What have we discovered so far about the causes of Alzheimer's?

Over a century after the first diagnosis, we still can't say for sure what the causes are. A point on what we know on the occasion of World Alzheimer's Day

(image: M. Pagnon de la Vega et al., Science Translational Medicine (2021)) 21 September 2021 is World Alzheimer's Day. A scary name, that of a highly disabling and dramatically common disease, for which truly effective therapies do not yet exist and which, according to estimates by the scientific community, will affect over 70 million people worldwide by 2050. A damned difficult disease to understand: more than a century after the first diagnosis, in fact, we still do not know with certainty the causes and mechanisms that lead to its onset.

Alzheimer's disease is a complex and multifactorial disease, the whose etiology includes a combination of changes in the brain related to aging (but not limited to, probably) and factors related to genetics, environment and lifestyle. And the contribution of each of these factors in decreasing or increasing the risk of contracting the disease can be significantly different from person to person, which further complicates the search for the causes and, in turn, that of effective therapies at least in reducing the progression of the disease. disease, if not in stopping it altogether.

A question of (healthy) neurons

To put order in these almost one hundred years of research and arrange what we know in a row, it is good to start with a minimum summary of how the brain works human. As experts from the National Institute of Aging, a research body of the US National Institutes of Health (Nih) explain, a healthy human brain contains tens of billions of neurons, specialized cells that process and transmit information through chemical and electrical signals. Neurons send and receive messages to and from different regions of the brain, as well as from the brain to the muscles and organs of the body, and Alzheimer's disease has been observed to progressively destroy this communication mechanism, resulting in a loss of function and cell death.

Neurons (or, more precisely, most of them) are composed of three main parts: a cell body, several dendrites and an axon. The cell body contains the nucleus, which houses the genetic "imprint" that directs and regulates the cell's activities. Dendrites are branch-like structures that extend from the cell body and collect information from other neurons. The axon is a structure similar to a cable, which starts from the opposite end of the cell body with respect to the dendrites and transmits information to the other neurons. The functionality and survival of these cells are linked to various biological processes, the most important of which are communication, metabolism and regeneration. And it appears that Alzheimer's disease - as well as other forms of dementia - affects all three of these processes, leading to the loss of function and death of neurons.

Interrupted communication

Communication , as the term suggests, is the process of exchanging information between a neuron and its neighbors. When a neuron receives signals from other neurons, it generates an electrical charge that travels through the axon and releases chemical neurotransmitters in a small gap, called a synapse. Like a key that goes into a lock, each neurotransmitter molecule binds to a specific receptor site on the dendrite of the neighboring neuron. This process triggers other signals (electrical or chemical) that stimulate or inhibit the activity in the neuron that receives the signal. More precisely, this communication process takes place on cellular networks: it is estimated that each neuron can have about 7 thousand synaptic connections with other neurons.

Metabolism, on the other hand, is the ability to process chemicals and nutrients to supply the energy necessary for the survival and functioning of cells. To do this, cells need energy in the form of oxygen and glucose, which comes through the blood circulating in the brain. The brain has a higher energy requirement than all other organs in the body and consumes about 20% of the energy used by the body.

Finally, regeneration is the process of forming new neurons or the repair of existing ones. Unlike most other cells in the body, which have a relatively short life, neurons have evolved to live very long, even up to a hundred years, acquiring the ability to constantly "repair themselves". Neurons continually remodel their synaptic connections depending on the stimulation they receive from others. For example they are able to strengthen or weaken specific connections, or even to suppress them, or even to build new ones. The adult brain is even capable of creating new neurons, a process called neurogenesis. Remodeling of synaptic connections and neurogenesis are fundamental elements for learning, for memory and probably also for brain care.

The causes and nature of Alzheimer's: beta-amyloid and tau

The currently most accepted hypothesis regarding the causes of Alzheimer's involves two proteins, the so-called beta-amyloid and tau. The beta-amyloid protein occurs in different molecular forms that cluster between neurons. It is formed from the breakdown of a larger protein, a precursor protein. One form of it, beta-amyloid 42, is highly toxic. In the brains of Alzheimer's sufferers, abnormal levels of this protein (present in lesser quantities even in healthy brains) accumulate together to form plaques that collect between neurons and destroy cellular function. Several researches are underway to better understand how and at what stage of the disease the various forms of beta-amyloid protein affect Alzheimer's. The same goes for the tau protein, which collects inside neurons. Healthy neurons are supported by internal structures called microtubules, which help nutrients and other molecules reach axons and dendrites from the cell body. In Alzheimer's disease, several abnormal chemical processes cause the tau protein to "detach" from microtubules and attach it to other molecules of the same protein, which forms "chains" that create clusters within neurons.

These clusters block the internal transport system of neurons and cause damage and death. Among other things, it seems that tau and beta-amyloid interact with each other: the tau protein tends to accumulate in very specific regions of the brain, linked to memory; beta-amyloid creates plaques between neurons. When beta-amyloid levels reach a "tipping point", tau rapidly spreads throughout the rest of the brain.

Vascular disorders and chronic inflammation

Beta-amyloid and tau are not the only factors associated with the onset of Alzheimer's. Other mechanisms that could play an important role in the etiology of the disease could also be those related to vascular disorders and a state of chronic inflammation of the brain.

Several studies, for example, suggest that chronic inflammation could be caused by the accumulation of a particular type of cell, the glia cells, which normally have the role of keeping the brain free of "debris". Microglia, in particular, is responsible for removing toxins in a healthy brain. In a brain with Alzheimer's disease, microglia cannot perform this task, which could be linked to the accumulation of beta-amyloid. Unfortunately, at the moment we do not know why microglia stop working.

A possible candidate is a gene, the so-called TREM2, which normally instructs the microglia to "clean up" the accumulations of beta-amyloid and helps fight the inflammation of the brain. It has been found that in patients with abnormal functioning of the TREM2 gene there is a tendency to accumulate beta-amyloid. Astrocytes, another type of glial cell, also appear to be involved in the process: they too normally do the "cleansing" of the brain, and for some reason stop functioning in Alzheimer's patients.

Disorders vascular (obstruction of the arteries, atherosclerosis, mini-infarcts), on the other hand, lead to a decrease in blood flow to the brain and to the breakdown of the so-called blood-brain barrier, designed to "protect" the brain from the entry of potentially toxic molecules. In patients suffering from Alzheimer's, the malfunctioning of the blood-brain barrier prevents glucose from reaching the brain and disrupts the processes of removal of beta-amyloid and tau, which causes, in a cascade, a state of chronic inflammation. It is a very complex cycle from a physiological point of view: Alzheimer's seems to be both the cause and the consequence of vascular problems in the brain, and it is not easy to understand how to intervene to stop this vicious circle.

Aging, genetics, lifestyle

The examination of the causes of Alzheimer's does not end here: a role is certainly also played by aging, which even if it does not cause the disease itself is certainly one of the main ones risk factors . The number of Alzheimer's patients doubles every five years after age 65. And about a third of those over 85 may develop the disease.

The scientific community is currently still trying to understand how changes in the brain related to aging, including atrophy of certain brain regions, cause vascular disorders, inflammation, the production of free radicals and the impaired metabolism may be linked to the onset of the disease, but there are still no definitive certainties in this regard.

Genetics also seem to play a role important: at the moment a specific gene or group of genes that directly cause the disease has not been identified, but there are genetic risk factors (for example having an apolipoprotein E hole - Apoe - on chromosome 19) that appear to increase the likelihood of contracting the disease.

Finally, the lifestyle: unsurprisingly, leading a healthy life, characterized by a balanced diet, physical, social and cerebral activity c Consistent, quality sleep is associated with better aging, and appears to be a factor that decreases the risk of cognitive decline and developing all forms of dementia. Several clinical trials are currently underway to prove this.

Other schools of thought

For the sake of completeness, it must be said that there are also those who have questioned the beta-amyloid hypothesis and tau. According to, for example, the results of several studies conducted by the group of Bryce Vissel, of the University of Technology Sydney, in Australia, there is insufficient data to suggest that amyloid plays a central or unique role in Alzheiemr.

The hypothesis is that, rather than a cause, the accumulation of beta-amyloid plaques is the consequence of an even more upstream phenomenon, perhaps linked to the presence of specific bacteria in the brain. A 2016 work, in particular, showed that beta-amyloids could be a kind of "defense" against bacteria: by injecting the pathogens into the brains of healthy mice, the researchers noticed the rapid development of amyloid plaques immediately afterwards. But at the moment, although suggestive, this too remains only a hypothesis.


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Topics

Alzheimer's brain Neurodegenerative diseases Neuroscience Health globalData.fldTopic = "Alzheimer's, Brain, Neurodegenerative Diseases, Neuroscience, Health"

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