We’ve spent billions of dollars over three decades to understand this disease’s causes and treat its dreadful symptoms—to virtually no effect. Leading researchers now argue that we’ve been on the wrong track all along—because Alzheimer’s may be caused by a virus. Say what? In this first part, we look at what we know about AD—and the shocking amount that we don’t.
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Researched by: Rachel John & Priyanka Gulati
A quick intro to Alzheimer’s disease
Everyone has heard of the disease and its monstrous effects, but most of us don’t understand what it is—lumping it together with other forms of dementia. But Alzheimer’s is unique in the regions of the brain that it targets: the hippocampus and the entorhinal cortex. The hippocampus is responsible for short/long-term and spatial memory—while the entorhinal cortex is all about pattern recognition and the perception of time.
Point to note: Patients often develop “mixed dementia”—a combination of two or more types. For example, people often have Alzheimer’s and vascular dementia—which affects blood vessels in the brain.
The three stages: The onset of Alzheimer’s is often gradual—which also makes it different from other types of dementia. The initial symptoms usually involve memory problems—but it can also surface as word-finding, vision/spatial issues or impaired judgement. There is no one-size-fits-all version of Alzheimer’s symptoms—which makes it especially challenging to diagnose. But usually there are three stages:
[A] preclinical period with no obvious symptoms, a middle stage of mild cognitive impairment, and a final stage marked by severe symptoms of cognitive decline. During severe stages of Alzheimer’s, patients often lose their ability to respond to their environment whatsoever and become unable to control their movements. As cognitive abilities worsen, communicating also becomes painful. Ultimately, Alzheimer’s disease is lethal…
Key point to note: AD most often surfaces in people over the age of 65—and the risk doubles every five years after that. But the first stage may start 10 years or more before the symptoms appear—which, again, makes early intervention very difficult:
By the time patients notice symptoms of cognitive decline and seek clinical help, damage to the neurons has already occurred and Alzheimer’s has taken hold of the brain. This has not only prevented researchers from pinpointing exactly what causes Alzheimer’s-induced brain atrophy but also makes it very difficult to develop preventative treatments.
AD by the numbers: Alzheimer’s affects 24 million people across the world. One in 10 people older than 65 and a third of people older than 85 suffer from the condition. What should worry all of us: Alzheimer’s accounts for the vast majority of cases of dementia—which affects 55 million people around the world. Over 60% of them live in low- and middle-income countries.
As for India: Alzheimer's and other forms of dementia caused 129,000 deaths in 2019. There were 5.3 million people over the age of 60 years living with dementia in 2020. That number is expected to increase to 14 million by 2050. But data and research on AD in India remains scarce.
Most importantly this: “[T]he proportion of older people in the population is increasing in nearly every country, this number is expected to rise to 78 million in 2030 and 139 million in 2050.” In other words, Alzheimer’s will become even more common in the future.
Big bad beta amyloid… or not
Alzheimer’s makes our brains shrink because it causes widespread damage to our neurons. Here’s a visual representation of a healthy human brain vs one affected with severe AD:
Until recently, researchers could at least agree on why that damage occurred.
The plague of the plaques: In 1906, a German doctor named Alois Alzheimer treated a 55-year-old woman named Auguste Deter—suffering from loss of memory, language problems and unstable behaviour. He detected the buildup of plaques—patches of abnormal tissue—in her brain. Decades later, doctors identified the plaques as key indicators of AD—caused by the buildup of two proteins: ß-amyloid and tau.
This “amyloid hypothesis”—first described in 1984—has shaped much of AD research over the past 30 years. The narrative goes something like this:
- A large protein called amyloid precursor protein (APP) is broken down to produce beta amyloid—which is usually cleared away in a normal brain.
- But with Alzheimer’s, APP breaks down into an aberrant version of amyloid—which is stickier and harder to clear. So it creates plaques that start to build up between our neurons.
- Separately, the tau protein starts to collect inside neurons. In a healthy brain, tau helps microtubules deliver nutrients through a cell.
- But when it develops chemical changes, tau starts to create fibrous ‘tangles’ that increase cell damage.
- Together, amyloid plaques and tau tangles block communication between nerve cells—which eventually begin to die—triggering the symptoms of Alzheimer’s.
- One key difference: amyloid plaques show up in the early stages of the disease and then disappear. But tau tangles remain throughout the course of AD.
This theory has been so influential that competing research has been sidelined: “Funding bodies and drug developers have largely shunned alternative explanations for why Alzheimer’s may occur, and instead have continued to pump resources into amyloid research.” Most of the funding has gone into developing drugs that prevent or reverse amyloid plaques.
But, but, but: That neat little story has started to fall apart in recent years. For starters, “almost 40% of patients with dementia do not have amyloid plaques in their brains while many people who die with normal cognition do have them.” And a number of studies show that cell damage and disruption occur long before amyloid plaques or tau tangles begin to appear.
Most notably: Almost all drug trials targeting amyloid have failed to stop the disease—despite lavish funding from the medical establishment. Even lecanemab—hailed as a “historic moment” in 2022—only offers modest benefits even though it is very good at clearing amyloid plaques. Some experts view the drug as yet more confirmation that amyloid is not the real villain in the AD story: “The fact that the drug has such effects on amyloid and still just barely slows the course of the disease, argues for that point of view.” In other words, we still don’t have a clue about the underlying cause of the disease.
The big bad gene called APOE4… or not
Advances in genetic mapping have allowed researchers to look for hereditary factors causing diseases—and AD is no exception. The main culprit is a mutation in the apolipoprotein E gene (APOE)—called APOE4. Recent studies show that this mutation triggers changes in the blood-brain barrier—which protects brain tissue from disease-causing pathogens circulating in the blood. APOE4 seems to weaken this protection—which in turn triggers the buildup of amyloid plaques. There are two other mutations also named as potential triggers. But no one knows exactly how they cause AD.
Point to note: A person whose biological mother or father carries a genetic mutation for one of these three genes has a 50/50 chance of developing Alzheimer’s.
But, but, but: Many people who carry APOE4 never develop AD—and many don’t have the mutation often do. In themselves, genetic risks are not sufficient to explain the underlying cause of Alzheimer’s. And that is why scientists are increasingly looking at other triggers that help set off this “genetic time bomb.”
The bottomline: Some neurologists like Davangere Devanand now suggest that we’ve been chasing the proverbial wild goose all along. Could the real villain be the most common form of herpes? We look at the ‘viral infection’ theory of AD in part two.
Reading list
The National Institute on Aging offers the best, most comprehensive guide to AD—in accessible language. Forbes has a multi-part series on Alzheimer’s. Part one offers an excellent introduction to the disease—while part two is a nerdier report on the genetic angle. For challenges to the amyloid hypothesis, read this Stat News column and Science research paper.
