for you in your twenties, thirties and forties,” he says. Over time, though, the accumulation of these rogue hits on neurons starts having consequences. “It adds up,” he says.

Weaver notes that researchers have proposed many different explanations for Alzheimer’s over the decades, and
most are still being actively investigated, including brain inflammation, dysfunction in our mitochondria (the power plants of our cells), and a shortage of the neurotransmitter acetylcholine. But despite decades of top-drawer research, the root cause
remains unknown.

Maybe several of these theories are correct, Weaver suggests. Maybe Alzheimer’s has different subtypes. Maybe it is truly multifactorial. Maybe that is the main lesson of decades of Alzheimer’s research. “We are obsessed with looking for the magic bullet for Alzheimer’s disease,” says Weaver. “I don’t think there’s going to be a magic bullet.”

With other complex diseases, like cancer or AIDS, we use a tailored cocktail approach, guided by biomarkers. Alzheimer’s may ultimately require the same approach, he says.