Two years ago, immunologist and medical-publishing entrepreneur Leslie Norins offered to award US$1 million of his own money to any scientist who could prove that Alzheimer’s disease was caused by a germ.
The theory that an infection might cause this form of dementia has been rumbling for decades on the fringes of neuroscience research. The majority of Alzheimer’s researchers, backed by a huge volume of evidence, think instead that the key culprits are sticky molecules in the brain called amyloids, which clump into plaques and cause inflammation, killing neurons.
Norins wanted to reward work that would make the infection idea more persuasive. The amyloid hypothesis has become “the one acceptable and supportable belief of the Established Church of Conventional Wisdom”, says Norins. “The few pioneers who did look at microbes and published papers were ridiculed or ignored.”
In large part, this was because some early proponents of the infection theory saw it as a replacement for the amyloid hypothesis. But some recent research has provided intriguing hints that the two ideas could fit together — that infection could seed some cases of Alzheimer’s disease by triggering the production of amyloid clumps.
The data hint at a radical role for amyloid in neurons. Instead of just being a toxic waste product, amyloid might have an important job of its own: helping to protect the brain from infection. But age or genetics can interrupt the checks and balances in the system, turning amyloid from defender into villain.
And that idea suggests new avenues to explore for potential therapies. To test the theory further, scientists are now developing animal models that mimic Alzheimer’s disease more closely. “We are taking the ideas seriously,” says neuroscientist Bart de Strooper, director of the UK Dementia Research Institute at University College London.
Choked by clumps
The amyloid hypothesis holds that Alzheimer’s results from a build-up of sticky, soluble proteins — amyloid-β peptides — in the spaces between brain cells. These peptides are cleaved from another protein embedded in the membranes of neurons. Once floating free, they clump together into larger structures which, if not cleared efficiently enough by special enzymes, aggregate into plaques. The plaques then trigger a deadly cascade: they provoke neuroinflammation and spawn bundles of stringy proteins called tau tangles. Faced with this litany of insults, neurons die.
Critics of the hypothesis note that the brains of many people who did not have Alzheimer’s disease have been shown to contain plaques on post-mortem. And they point to the failure of many clinical trials of treatments designed to dissolve amyloid plaques, none of which has slowed the disease. Researchers who support the amyloid theory counter that although the density of the plaques varies a lot between individuals, the density of tau tangles that they trigger correlates tightly with the severity of disease. And clinical trials probably failed, they say, because the treatments were given too late in the course of disease.
They also have strong evidence on their side. There are certain rare and aggressive forms of Alzheimer’s disease that emerge early — between the ages of 30 and 60 — and run in families; these conditions are caused by mutations in genes that govern the amyloid-making process and inflammation in the brain. Scores of other genes have been associated with the risk of the more common late-onset form of the disease. Several code for proteins that comprise elements of the amyloid cascade, and some are involved in the innate immune system — a group of mechanisms that activate quickly to prevent the spread of pathogens in the body, and which drive inflammation.
Agents of infection
Researchers hoping to test the infection hypothesis have gone hunting for microbes in thousands of post-mortem brains from people with Alzheimer’s. In many, they have found them. “But these studies only show correlations which may have explanations that have nothing to do with mechanisms,” says de Strooper.
Ruth Itzhaki, a biophysicist at the University of Manchester, UK, who reported observations of herpes simplex virus 1 (HSV1) in post-mortem Alzheimer’s brains in the 1990s1, bristles at such criticisms. She thinks that the presence of microbes in the brain must indicate a role for them, and she and others think they have good evidence that viruses are a linchpin in Alzheimer’s. “Most of us always acknowledged that amyloid was a very important feature of Alzheimer’s — but it is just not the cause,” she says.
“Several microbes have been proposed as triggers of Alzheimer’s, including three human herpes viruses and three bacteria: Chlamydia pneumoniae, a cause of lung infections; Borrelia burgdorferi, the agent of Lyme disease; and, most recently, Porphyromonas gingivalis, which leads to gum disease. In theory, any infectious agent that can invade the brain could have this trigger role (there’s no good evidence, however, that SARS-CoV-2, the virus behind COVID-19, has this ability).”
Most groups in this field have a favoured microbe, and two attention-grabbing papers in 2018 examined the role of the herpes viruses. One, from the group of Joel Dudley at the Icahn School of Medicine at Mount Sinai in New York City, analysed huge tranches of data on genes, proteins and tissue structure generated from nearly 1,000 post-mortem brains available in various databases. The team looked for telltale signatures of viruses in brain tissue — snippets of genes or proteins specific to herpes — and concluded that levels of human herpes virus 6A (HHV-6A) and human herpes virus 7 were higher in people who had Alzheimer’s disease than in controls2.
But other researchers, including virologist Steven Jacobson at the National Institute of Neurological Disorders and Stroke in Bethesda, Maryland, whose team studied a sample of more than 1,000 post-mortem brains, failed to replicate Dudley’s finding3.
And despite the impressive number of individual brains in Dudley’s study, the results are correlative. The source of the data is worrisome, too, says Michael Heneka at the German Centre for Neurodegenerative Diseases in Bonn. The brains of people with Alzheimer’s are in bad condition before death, and tissue breaks down further before autopsy; microbes could easily leak into them in the last days of life or after death. “We can’t make too many assumptions from post-mortem material about the pathogenesis of a disease which has a trajectory of approximately three decades,” he says.
Dudley’s paper came hot on the heels of a decade-long study in Taiwan, which followed more than 8,000 people who were diagnosed with herpes simplex virus, and compared them with a control group of 25,000 who had not received the same diagnosis. The group of people with herpes had a 2.5-fold increased risk of developing Alzheimer’s disease, but that increase was almost eliminated in those who received aggressive drug treatment4.
Even before this recent uptick in the theory’s prominence, the idea that infections might somehow provoke Alzheimer’s had enough traction for researchers to launch a clinical trial. In 2017, a team at Columbia University in New York City began to test whether the antiviral drug valacyclovir could slow cognitive decline and amyloid-plaque formation in people with mild Alzheimer’s disease who had also tested positive for antibodies to herpes simplex virus. Results are expected in 2022.
Burden of proof
When human studies provide only correlation, researchers often turn to animal experiments to look for cause. But animal models of Alzheimer’s aren’t perfect; mice, for instance, don’t develop the hallmark plaques as they age, unless they are genetically engineered to produce them. The widely used 5xFAD transgenic mouse expresses five relevant mutations in genes that code for the pre-amyloid protein and one of the enzymes that chops it into amyloid-β. These mice express the genes at super-high levels, and they start to develop plaques when they are only two months old.
