Can Alzheimer’s disease be prevented?

Post by Shireen Parimoo

Overview

Alzheimer’s disease (AD) is a neurodegenerative disorder that affects millions of older adults globally, with five million new cases every year. In the brain, AD is characterized by the accumulation of amyloid beta plaques and neurofibrillary tangles made up of misfolded tau proteins. These plaques and tangles accumulate in brain areas like the hippocampus that are important for memory, eventually leading to cell death and atrophying of affected regions. As a result, common cognitive impairments in AD include memory problems, diminished attentional and decision-making capacity, and loss of language abilities. Alzheimer’s disease also impacts mental health and day-to-day functioning as patients experience problems with sleep, depression, apathy, aggression, and psychosis. Although there is no known cure for AD, treatments currently exist to alleviate some of the cognitive symptoms of the disease.

Risk Factors for Alzheimer’s disease

One of the major risk factors for AD is genetic susceptibility. Normally, we inherit one copy of a gene - called an allele - from each parent.  A small subset of individuals with AD have early-onset or familial AD that they develop due to inherited gene mutations from one or both of their parents. Symptoms of early-onset AD generally begin in the 30s and 40s and quickly lead to deteriorating health and well-being. For most patients, however, symptoms of AD emerge later in life, around 65 years old. In these cases of sporadic AD, the apolipoprotein E (APOE) has been identified as a key genetic risk factor. Specifically, having one or two copies of the APOE-4 allele increases the risk of AD because it leads to higher levels of amyloid plaques in the brain. 
 
Besides genetic risk, many lifestyle and medical factors can also increase the risk of developing AD. For example, hypertension and elevated cholesterol levels are both associated with a higher risk of developing AD, as are obesity and diabetes. Research studies have also identified smoking, poor sleep, social isolation and loneliness, and chronic stress as lifestyle predictors of AD and cognitive decline later in life. Fortunately, many of these risk factors are modifiable, which means that it is possible to make lifestyle changes to lower the odds of developing AD.

The Importance of Lifestyle // Protective Factors

Protective factors are variables that - as the name suggests - protect against the risk of developing AD. As with risk factors, protective factors can be immutable or modifiable. A genetic protective factor, for instance, is the presence of two copies of the APOE-2 allele. Unlike APOE-4, the APOE-2 variant of the gene reduces the risk of developing AD. Interestingly, although genetic risk itself is not currently modifiable, studies show that there is an interaction between genetic and lifestyle factors, or in other words, between nature and nurture.
 
Fortunately, research studies over the past few decades have identified several modifiable lifestyle factors that have a protective effect against dementia and cognitive decline, even if there is a genetic risk for developing AD. This means that we can take measures to improve our brain health into our own hands and, at the very least, mitigate the rate of cognitive decline in older age.

1. Physical activity is an all-around protective factor against multiple conditions including AD and dementias. Exercising reduces blood pressure and proinflammatory activity, both of which are risk factors for AD. In the long term, physical activity also improves blood flow to the brain, which is important for brain health and functioning in general. Aerobic exercises like running, walking, and cycling increase neurotrophic factors in the brain, which are proteins that promote the growth, plasticity, and survival of neurons. The effects of exercise on the hippocampus in particular are well-documented. Both healthy older adults and AD patients who engage in physical activity have higher levels of neurotrophic factors and in some cases, larger hippocampal volume because of exercise. Older adults at risk for AD who engage in physical activity also show less hippocampal atrophy, which could slow down the onset of dementia and memory-related symptoms.

1. Diet and nutrition are also important for maintaining brain health and protecting against cognitive decline. Sources of unsaturated fats like olive oil and nuts are important for helping neurons maintain the integrity of their synapses (i.e., gaps between neurons). Antioxidants like folic acid from fruits and vegetables, as well as vitamins like vitamin D confer some protection against neurodegeneration by regulating neurotrophic factors to maintain neuronal health and by clearing amyloid protein in the brain. In fact, individuals with a vitamin D receptor gene mutation tend to be more at risk for developing AD. Thus, a well-balanced and nutritious diet - such as the Mediterranean diet, which is rich in antioxidants - can reduce the risk of developing AD in older age.

1. Psychosocial factors also have a protective effect against dementia, including social enrichment, educational attainment, leisure activities, and psychological well-being. Older adults with an active social life are more likely to be intellectually and socially stimulated, which is linked to increased neurogenesis and lower levels of stress. Similarly, having a strong social support system increases our sense of belonging, reduces feelings of loneliness, and improves our mental well-being. Higher educational attainment early in life and stimulating leisure activities - like learning a new language or playing an instrument - also help prevent the onset of dementia. The idea is that engaging in these social and intellectual domains ensures that the neural circuits in the brain remain active and are less likely (or at the very least slower) to deteriorate during aging.

1. Sleep disturbances are linked to a higher risk of cognitive decline and AD. For example, amyloid and tau accumulation and clearance are modified by sleep patterns. Getting enough good quality sleep is important because that is when toxins like amyloid and tau are cleared through the glymphatic (fluid flow) system in the brain. Interestingly, the relationship between sleep and AD appears to be bidirectional: healthy individuals with amyloid and tau pathology (precursors to AD) and individuals with AD tend to have poor sleep quality and more sleep disturbances. As a result, it is unclear whether sleep quality contributes to the onset of AD, whether it is one of the outcomes of AD pathology, or some mix of the two.

 
Overall, there are many modifiable lifestyle variables that can help prevent cognitive decline and protect against the onset of neurodegenerative disorders like AD. Emerging research indicates that a personalized, multidomain, lifestyle-based interventional approach will have the most beneficial effects on slowing down pathological processes in aging, especially in older adults who might be genetically at risk for developing dementia.

References +

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Wang et al. (2021, Alzheimer’s & Dementia). Shared risk and protective factors between Alzheimer’s disease and ischemic stroke: A population-based longitudinal study. Link: https://alz-journals.onlinelibrary.wiley.com/doi/full/10.1002/alz.12203

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How Neurons in the Human Brain Encode the “When” of Experiences

Post by Meagan Marks

The takeaway

Neurons in the medial temporal lobe help distinguish temporal patterns within recurring experiences, influencing the implicit prediction of future events and guiding subsequent behavior.

What's the science?

Whether performing a daily routine or learning a new task, the human brain is constantly integrating aspects of experience—specifically, the “what” (objects/events), “where” (spatial location), and “when” (temporal structure)—to create a cohesive understanding of the world. 

Temporal structure—the “when” of an experience—allows the brain to organize information based on order in time. Encoding information in such a manner is crucial to memory formation, sequential learning, and decision making. By recognizing subtle sequences and patterns in time, the brain can predict future outcomes and adapt behavior accordingly. This process is needed for everyday tasks, like comprehending the words on a book page or responding to the flow of ideas during a conversation.  

Temporal structure is vital for survival and success, but the specific neuronal mechanisms behind this cognitive process remain unclear. This week in Nature, Tacikowski and colleagues explore how neurons encode the temporal structure of experiences into memory by observing the neural activity of human participants. 

How did they do it?

To determine how human neurons encode temporal structure, the authors recruited 17 participants, all of whom had intracranial electrodes implanted for clinical reasons. The authors then recorded the activity of individual neurons within the medial temporal lobe (MTL)—a region of the brain known for its role in memory and spatial cognition. A complex behavioral task was also created to ensure that subtle temporal patterns were presented to the participants as neuronal activity was recorded.   

The behavioral task consisted of three phases. During the first, participants were repeatedly shown six images of people that elicited a strong response from neurons in the MTL. These images were displayed at random and participants were asked to identify the gender of each person shown. 

During the second phase, the same six images were repeatedly presented over the course of six trial rounds, but this time in a predetermined sequence. This sequence was based on a pyramidal structure established behind the scenes, where one image was assigned the top of the pyramid, two were assigned to the middle, and three were assigned to the bottom. Although the participants were only shown one image at a time, these images were shown in alignment to this pyramidal arrangement, so that only images “touching” each other on the pyramid could follow each other in the display line up. During these trials, the participants were engaged in a separate task—determining if the images had been flipped—and were not aware of the display pattern. 

The third and final phase mimicked the first, however, the participants had been sufficiently exposed to the display sequence. 

What did they find?

During the first phase of the behavioral experiment, the researchers noticed that certain neurons in the MTL exhibited a significantly stronger response to one particular image compared to the others. As the experiment progressed, these neurons adjusted their activity based on the display pattern. With continued exposure, some of the initially selective neurons began responding more strongly to images that were connected on the pyramid to the original image they had favored (i.e., images connected within the sequence). This strengthening of neuronal activity directly aligned with exposure to the pattern, indicating that these adaptable neurons made associations between images and embedded the sequence into memory. The sequence was even ‘replayed’ by the neurons spontaneously during study breaks, strengthening the memory of the pattern. These neurons were distributed across the hippocampus and entorhinal cortex, suggesting that the hippocampal-entorhinal system plays a key role in encoding temporal structure.

Participants also exhibited delayed behavioral responses in the final phase when an image broke the learned sequential pattern. Given that participants remained unaware of the display pattern, it can be inferred that their recognition and memorization of the sequence occurred largely implicitly.

What's the impact?

This study is the first to show that neurons in the hippocampus and entorhinal cortex work together to encode the temporal structure of experience. These neurons play a crucial role in recognizing and memorizing patterns, influencing the implicit prediction of future events, and guiding subsequent behaviors. These findings offer a deeper understanding of the neuronal mechanisms that underlie human behavior and experience. 

Access the original scientific publication here

Oligodendrocytes Provide Energy Reserves to Axons

Post by Laura Maile

The takeaway

When the brain is exposed to low glucose and decreased metabolism, as it is in diseases like Alzheimer’s, myelin slowly breaks down. Oligodendrocytes - cells that create myelin - can provide a reserve of energy for the axons of neurons, supporting them through periods of disease or other insults.   

What's the science?

Oligodendrocytes are the cells of the central nervous system that create myelin, the fatty substance that surrounds the axons of neurons and helps action potentials propagate down the axon. In addition to creating myelin, oligodendrocytes also support the production of ATP, the energy-associated molecule necessary for many cellular processes. This is important because myelin insulates axons, blocking their access to metabolic molecules in the extracellular space. As we age, myelin must be maintained by the constant turnover and production of new myelin proteins and fatty acids. Fatty acid oxidation is the process that occurs in the mitochondria and peroxisomes where fatty acids are broken down into acetyl-CoA, which can then be used in the production of ATP or of new fatty acids. In disorders associated with loss of myelin such as Alzheimer’s Disease, there is also reduced glucose metabolism in the brain. Scientists don’t yet know whether fatty acid and myelin production are connected to metabolism in oligodendrocytes. This week in Nature Neuroscience, Asadollahi and colleagues studied isolated optic nerves to determine whether axons depend on oligodendrocyte energy metabolism and whether myelin is disrupted when glucose is low.

How did they do it?

The authors studied the optic nerve of young adult mice because of its long, isolated axons. They used transgenic mice bred to express fluorescent proteins in oligodendrocytes. After isolating the optic nerves, they were exposed to different amounts of glucose, and fluorescent staining was used to analyze the total number and identity of surviving and dying cells. Next, they determined whether fatty acid metabolism provides an energy store by starving optic nerves of glucose and exposing them to a drug that blocks fatty acid oxidation in the mitochondria. They also used a high-resolution technique called electron microscopy to examine myelin structure in low glucose environments. 

Next, the authors sought to determine whether fatty acid metabolism in oligodendrocytes is important for axon function. They electrically stimulated isolated optic nerves while measuring the size of the evoked action potentials.  By increasing the frequency of stimulation, they could observe enhanced firing frequency of axons and measure the area of the resulting action potentials. They next disrupted fatty acid oxidation specifically in the peroxisomes of oligodendrocytes through a genetic mouse model that knocked out a specific gene. Using the same electrical stimulation experiment, they measured the action potential area of stimulated axons that were starved of glucose. Finally, to determine the role of oligodendrocytes in long-term glucose deprivation, the authors generated transgenic mice with an inducible knockout of the GLUT1 glucose transporter in oligodendrocytes. Using this model, they could disrupt glucose availability in oligodendrocytes in adult mice and then observe behavior and myelin structure using electron microscopy.  

What did they find?

The authors found that after 24 hours of low glucose exposure, oligodendrocytes and other glial cells suffered little to no cell death in the optic nerve, meaning they had access to some additional energy store.  When the optic nerve was exposed to an environment with no glucose and an inhibitor of fatty acid metabolism, 70% of cells died. After 24 hours of low glucose exposure, cells showed signs of cell death and loss of myelin integrity. When optic nerves were deprived of glucose and then electrically stimulated in the presence of a fatty acid oxidation blocker, their evoked action potentials decayed quicker than controls that had normal fatty acid oxidation. This shows that in low glucose environments, axonal function is supported by fatty acid metabolism. In transgenic mice that had a genetic block of fatty acid oxidation in oligodendrocyte peroxisomes, a similar decay in action potential area was observed, indicating that axonal function is supported specifically by oligodendrocytes. Finally, in mice that lacked the GLUT1 glucose transporter in oligodendrocytes, the authors observed loss of myelin even in the absence of behavioral deficits. This suggests that when glucose uptake by oligodendrocytes is low, normal myelin metabolism continues. 

What's the impact?

This study found that when neurons are exposed to low glucose, myelin loss, and oligodendrocyte fatty acid breakdown continues, providing support to axons and possibly avoiding permanent axon degeneration. This suggests that oligodendrocytes are important for providing energy reserves for neuronal axons and additionally, that in diseases associated with axonal degeneration and in normal aging, the imbalance between myelin production and degradation may be responsible for progressive loss of myelin.   

Access the original scientific publication here.