Know Your Brain: Alzheimer's Disease

Background

Auguste Deter, the subject of Alois Alzheimer’s case study describing what would come to be known as Alzheimer’s disease.

In 1906, at a meeting of psychiatrists in Germany, Alois Alzheimer gave a lecture in which he detailed the unusual case of Auguste Deter. Alzheimer had encountered Deter about five years prior, when he was working as an assistant physician at a psychiatric institution in Frankfurt am Main in Germany. Deter had made an impression on Alzheimer because she was relatively young, but was suffering from a unique constellation of severe, dementia-like symptoms.

Deter was 51 years old when Alzheimer met her. Her most noticeable symptoms had begun in the previous year, when her behavior became alarmingly erratic. First, she began displaying uncharacteristic jealousy of her husband. Then, her memory started to deteriorate rapidly. She would easily become disoriented, and often lose touch with reality, consumed with paranoid delusions. As Alzheimer described it:

“…sometimes she thought somebody was trying to kill her and started to cry loudly…Sometimes she greets the attending physician like company…sometimes she protests loudly that he intends to cut her…Then again she is completely delirious, drags around her bedding, calls her husband and daughter and seems to suffer from auditory hallucinations. Often she screamed for many hours.”

Alzheimer was intrigued by the case. Deter seemed to be afflicted with a form of senile psychosis, which was probably a symptom of dementia. But it was rare to see dementia this severe in someone so young.

In addition to being a physician, Alzheimer was also an industrious researcher. He was intensely interested in pathological changes in the nervous system that accompanied psychiatric and neurological illnesses. Thus, when Deter died at the age of 55, Alzheimer requested her brain be sent to him for study. Upon examination, Alzheimer found the brain had suffered widespread neuronal loss and was riddled with abnormal structures (later learned to be the protein deposits discussed below).

Deter’s age, symptom profile, and neural deterioration convinced Alzheimer that she was a unique case. The psychiatrists present at his lecture on the topic didn’t seem to feel the same way, however, as there were no questions, comments, or other indications of interest following his presentation (the attendees seemed much more intrigued by the next presentation on compulsive masturbation). But little did Alzheimer know that his lecture would mark a historic moment, as only a few years later the renowned psychiatrist (and Alzheimer’s colleague) Emil Kraepelin introduced the term Alzheimer’s disease (AD) to describe an early-onset form of senile dementia.

It wasn’t until the late 1970s that researchers began to recognize that most cases of AD are not early-onset, and occur in patients over the age of 65. Today, AD is one of the greatest health concerns for people in this age group, and due to the fact that this population continues to increase in number (which is, ironically, a result of our improved ability to keep people alive longer), it is a rapidly growing problem. Today, about 1 in every 10 people over the age of 65 suffers from AD, and the number of people with AD in the United States is expected to nearly triple by the year 2050.

What are the symptoms of Alzheimer’s disease?

AD is a type of dementia, a term used to describe a condition that involves memory loss and other cognitive difficulties. There are a number of different types of dementia, however—each with its own causes and specific symptom profile. AD is just one variation.

The best-recognized sign of mental decline in AD is problems with memory. In the early stages of the disease, this often manifests as difficulties creating new memories, and problems are especially noticeable with declarative memories, or memories about information and events (as opposed to memories for how to do routine things like tie your shoes or eat with utensils, which are known as non-declarative memories). Early on, patients are typically able to maintain older memories and non-declarative memories. Over time, however, all memory can be affected, and even the most enduring memories may deteriorate.

But memory deficits are just one aspect of AD symptomatology. Patients can also experience problems with communication, and the ability to read and write may be impaired. Unpredictable mood disturbances, ranging from apathy and depression to angry outbursts, can occur. Thinking often becomes delusional, and a substantial subset of patients (up to 20%) even experience visual hallucinations.

It’s not just cognition that’s affected, though. Movement is hindered, causing patients to begin to lose mobility and have trouble performing even the simplest acts of self-care. Basic motor functions like chewing and swallowing become faulty, and incontinence eventually occurs.

In the end (if a patient survives this long), there aren’t many brain functions that haven’t been affected in some way, and patients become completely dependent on caregivers to help with even the most basic daily activities like eating and going to the bathroom. The disease is always fatal.

What happens in the brain in Alzheimer’s disease?

When Alois Alzheimer examined the brain of Auguste Deter, he noted a few distinct pathological changes. The first was that the brain had undergone significant atrophy. It appeared somewhat shrunken compared to a healthy brain.

This atrophying of the AD brain is due to the death of brain cells that occurs in the disease. AD is what is known as a neurodegenerative disease, which is a classification used to refer to diseases that cause the degeneration and death of neurons. A number of diseases fall into this category (e.g. Parkinson’s disease, amyotrophic lateral sclerosis), but AD is the most common of the group.

Alzheimer also noted unusual formations both within and surrounding neurons. He remarked that “distributed all over the cortex…there are…foci which are caused by the deposition of a special substance,” and he also mentioned “many fibrils located next to each other…they appear one by one at the surface of the cell.” Alzheimer was describing what today are the two hallmark neurological signs of AD: amyloid plaques and neurofibrillary tangles.

The first of these structures, amyloid plaques, consist of collections of small peptides (essentially a smaller version of a protein) known as amyloid beta, or Aβ, that form large clusters outside of neurons. Normally, enzymes called proteases can help to get rid of unwanted peptides and proteins in the brain. But amyloid plaques are especially resistant to degradation by proteases. Thus, they build up in the brain as the disease progresses; their presence is a defining feature of an AD brain.

Watch this 2-Minute Neuroscience video for a summary of the way Alzheimer’s disease affects the brain.

The other structure observed by Alzheimer, neurofibrillary tangles, also consist of abnormal deposits of proteins. In this case, the protein culprit is called tau. Tau normally plays an important role in helping to transport materials throughout the cell, but in AD it loses its normal function and clusters together in the tangles Alzheimer described. Like amyloid plaques, normal mechanisms the brain uses to remove unwanted protein deposits fail to effectively clear away neurofibrillary tangles. In fact, even after an affected neuron dies, the tangles found within it remain like a reminder of the neuron that was.

As the disease progresses, amyloid plaques and neurofibrillary tangles accumulate more and more in the brain. Thus, the appearance of these abnormal structures is correlated with the severity of the symptoms of AD. At the same time, exactly what role these structures play in the development of the disease remains unclear. For example, researchers are still unsure if amyloid plaques themselves are damaging to neurons, or if they represent an effort by the brain to sequester toxic Aβ peptides to protect neurons from their detrimental effects. There are similar questions about neurofibrillary tangles. Their appearance seems to be disruptive to neuronal function, and their spread throughout the brain correlates even better with neurodegeneration and symptoms than the proliferation of amyloid plaques. Nevertheless, their specific contribution to the progression of AD remains uncertain.

Causes and treatments

Thus, there are a lot of questions still surrounding the disease process of AD. Similarly, uncertainty surrounds why the disease affects some people but not others. In a small fraction of AD cases, the disease can be linked to mutations in a handful of identified genes whose protein products are involved in the production of the Aβ peptides mentioned above. But for most patients, there is no clear genetic or environmental cause of the disease.

There are, however, some known risk factors. For example, a variant of a gene called Apolipoprotein E, or ApoE, is known to increase the risk of AD by 10 to 20 times. ApoE encodes for a protein that is involved with the transport of cholesterol and other lipids in the blood, but it’s not yet clear why it might be involved with AD risk. High lipid and cholesterol levels, however, have also been identified as possible risk factors for the disease.

There are a number of other potential risk factors, like smoking, repetitive head injuries, poor cardiovascular health, and diabetes. Researchers are still unsure, however, just how these factors might increase the chances of developing AD. And by far the greatest risk factor remains one that we can’t avoid: old age.

Thus, the causes of AD remain somewhat obscure, which perhaps makes it unsurprising that our treatments are similarly unsatisfying. The most common treatment for the disease involves drugs that raise levels of the neurotransmitter acetylcholine in the brain. Acetylcholine is thought to play important roles in learning and memory, and large repositories of acetylcholine neurons (e.g. the nucleus basalis) are decimated during AD—likely contributing to memory loss.

Drugs called acetylcholinesterase inhibitors (AChEIs) suppress the activity of an enzyme called acetylcholinesterase, whose normal function is to remove acetylcholine from the synapse—in effect reducing the effect the neurotransmitter can have at that synapse. By inhibiting acetylcholinesterase activity, AChEIs cause acetylcholine levels to increase. In the process, these drugs can lead to modest improvements in memory. Because the effects are modest, however, AChEIs are often not very useful in the later stages of the disease. In fact, clear improvement in cognitive symptoms is only seen in less than 10% of patients taking the drugs. Additionally, AChEIs can only treat the symptoms of AD—they don’t do anything to stop the disease from progressing.

There are a handful of other treatments, and many others being explored, but at this point we don’t have any means of halting the neurodegeneration that underlies the symptoms of AD. Thus, we remain somewhat limited in our ability to treat the disease. Hopefully, continued neuroscience research allows us to one day develop better methods of addressing the pathological changes that occur in the AD brain.

References (in addition to linked text above):

Alzheimer A, Stelzmann RA, Schnitzlein HN, Murtagh FR. An English translation of Alzheimer's 1907 paper, "Uber eine eigenartige Erkankung der Hirnrinde". Clin Anat. 1995;8(6):429-31.

Cipriani G, Dolciotti C, Picchi L, Bonuccelli U. Alzheimer and his disease: a brief history. Neurol Sci. 2011 Apr;32(2):275-9. doi: 10.1007/s10072-010-0454-7.

Sanes JR, Jessell TM. The Aging Brain. In: Kandel ER, Schwartz JH, Jessell TM, eds. Principles of Neural Science, 5th ed. New York: McGraw-Hill.

Know your brain: Fornix

Where is the fornix?

The term fornix comes from Latin and means "arch." It is used to refer to various arch-like structures in the body, but when used in reference to the brain it indicates a bundle of white matter fibers that arches around the thalamus. The fornix originates in the hippocampus, where it emerges from a collection of fibers called the fimbria. It then stretches up and around the thalamus toward the front of the brain. When it reaches a tract called the anterior commissure, it branches downward. Some fibers then split off and terminate mainly in the septal nuclei, preoptic nuclei, and ventral striatum, while others enter the hypothalamus and form connections with the mammillary bodies.

What is the fornix and what does it do?

In 1937 the neuroanatomist James Papez described what came to be known as the Papez circuit. The Papez circuit consisted of a group of structures---including the hippocampus, mammillary bodies, anterior nucleus of the thalamus, cingulate gyrus, and parahippocampal gyrus---that Papez hypothesized were the "anatomic basis of emotions." The fornix was a critical component of the Papez circuit, acting as a primary connection among several structures within the circuit. The Papez circuit would later be expanded upon and termed the limbic system. 

The diverse group of structures known as the limbic system is now thought to be involved in much more than emotion, and the fornix is still considered an important part of the limbic system. The fornix acts as the primary outgoing pathway from the hippocampus, and thus its most recognized function is its involvement in memory. The hippocampal projections that travel in the fornix are thought to be important for memory consolidation, and damage to the fornix has been associated with anterograde amnesia, which involves the inability to create new memories. Fornix damage is primarily linked to deficits in declarative memories, or memories for factual information---and especially episodic memories, which are a type of declarative memory that deals with autobiographical information.

Neurodegeneration in the fornix has also been associated with the cognitive impairment seen in Alzheimer's disease. The integrity of the fornix may be compromised in the early stages of Alzheimer's disease, and thus may be an early indicator of the disease that can predict the progression of Alzheimer's disease from preclinical (i.e. asymptomatic) to clinical (i.e. symptomatic) stages. Degeneration of the fornix in Alzheimer's disease seems to precede degeneration of the hippocampus, an area that is known to be severely affected by the disease.

Although the functions of the fornix are still relatively poorly understood, its role in memory processes seems to be one that is relatively well supported. Due to its diverse connections, the fornix likely is involved in a list of other brain activities, but more research will be needed to further elucidate these roles.

2-Minute Neuroscience: Alzheimer's Disease

a coronal slice of a brain that has atrophied severely due to the effects of alzheimer's disease.

a coronal slice of a brain that has atrophied severely due to the effects of alzheimer's disease.

In this video, I discuss Alzheimer's disease---the most common form of neurodegenerative disease. In addition to the widespread neurodegeneration that occurs in Alzheimer's disease, there are specific neurobiological abnormalities that appear in the brains of Alzheimer's disease patients. For example, clusters of a misfolded form of a protein called amyloid beta develop around neurons; the clusters are called amyloid plaques. Additionally, clusters of misfolded tau protein develop inside neurons; these clusters are called neurofibrillary tangles. The most common treatments for Alzheimer's disease are acetycholinesterase inhibitors, which are drugs that inhibit the breakdown of the neurotransmitter acetylcholine. Acetylcholine is thought to be important to healthy cognition, but acetylcholinesterase inhibitors have relatively modest effects on the symptoms of Alzheimer's disease.

The unsolved mysteries of protein misfolding in common neurodegenerative diseases

Throughout the 1970s, biochemist Stanley Prusiner was obsessed with trying to find the causative agent for a mysterious group of diseases. The diseases, which included kuru and Creutzfeldt–Jakob disease in humans and scrapie in sheep, were characterized by slowly-developing symptoms and neurodegeneration so severe it eventually caused the brain to take on the appearance of a sponge (due to myriad little holes that developed where grey matter was lost). By the time Prusiner began studying these diseases, they had all been experimentally transmitted to chimpanzees or other animals by injecting the animals with biological material from an infected host. So, the diseases seemed to be spread in an infectious manner, but scientists were still trying to identify the agents (e.g. viruses, bacteria, etc.) responsible for their transmission.

Prusiner focused on trying to classify the agent involved in the transmission of scrapie. He expected the agent to be a virus, but was confused when his tests repeatedly suggested it was composed of protein rather than the nucleic acids that would make up viral DNA. For, although there were others before Prusiner who had proposed ways proteins might be involved in the transmission of infectious diseases, these ideas had not been widely embraced by the scientific community. If Prusiner were to accept what his tests were indicating it would mean challenging the conventional understanding of the nature of infectious agents--which were thought to at least possess DNA or RNA--as well as the fundamental characteristics of proteins, which were not previously known to have infectious capabilities.

In 1982, Prusiner published a manuscript outlining a hypothesis that scrapie was caused by a protein that had infectious qualities. He termed this protein a prion, for "proteinaceous infectious particle." Prusiner's ideas were considered somewhat heretical to virologists and others studying these diseases, and Prusiner was faced with criticism from scientists and non-scientists alike. But eventually Prusiner isolated the prion responsible for the transmission of scrapie, confirming his suspicions and silencing the naysayers. In 1997, he was awarded the Nobel Prize in Medicine for his discovery.

Now it is well established that prions are agents of disease, in that they can spread from host to host just like typical pathogens. Once inside their host, however, they also have a unique capability of "infecting" other proteins. This results in the spreading of pathology through different regions of the brain, eventually leading to widespread neurodegeneration. But the story of infectious proteins does not end with the rare group of diseases studied by Prusiner. What we are coming to learn now is that this prion-like transmission of pathology between proteins may be a characteristic of other--much more common--diseases that involve neurodegeneration. While these diseases are very different from prion diseases in that they are not spread between individuals, the evidence suggests that the pathophysiology of neurodegenerative diseases like Alzheimer's disease (AD) and Parkinson's disease (PD) may involve proteins that behave like prions in their ability to infect other proteins within the brain of an affected individual.

Alzheimer's, Parkinson's, and protein misfolding

There are a number of diseases that are characterized by neurodegeneration, but AD and PD are the two neurodegenerative diseases that have the greatest impact on our society today in terms of mortality, disability, and economic burden. While both diseases involve neurodegeneration, however, they differ in the areas of the brain most affected (which plays a large role in determining their different symptomatic profiles). In AD, neurodegeneration becomes extensive in several areas of the brain, including areas of the cortex and hippocampus. These are areas that are especially important to cognition and memory, which helps to explain some of the deficits seen in the disease. In PD, neurons in structures that are part of the basal ganglia--a group of nuclei that play an important role in facilitating movement--are severely affected. The substantia nigra is particularly impacted, with somewhere between 50% and 70% of the neurons in this area being lost by the time of death. While the mechanisms underlying the large-scale neurodegeneration that occurs in AD and PD are not yet fully understood, in both diseases the neurodegeneration is associated with the accumulation of misfolded proteins in or around neurons.

Proteins are essential to an extensive list of biological functions, including many vital processes like cellular metabolism, DNA replication, and cell signaling. When a protein is formed from a chain of amino acids, one of the final steps in its synthesis is to undergo a process of folding. The chain of amino acids (known as a polypeptide) that came together to create the protein is folded into a three-dimensional structure, and it is this three-dimensional structure--known as the tertiary structure--that decides the protein's eventual function. In other words, the folding--not simply the amino acid chain that makes up the protein--is what determines the role the protein will play in the body.

Thus, protein folding is essential to synthesizing functional proteins. In AD and PD, however, proteins seem to fold incorrectly. This creates proteins composed of filaments that are pathologically twisted together instead of folded into a typical three-dimensional structure. These proteins are said to be in an amyloid state, because when this abnormal configuration was first noticed by renowned scientist Rudolf Virchow, he mistakenly identified them as starch (amyloid means starch-like). Once they have formed, these amyloid proteins have a tendency to aggregate into insoluble clumps.

AD is characterized by aggregations of two types of proteins, called amyloid beta and tau, respectively. Amyloid beta is always present in the brain in the extracellular space around neurons, although its function has yet to be elucidated. In AD, however, it accumulates into clusters called amyloid plaques (aka senile plaques) that aggregate outside and around neurons. These amyloid plaques often begin to form in the cortex in the earlier stages of the disease, but propagate and eventually spread to the brainstem in the later stages. Tau is found within neurons, and is normally involved in maintaining the structure of the neuron through the stabilization of microtubules. When tau becomes misfolded, it can accumulate inside neurons into bundles called neurofibrillary tangles. In AD, these tangles generally begin to form in the brainstem, then spread to the temporal lobes and cortex.

PD is characterized by the aggregation of a protein called alpha-synuclein. Alpha-synuclein is found within neurons, and may play various roles in regulating neurotransmitter release. In PD, it clumps into clusters called Lewy bodies (named for Frederic Lewy, who discovered them in 1912), which form inside the neuron. There is no consistent site of origin for Lewy bodies in the brain, but often they are first seen in the brainstem or olfactory bulb.

Just like prions, misfolded proteins in neurodegenerative diseases like AD and PD seem to be able to influence previously healthy proteins to also undergo a process of misfolding, causing them to be transformed into an amyloid state. In one of the earliest studies to provide experimental evidence of this, amyloid plaque formation was induced in the brains of monkeys after brain tissue from human AD patients was injected into the monkeys' brains. This process of the spread of pathological misfolding from one protein to the next is referred to as seeded aggregation.

Misfolding, however, is not only spread from protein to protein, but also from neuron to neuron. The way this happens is also still not very clear, but it is suspected that misfolded proteins may be taken up from the extracellular space into neurons, where they begin to infect susceptible proteins and further spread pathological misfolding. Whatever the mechanism, this neuron-to-neuron transmission of protein misfolding allows disease to spread from relatively confined sites of origin to widespread areas of the brain.

What damage does protein misfolding cause?

Although misfolded proteins are characteristic of neurodegenerative diseases, how exactly they contribute to the pathology of these diseases is still unknown. In other words, while AD and PD patients have clumps of these proteins throughout their brains, we don't actually know what role the aggregates play in causing neuronal death--or if they cause cell death at all.

According to one perspective, amyloid proteins and the aggregates they form are themselves neurotoxic and can lead to the death of neurons. Additionally, it has been hypothesized that aggregates can disrupt neuronal function by affecting the integrity of neuronal structure and impairing communication within neurons in the process (also leading to neurodegeneration). However, neuronal death is often not well correlated with the degree of aggregate formation, and the most extensive areas of cell death may occur at some distance from sites of aggregation. These findings have led to the hypothesis that it is not the amyloid proteins found in aggregates that are most harmful, but rather smaller soluble forms of amyloid (called amyloid oligomers and protofibrils) that are more detrimental to neurons. These smaller amyloid species are not easily detectable when testing the brain for the presence of amyloid, and can be found in areas where aggregation isn't apparent, potentially explaining the poor correlation between amyloid aggregates and neurodegeneration.

Some have also suggested that amyloid aggregates are formed by the brain as a means of controlling the spread of potentially damaging misfolded proteins. According to this perspective, molecular chaperones--proteins that facilitate the folding process of other proteins--recognize when a protein has become folded incorrectly. The chaperones can then sequester these misfolded proteins into benign aggregates, which keeps them from having toxic effects on neurons. It may be, however, that the smaller amyloid species mentioned above escape sequestration and are still able to cause damage.

Questions still to be answered

We are still in the dark about many of the details of protein misfolding diseases. We know the misfolding occurs as part of the pathophysiology of these diseases, and that it is correlated with neurodegeneration in some way. But we don't know what prompts misfolding, how it seems to spread from protein to protein and neuron to neuron, or in what way it is related to the death of neurons. When the answers to some of these questions become clearer, it may open the way for more effective treatments for these diseases. If, for example, we can identify how neurodegenerative disease proteins are spread between neurons, we can try to develop ways to block such a mechanism (e.g. blocking a receptor they are utilizing to gain entry into the neuron). Until we learn more, however, we will continue to be somewhat at the mercy of these diseases that imbue proteins with a type of "infectiousness" that was unheard of less than 40 years ago.

Brettschneider, J., Tredici, K., Lee, V., & Trojanowski, J. (2015). Spreading of pathology in neurodegenerative diseases: a focus on human studies Nature Reviews Neuroscience, 16 (2), 109-120 DOI: 10.1038/nrn3887

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Why do we sleep?

Why do we sleep? Sleep is an activity that takes up about 1/3 of our lives, so you would probably guess that neuroscience has a clear answer to why we do it, right? Wrong. The fundamental reason behind why we sleep is still shrouded in mystery. We know that we have to sleep (without it we would die). But we still don't know what its physiological function is.

There are a variety of hypotheses about why we sleep that have garnered some support. For example, sleep may have evolved in order to help our ancestors save energy during a time when food was more difficult to obtain. According to this hypothesis, sleep is a period of adaptive inactivity, and may also have protected our ancestors during the time when their poor night vision would have made them more susceptible to predatory attacks.

Sleep also seems to serve a restorative function. While sleeping, we may be replenishing energy reserves that we have utilized throughout the course of our day. For example, to meet daily needs, your brain uses up stores of glycogen for energy. Sleep is an opportunity to decrease demands on the brain so those stores can be replenished.

Another hypothesis suggests that sleep is important for memory consolidation. Disrupting sleep has been shown to make recall of information learned the previous day more difficult (at least in some circumstances). This has led to the suggestion that sleep is crucial to the consolidation and integration of information learned throughout the day.   

Of course, none of these hypotheses are mutually exclusive. But recent research has begun to elucidate one of the ways that sleep may work to maintain a healthy brain - and what happens when it is prevented from doing so. Late last year, a study published in Science suggested that during our waking hours, waste products begin to accumulate in the fluid between the cells in our brain. These waste products include proteins (e.g. amyloid-beta and tau proteins) whose buildup is associated with neurodegenerative diseases like Alzheimer's disease. The study showed that during sleep in mice, the flow of cerebrospinal fluid (CSF) throughout the brain is increased. One of CSF's most important roles is waste removal, so increasing CSF flow facilitates the removal of these potentially damaging proteins. If this increased CSF flow and waste removal turns out to be a feature of human sleep as well, it might help to explain why poor sleep quality and shorter sleep duration have been found to be associated with higher levels of amyloid-beta protein accumulation in the brain. 

A study published last week also showed that chronically shortening the amount of time mice had in the light each day (which reduced the amount of time they slept because mice are nocturnal) led to impaired cognition. The study was done using a strain of mice genetically engineered to be a model for human Alzheimer's disease. These mice begin displaying signs of cognitive dysfunction at around a year of age, and then within a couple of months generally show the hallmark signs of Alzheimer's disease in the brain, which include aggregations of amyloid-beta and tau proteins. These aggregations are referred to as amyloid-beta plaques and neurofibrillary tangles, respectively. Although the mice subjected to sleep deprivation didn't display overall differences in amyloid-beta and tau accumulation, tau metabolism was altered in the sleep-deprived mice, which may have been an early indicator of tau aggregation. There were also other markers of synaptic pathology that would be consistent with neurodegeneration.

The purpose of sleep remains a mystery, but some of these recent studies underscore its significance to the health of the brain. It is important, however, to avoid misinterpreting findings like these as support for the idea that everyone needs a certain amount of sleep (in truth, everyone varies in the amount of sleep they need). What these findings suggest, though, is that chronic sleep disturbances may be especially detrimental to our brains as we get older.


Di Meco, A., Joshi, Y., & Praticò, D. (2014). Sleep deprivation impairs memory, tau metabolism, and synaptic integrity of a mouse model of Alzheimer's disease with plaques and tangles Neurobiology of Aging DOI: 10.1016/j.neurobiolaging.2014.02.011