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Start Rethinking Alzheimer’s: What if What We Thought We Knew Isn’t True?
12 February 2020

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

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Alzheimer’s disease is one of the ailments that most concern citizens of developed countries, not only because it can truncate the expectation of an old age with full use of one’s faculties, but also because the lack of knowledge regarding its triggers turns it into a lethal lottery against which there is no possible prevention. Moreover, although intense research in this field provides a constant stream of clues, the truth is that our knowledge is not advancing as we would like. To such an extent is it still a mystery to science that even what we thought was solid knowledge can be toppled. As an example, more and more studies question whether the formation of amyloid plaques in the brain is the origin of neurodegeneration, as has been believed up to now.

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.

Cerebral autopsy specimen of a patient diagosed having Alzheimer Disease. In the HE stain numerous amyloid plaques. Credit: Jensflorian

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 abnormal protein called beta amyloid, 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.

Challenge to the dogma of amyloid plaques

But over time, this hypothesis has also been weakened. As with cholinergic therapies, treatments for 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 balls or the death of the 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.

Researchers at the University of Queensland increased the production of amyloid precursor protein in neurons grown in vitro. Credit: D Ovchinnikov

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 first 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 have 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

So, if amyloid is not the primary cause, what is? Now researchers are turning their attention to the other, more visible abnormality, tau balls. Another new study led by the University of California, San Francisco, has found that, in 32 patients with early-stage Alzheimer’s, tau balls 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 write. The study joins many others that have already suggested a central role for tau in Alzheimer’s.

Alzheimer’s affected brain, with abnormal levels of the beta-amyloid protein (seen in brown) and abnormal collections of the tau protein, which forms tangles (seen in blue). Credit: National Institute on Aging, NIH

Actually, the tau hypothesis is not new, but it has only recently gained wider acceptance. And everything seems to fit; for example, chromosome 21 contains genes like DYRK1A that promote tau phosphorylation, which could explain the link between Alzheimer’s and Down syndrome. Variants of another gene called ApoE 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 higher or lower 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 a recent review concluded, this still leaves an essential question hanging in the air: what causes this abnormal tau behaviour? And the surprises keep coming, because the evidence suggesting a possible infectious origin is also growing. If there is one thing that now seems certain, it is that the task of rethinking Alzheimer’s is not yet over.

Javier Yanes


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