Rethinking Alzheimer’s: What if What We Thought We Knew Isn’t True?

Statistically speaking, every human being who reaches old age has a one in three chance of suffering from Alzheimer’s disease, an incurable and progressive ailment that destroys the person before ending his or her life. Some 55 million people worldwide suffer from dementia, with Alzheimer’s accounting for almost 70% of diagnoses. According to the World Health Organisation, 10 million cases are reported each year, with projections of 78 million people affected by 2030 and 139 million by mid-century. It is therefore not surprising that it is one of the ailments that most worries the citizens of developed countries, all the more so because ignorance of what triggers it makes it, in our eyes, a lethal lottery against which there is no sure prevention. Theories about its causes have been put forward one after the other, and research in recent years has provided new clues that have narrowed the field.

When German psychiatrist and neuropathologist Alois Alzheimer first described the disease in 1906, other scientists had already found two clear abnormalities in the brain tissue of some people who had died of dementia, namely so-called neurofibrillary tangles and amyloid plaques. But despite these observations, biochemical studies in search of a pharmacological cure led to the hypothesis in the late 1970s that the true origin of the disease was the loss of the neurotransmitter acetylcholine.

However, when therapies based on this deficit did not achieve the expected success, the cholinergic hypothesis gradually lost favour with researchers. Instead, the idea began to take hold that amyloid plaques, extracellular deposits of a fragmented and abnormally misfolded protein called amyloid beta, were the cause of neuronal death and therefore the real origin of Alzheimer’s. Since 1991, the amyloid hypothesis has been the predominant one to explain the pathology of this disease.

If these proteins are primarily responsible for the disease, and not an effect subordinate to other causes, it can be assumed that the misfolding would arise in the first place as a consequence of a genetic mutation that would alter the protein produced by a particular cell. “In virtually all cases, it originates within the brains of the affected persons,” Lary Walker, a neuroscientist at Emory University in the US, tells OpenMind. But how can this defective protein configuration spread and colonise large regions of the brain? 

In 2006, a team of researchers led by Walker and Mathias Jucker of the University of Tübingen (Germany) showed that the defective amyloid beta is capable of seeding the appearance of plaques by spreading its defect to other healthy copies. In other words, the Alzheimer’s protein behaves like a prion, the agent responsible for mad cow disease. This pathology become famous in the late 1990s when cases of transmission to humans through the ingestion of products from sick cows began to be detected. The cause is an abnormal prion protein that transmits its defect to normal proteins. As a result, the affected proteins become sticky, clumping together to form deposits that cause the death of neurons. “We found that this molecular mechanism is virtually identical for amyloid beta and the prion protein,” Walker summarises. 

Walker and Jucker’s finding ushered in a new approach for research into Alzheimer’s and other neurodegenerative diseases, which are now viewed as unconventional infectious diseases. But as with the human variant of mad cow disease, contagion is something that would only occur in very rare cases. According to Walker, “there is still no evidence of Alzheimer’s transmission under normal circumstances”; spontaneous mutation would remain the main source of the disease. 

However, these exceptional situations do exist. In recent years, several studies have shown that contamination with amyloid beta in surgical instruments or in growth hormone preparations from human cadavers—a source that is no longer used for treatments—can seed the growth of typical Alzheimer’s plaques in the brain. Even so, Walker says it is not yet known “whether fully-manifested Alzheimer’s will eventually emerge in at-risk subjects.”

Challenge to the dogma of amyloid plaques

But over time, this hypothesis that amyloid plaques are at the root of Alzheimer’s has also been weakened. As with cholinergic therapies, treatments against amyloid plaque formation have also failed to work as they should. Moreover, it used to be thought that these plaques caused the formation of neurofibrillary tangles, deposits of a protein called tau in a hyperphosphorylated state—with an excess of phosphates added—inside the neurons. But in recent years, several studies have cast doubt on this causal relationship and, with it, on the role of amyloid plaques as a primary cause of Alzheimer’s.

In one such study, published in 2018, researchers at the University of Queensland (Australia) increased the production of amyloid precursor protein (APP) in neurons grown in vitro. As they expected, this manipulation increased the formation of plaques, but this did not result in the appearance of tau tangles or the death of neurons. The scientists also generated neurons from stem cells of people with Down syndrome, whose propensity to suffer from Alzheimer’s is attributed to the fact that their triple chromosome 21 provides an extra copy of the APP gene. But when this extra copy was removed by genetic engineering, no changes in tau phosphorylation were observed as would be expected.

For study director Ernst Wolvetang, their results “challenge the current dogma in the field that amyloid plaques are sufficient to cause neurodegenerative changes associated with Alzheimer’s disease.” In their model, there is clearly no effect of plaques on tau and neuronal death. “Our data add to an increasing number of studies that indicate that this hypothesis perhaps needs to be re-evaluated,” the scientist added.

The evidence against the amyloid hypothesis does not only come from in vitro research. In November 2019, the curious case was published of a woman belonging to a Colombian family whose members carry a genetic mutation that invariably causes early onset Alzheimer’s, except for her, whose initial mutation was counteracted by another chance mutation. And yet her brain shows the same accumulation of amyloid seen in her relatives afflicted by the disease.

This is an isolated case, but other evidence continues to accumulate: in a University of California, San Diego study published in January 2020, researchers scanned the brains of 747 people, 153 of whom showed small cognitive difficulties that pointed to an early stage of the disease. These patients show increased amyloid accumulation over time, but this occurs after the appearance of cognitive signs. The authors propose that the results of neuropsychological tests can predict the formation of amyloid plaques, and not vice versa. Study director Mark Bondi notes that “cognitive changes may be occurring before significant levels of amyloid have accumulated.”

Tau balls, the other visible abnormality

The most widespread alternative hypothesis in recent years attributes a leading role in the disease to tau tangles. Another study led by the University of California, San Francisco found that, in 32 patients with early-stage Alzheimer’s, tau tangles predict later deterioration much more accurately than amyloid plaques. “These data support disease models in which tau pathology is a major driver of local neurodegeneration,” the authors wrote. The study joins many others that have already suggested a central role for tau in Alzheimer’s disease.

In fact, the tau hypothesis is not new, but it has only recently gained wider acceptance. Some data support it: for example, chromosome 21 harbours genes like DYRK1A that promote tau phosphorylation, which could explain the link between Alzheimer’s and Down syndrome. Variants of another gene called APOE, responsible for a protein (apolipoprotein E) involved in fat metabolism, correlate with a greater or lesser propensity to suffer from the disease, and there also seems to be an association between these variants and the greater or lesser accumulation of tau.

However, despite the progressive convergence of experts towards the idea that “the main factor underlying the development and progression of Alzheimer’s Disease is tau, not amyloid beta,” as one review concluded, this still leaves an essential question hanging in the air: what causes this abnormal tau behaviour? And the surprises are not over, because the evidence suggesting a possible infectious origin is also growing. 

Infectious agents to encourage the disease

This new hypothesis about the cause of Alzheimer’s relates to a variant of APOE called APOE4, which is closely linked to the risk of developing the disease. According to David Holtzman, a neurologist at Washington University School of Medicine in St Louis (USA), “APOE4 enhances the ability of amyloid beta to convert from a soluble to an insoluble form,” he tells OpenMind. Thus, this protein would facilitate the seeding of amyloid plaques, which would explain its relationship with the disease. The link with a possible infectious origin arises because some pathogens can cause a similar phenomenon: “Work in animal models has shown that certain infectious agents can facilitate amyloid seeding,” adds Holtzman. And while this effect has not yet been demonstrated in humans, it points to the possibility that some conventional infections may encourage the development of the disease.

Various infectious agents have been proposed as possible candidates. Of particular interest in recent years has been the bacterium Porphyromonas gingivalis, which causes pyorrhoea or periodontitis—gum disease. In early 2019, work by a large international team of researchers not only revealed that the bacteria is present in the brains of Alzheimer’s patients, but also that oral infection in animals leads to the invasion of the brain by this microbe and the production of amyloid beta. Furthermore, researchers have found toxic enzymes produced by the bacteria, called gingipains, that appear before the development of the disease.

A further aspect that reinforces the possible role of P. gingivalis in Alzheimer’s is that the authors have linked the bacteria to other pieces of the puzzle. In a further study they have shown that gingipains break down APOE proteins, and that APOE4 is more susceptible to this, causing a loss of normal APOE functions such as inhibiting excess inflammation in the brain. Moreover, gingipains also exert a detrimental effect on the tau protein.

New drugs to treat Alzheimer’s disease

Based on these findings, the company Cortexyme, which led the original study, developed an orally administered gingipain inhibitor called COR388, which in animals reduces the presence of the bacteria in the brain, blocks the production of amyloid beta and prevents neuronal death. The Phase 1 human clinical trial demonstrated the safety of the drug. Unfortunately, however, the Phase 2/3 trial failed to demonstrate a statistically significant overall benefit in the progression of Alzheimer’s. In addition, the US Food and Drug Administration (FDA) has placed a clinical hold on the trial because of possible liver toxicity. Cortexyme is currently testing a new gingipain inhibitor called COR588 that appears to show a better safety profile than the previous one.

In contrast, the FDA approved in 2021 a new drug called aducanumab (trade name Aduhelm), from the biotechnology company Biogen, an antibody targeted against aggregated amyloid beta protein that improves the results of biomarkers associated with Alzheimer’s, although there is controversy about its real clinical benefits. In any case, it is the first drug to treat Alzheimer’s disease approved by the FDA since 2003. 

Interestingly, Aduhelm is a drug that targets the amyloid protein, a factor that many researchers consider to be secondary in the aetiology of Alzheimer’s, which only goes to show that there is still no firm hypothesis about the primary cause of the disease. Recent studies have attempted to explore non-genetic risk factors, such as diet and obesity, which may influence the development of the disease through brain metabolism. A 2021 study showed that, in mice, an excess of potentially toxic fat-protein complexes in the blood can damage brain capillaries and spill into the brain mass, causing inflammation and neuronal death. The authors suggest that dietary fat control and certain medications may provide benefits against the disease.

Studies such as this one suggest that perhaps, in the end, the chances of any individual suffering from the scourge of Alzheimer’s are not one in three, but that the right habits could reduce the individual risk. At the very least, trying to lead a healthier lifestyle is a gamble that always pays off.  

Javier Yanes

@yanes68