Do we finally know what causes Alzheimer’s?

Recent clinical trials offer the strongest evidence yet for the “amyloid hypothesis.”

When Alois Alzheimer interviewed Auguste Deter, a 51-year-old patient in a psychiatric hospital in Frankfurt, she repeatedly told him: “I have lost myself.” 

“She is completely disoriented in time and space,” Alzheimer wrote in 1907 of the first known patient with the condition that bears his name. “Sometimes she says that she does not understand anything and that everything is strange to her.”

After her death, a postmortem revealed fibrous plaques and tangles in her brain.

More than a century after Alzheimer described what he called “the disease of forgetfulness,” we at last have treatments that can slow it down — albeit modestly — and these offer powerful evidence that those plaques, found in the brains of patients with the disease, really are behind the brain’s descent into dementia.

The amyloid hypothesis

For 30 years, the leading origin story for the disease was the amyloid hypothesis, which asserts that this sticky protein triggers a cascade of changes in the brain that disrupt synapses, stoke inflammation, kill nerve cells, and cause progressively worsening dementia.

But a slew of contradictory evidence from brain-imaging studies over the past decade — and a long run of depressing failures in trials of anti-amyloid drugs and vaccines — led to a slow-building crisis for the amyloid hypothesis.

The origin of Alzheimer’s is not merely a question of academic curiosity. The number of people living with dementia globally is set to rocket from around 57 million in 2019 to 153 million in 2050. Alzheimer’s accounts for 60-70% of these cases. Its prevalence doubles every 5 years after age 65, so the toll on aging populations — both in human suffering and healthcare costs — can only get worse.

Almost all current treatments for Alzheimer’s only address cognitive and behavioral symptoms, not their causes. There remains no known way to prevent, let alone cure the disease.

We now know that the plaques in Auguste Deter’s brain were made of beta amyloid that had coalesced between her brain cells, and the tangles comprised another rogue protein, phosphorylated tau, that had accumulated inside them. The two proteins may well interact to cause dementia, but according to the amyloid hypothesis, it is beta amyloid that initiates the cascade of pathological changes, decades before any symptoms develop. 

Soluble units of beta amyloid are created when an enzyme cleaves amyloid precursor protein (APP) — a larger molecule that plays a pivotal role in the development of the central nervous system and the preservation of nerves after an injury. 

The hypothesis is that things start to go awry when beta amyloid is generated faster than it is cleared from the brain. Several units can clump together to form toxic, free-floating “oligomers”, which spread and form into insoluble plaques.

Pros and cons

Definitive proof of the hypothesis has been lacking, however. Until recently, genetics provided the strongest evidence by linking genes involved in the creation and processing of amyloid to a person’s risk of developing Alzheimer’s.

For example, people with Down’s syndrome tend to develop Alzheimer’s in their 40s or younger. Down’s is caused by an extra copy of chromosome 21, which is where the gene for APP sits. This means that patients with Down’s produce lots of beta amyloid.    

Early-onset Alzheimer’s can also run in families, and the gene variants that confer this extra risk either boost total beta amyloid production, or generate more of a particularly glutinous type that is more prone to clump together.

In spite of these genetic smoke signals, however, the amyloid hypothesis has major challenges. Among these was the finding that there are elderly people without dementia who have extensive plaques in their brain, and patients with clinical Alzheimer’s symptoms who have hardly any. In fact, the spread of tau fibrils through the brain correlates much better with worsening symptoms.

Some neuroscientists have taken this evidence to argue that Alzheimer’s has no single initial trigger, but rather originates as two or more partially independent chains of events.

A run of dismal failures of treatments that target beta amyloid — both monoclonal antibodies and vaccines — seemed to bear out this view. Despite several drugs successfully clearing amyloid plaques from the brain, they failed to slow cognitive decline.

The implication was that beta amyloid was a consequence of the disease, not its cause. The real cause, some argued, were infectious agents such as herpes simplex virus that, having lain dormant for years, reawakened in aging brains as a result of stress and waning immunity. In this theory, it was the pathogens that damaged nerves, either directly or indirectly through inflammation, whereas beta amyloid (which has antimicrobial properties) was simply a defense mechanism.

Others pinned the blame on Porphyromonas gingivalis, a microbe that causes gum disease and has also been found in the brains of patients with Alzheimer’s. The bacterium produces toxic enzymes, called gingipains, that may promote the creation of tau tangles.

New hope

Despite issues with the amyloid hypothesis, and against the recommendation of its own advisory panel, the FDA approved an anti-amyloid therapy called aducanumab in June 2021. The treatment, a monoclonal antibody, clears amyloid, but two identical clinical trials produced conflicting evidence of any clinical benefit.

“People with Alzheimer’s disease and their families need hope, not false hope,” several public health experts responded in the BMJ. Genuine hope finally materialized in January this year with FDA approval of another anti-amyloid antibody, lecanemab. It was the first clinical trial to provide proof that targeting free-floating amyloid oligomers can slow cognitive decline in early Alzheimer’s.

The relief of many Alzheimer’s researchers was palpable. “It’s fantastic to receive this confirmation that we’ve been on the right track all along, as these results convincingly demonstrate, for the first time, the link between removing amyloid and slowing the progress of Alzheimer’s disease,” said Professor John Hardy of the UK Dementia Research Institute at UCL.

“It’s fantastic to receive this confirmation that we’ve been on the right track all along…”

Professor John Hardy of the UK Dementia Research Institute at UCL

However, the actual clinical effect of the drug was modest, slowing decline by 27% over 18 months. Better news came last month in a press release from the maker of another monoclonal, donanemab. Its clinical trial found that, in patients in the early stages, the treatment caused a 35% slowing of cognitive decline over 18 months compared with placebo, and a 40% slower decline in their performance of daily activities, such as managing finances.

How do researchers explain the failure of so many earlier trials, of such similar drugs? They contend that these trials did not start early enough in the disease process, the course of treatment was too short, or the doses too low. As a side effect of plaque removal, monoclonals can cause brain swelling or small bleeds, which fully justified the caution, but the newer monoclonals help to minimize these side effects. And by targeting a sweet spot on the beta amyloid molecule, they may be better at preventing the generation and spread of toxic oligomers.

The latest trials confirm the importance of stopping the spread of plaques before they initiate the next disease stage: the formation of tau tangles inside neurons. When the amyloid hypothesis was first proposed, neuroscientists had no inkling of a hidden variable in the disease process that might explain the apparent anomalies in brain imaging studies: cells such as microglia, which are the brain’s own immune cells. These play a crucial role in curbing the generation and spread of amyloid oligomers, and numerous genetic factors help to determine how well they succeed.

Many challenges remain. Monoclonals only slow down the disease — in the latest trials, patients’ symptoms did not actually improve or even stop worsening. In addition, screening for biomarkers of the disease — a very difficult problem on its own — will be essential to getting benefit from these drugs, because the treatments must be started early, before the toxic effects of tau kick in. 

Other challenges include sky-high costs and the need to establish specialist treatment centers for regular infusions. Vaccines that could effectively recruit our own immune system to clear beta amyloid oligomers would be cheaper and probably safer. A few are in development.Finally, it turns out the disease has multiple modifiable risk factors, including sleep apnea, gut bacteria, cardiovascular disease, and social isolation. Alzheimer’s may turn out to have simple origins, but how its story unfolds is proving far from simple.

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