Identify/understand all Alzheimer's-related genes

by Cure Alzheimer's Fund
Identify/understand all Alzheimer's-related genes
Identify/understand all Alzheimer's-related genes
Identify/understand all Alzheimer's-related genes
Identify/understand all Alzheimer's-related genes

A new study from Drs. Iadecola and Faraco published in Nature offers new insights into why and how skipping the salt-shaker might protect your cognitive health. The National Institute of Health has long advised that high-salt diets are associated with high blood pressure and can raise the risk for heart disease, stroke, kidney failure, and can cause immune-related changes in the gut. This most recent study suggests that high salt intake can also impact cognitive function by causing a deficiency in a compound – nitric oxide – that is crucial for maintaining vascular health in the brain and that new findings tie to tau, one of the hallmark Alzheimer’s proteins.

A study in 2018 from the same team found that a high-salt diet contributed to cognitive deficits in mice. The mice in this study had memory impairment and were unable to complete the tasks of daily living such as building their nests. The conclusion from this earlier study was that the high-salt diet caused cells in the small intestine to release a molecule known as interleukin-17 (IL-17) which promotes inflammation as part of the body’s immune response. IL-17 enters the bloodstream where it prevented cells in the walls of the blood vessels from providing the brain with nitric oxide. Nitric oxide is crucial for relaxing and widening the blood vessels to allow blood to flow; a shortage of nitric oxide can restrict blood flow.

Following up on these initial findings, the study recently published in Nature takes the research a step farther by investigating how a change in nitric oxide production in the blood vessels affects the stability of tau proteins in neurons.

In an interview about the research, Dr. Iadecola said: “tau becomes unstable by coming off the cytoskeleton. Tau is not supposed to be free in the cell. Once tau detaches from the cytoskeleton, the protein can accumulate in the brain, causing cognitive problems.” The research provides evidence for nitric oxide playing a role in keeping tau in check.

In a crucial experiment, the researchers gave mice eating a high-salt diet an antibody to promote tau stability. Despite restricted blood flow in these mice, the researchers observed that they had normal cognition. This experiment demonstrated that the cognitive deficits in the mice on the high-salt diet were due to the effect of tau rather than restricted blood flow alone.

This research paves the way to conduct research on how salt intake affects cognition in humans – specifically Alzheimer’s patients. CureAlz is actively supporting research investigating the links among dietary salt, cardiovascular function, tau deposition, and cognitive decline.


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New research shows that measuring proteins in the blood may predict both health and lifespan. The research was published in Nature Medicine with support from a grant from Cure Alzheimer’s Fund. Tony Wyss-Coray, PH.D. and a team of scientists have used advances in protein profiling technology to measure thousands of proteins in the plasma at points across the human lifespan in order to determine what profiles are associated with healthy aging and with disease.

Blood has cells that transport oxygen, fight infectious disease, and carry messenger molecules with information across organ systems. The blood contains hormone-like factors that promote growth and survival; the composition of these factors changes during aging and with disease. The hormone-like factors involved in cell injury, repair, and inflammation increase during aging while those involved in the maintenance and development of tissue decrease with age. Blood tests are beginning to be used as a diagnostic and prognostic tool for many diseases including cancer, brain trauma, and heart failure, as well as amyloid plaque levels in the brain.

Using a technology called SOMAmer the researcher team measured the levels of nearly 3,000 different plasma proteins from more than 4,000 healthy individuals ages 18 – 95. As a key part of the study, the team identified 373 proteins in the blood that showed consistent changes with age across the lifespan of both mice and humans. Using machine learning techniques, this protein change data was used to train an artificial intelligence tool to predict biological age based on a sample donor’s protein profile.  In validation testing, the tool predicted a biological age that was younger than a person’s chronological age for individuals who were indeed healthier both cognitively and physically than individuals of the same chronological age but for whom the tool predicted a correct or older biological age.  The authors hope that this proteomic clock may someday be used to identify individuals at risk for disease.


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CELL has published the results of a collaboration between Rudy Tanzi, PH.D. and Huda Zoghbi, M.D. The work shows that a rare gene associated with an increased risk of Alzheimer’s, ATXN1, regulates an increase in BACE1, an enzyme that contributes to amyloid plaque accumulation.

Neurodegenerative disorders tend to fall into two distinct categories that are not thought of as overlapping: those that affect movement, called ataxias, and those that affect mental functioning, called dementias. ATXN1 is a rare Alzheimer’s associated gene that has been extensively studied in spinocerebellar ataxia type1 (SCA1), a neurodegenerative disorder.  SCA1 has no known effective treatment or cure and can affect anyone at any age. In many cases, people are not aware that they carry a relevant gene until after they have children. An estimated 150,000 people are living with spinocerebellar ataxia in the United States and the average age of onset is in the forties. SCA1 symptomsvinclude the deterioration of motor coordination, balance, and progressive difficulty in swallowing and breathing in late stages. Impairments in verbal memory and frontal executive dysfunction also occur in later stages of the disease.

ATXN1 is a rare Alzheimer’s associated gene that has been studied in the neurodegenerative disorder, spinocerebellar ataxia type 1. Those who suffer from this disorder experience Alzheimer’s like dementia later in the progression of the disease. To test the hypothesis that ATXN1 might be involved in Alzheimer’s disease, the researchers used mice that were genetically modified to have the ATXN1 gene knocked out. The researchers were interested in determining whether the loss of ATXN1 would lead to biochemical changes that resembled the changes observed in the brain during Alzheimer’s disease. BACE1, the b-secretase enzyme that cleaves amyloid precursor protein and generates amyloid plaques, was increased by 45% in the ATXN1 knockout mice. These mice display impairments in learning in the hippocampus. This paper provides evidence that ATXN1 plays a role in learning and memory.

Prior to this study, there has been no evidence that any known candidate genes for Alzheimer’s disease could regulate BACE1 expression in the brain.

This paper is groundbreaking for its ability to demonstrate a unique regulatory mechanism by which ATXN1, a gene more commonly associated with motor neurodegeneration, can affect BACE1 levels. An increase in BACE1 expression can decrease neural precursor cell proliferation and negatively impact learning, memory, and the birth of new neurons. An interesting next direction for the field will be to determine how altering levels of amyloid precursor protein or BACE1 influences adult hippocampal neurogenesis – a process that is known to go awry in Alzheimer’s.


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There are 50 million people worldwide with Alzheimer’s disease, and while much remains mysterious about Alzheimer’s, progress is being made. Many of our researchers are investigating lifestyle activities and interventions to determine which would assist with keeping our brains as healthy as possible for as long as possible.

Dr. Rudy Tanzi of Harvard Medical School, the Chair of the Cure Alzheimer’s Fund Research Leadership Group, says we know more than you might think about how to keep our brains healthy. The good news is that there are proven ways to reduce the inflammation in the brain that is a hallmark of Alzheimer’s disease, and he refers to six steps everyone can take as a SHIELD for their brain.


The impact of sleep on Alzheimer’s disease development has been studied extensively. During sleep, your brain has a natural system for clearing out the debris that builds up and can be destructive, including amyloid beta plaque and tau. When there is too much plaque in the brain, cell function may be compromised and the plaque can bind to nerve cells, harming them over time. Lack of sleep interferes with the brain’s ability to clear the debris. Aim for at least eight hours of sleep each night to ensure your brain has the chance to carry out this cleanup process. “If you are not able to get eight hours of continuous sleep, take naps,” Dr. Tanzi says.


Studies show that stress affects how the brain functions. Excessive levels of stress can cause and exacerbate disease, in large part through the activation of the Hypothalamic-Pituitary-Adrenal (HPA) axis which elevates cortisol levels. High levels of blood cortisol have a negative impact on memory and can increase levels of inflammation. There is evidence that ongoing, chronic stress may rewire the brain. It is important to find ways to reduce stress. Incorporating relaxation techniques such as meditation into our daily lives can help with overall stress management.


A six-year study published in 2013 with adults older than 65 who had not yet shown cognitive impairment found that those with higher levels of social interaction were less likely to develop dementia. Since this study was finalized, numerous other studies have shown that social interaction preserves cognitive function, as well as a strong connection between loneliness and impaired cognitive function. Numerous studies confirm that older adults with dementia who have a strong social network experience delayed cognitive function. There are many benefits to staying socially active by engaging with friends and family and meeting new people. These include a protective influence on the comprehension and reasoning ability as well as a lower risk of developing symptoms of memory loss. An active social life can open up a new world of opportunity and provide motivation to introduce healthy habits into your life.


Exercise has been shown to create biochemical changes in the brain related to the health of our nerve cells. In short, exercise facilitates the creation of new nerves and synapses, referred to as neurogenesis, in the hippocampus of the brain. The hippocampus is crucial for memory retrieval and the formation of new memories. Research has found that one of the first areas in the brain affected by Alzheimer’s disease is the hippocampus. Exercise helps prevent atrophy in this area of the brain. The recommendation is to move more: whatever your current level of exercise, just move a little more. Even if you are sedentary, begin by taking a short walk, and increase the length of your walks over time.


In addition to physical exercise, mental exercise is a factor in delaying cognitive decline. Learning new things as we age can keep us mentally sharp and builds our neural networks. For example, reading books, learning a new language or new field of knowledge, practicing memorizing lists or engaging in a new hobby helps keep the brain stimulated. The more challenging and complex, the greater the benefit. “The more synapses you make, the more you can lose before you lose it,” Tanzi says.


The Mediterranean diet has been shown to benefit your brain the most. That diet emphasizes eating more fruits and vegetables, nuts, olive oil and fish, and reducing consumption of red meat. “The Mediterranean dietis best for your brain,” says Tanzi, adding that your diet has an effect on your microbiome and neuroinflammation.

Dr. Tanzi stresses that making small changes every day can help the health of your brain. “And,” he points out, “these are all things you can do now.”

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Teresa Gomez-Isla
Teresa Gomez-Isla

Dr. Teresa Gomez-Isla’s lab is on a mission to understand why some unique individuals are able to tolerate severe amounts of the pathological hallmarks of Alzheimer’s disease, including amyloid plaques and neurofibrillary tau tangles, without experiencing dementia. In a research paper supported with a grant from Cure Alzheimer’s Fund, Dr. Gomez-Isla and her colleagues uncovered new insights into what differentiates the brains of these resilient individuals. The research was published in the journal Neurobiology of Disease and makes the case that suppression of the neuroinflammatory response may enhance resilience to dementia.

While the brains of these individuals are riddled with plaques, these rare resilient cases do not exhibit the typical patterns of synapse loss that are normally found in the brains of Alzheimer’s patients. The synapse is the junction between two nerve cells through which neurons communicate either electrically or chemically. These resilient brains provide a rare glimpse into the protective mechanisms that may be at play in individuals who would be expected to have dementia as a result of the heavy burden of plaques and tangles in their brains.

The scientists used markers to determine the levels of microglia and astrocyte activation in the resilient brains compared with the brains of the controls and the brains from individuals who had experienced dementia and Alzheimer’s disease while alive. In an interesting turn of events, the experiment revealed that resilient brains had less activation of two markers: GFAP and CD68. This finding indicated a suppressed neuroinflammatory response in the resilient brains.

Not content to simply show evidence for differences in activation between the two groups, the researchers performed an experiment that profiled 27 different cytokines in the resilient brains and the brains from those with Alzheimer’s disease. Cytokines refer to substances that are secreted by cells in the immune system and regulate other cells. Dr. Gomez-Isla uncovered that not only were the profiles of cytokines in the resilient brains different from the other groups, but the difference was the most pronounced in the entorhinal cortex. The entorhinal cortex is one of the earliest and most severely affected brain regions in Alzheimer’s disease. In the resilient brains that had the highest probability of developing Alzheimer’s disease dementia based on the severity of the plaque accumulation, the cytokine profile showed differences in levels of IL-1b, IL-6, IL13, and IL-4. This data suggests specific cytokine targets that may play a role in enhancing resilience to Alzheimer’s disease.

Teresa Gomez-Isla’s research was highlighted in Harvard Magazine:


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Cure Alzheimer's Fund

Location: Wellesley Hills, Ma - USA
Project Leader:
Laurel Lyle
Wellesley Hills, MA United States
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