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Thursday, November 06, 2014

Does Midlife Personality Increase AD Risk in Women?


Dear Readers,

There is an abundant amount of literature about stress and its relation to cognitive decline and Alzheimer’s Disease – with most results suggesting that perceived stress over time is detrimental to cognitive health. Knowing this, the next question often is –“Is stress and one’s reaction to stressful situations the determinant or is it “personality type” that leads to the cognitive decline and eventual dementia? A recent paper by Johansson and colleagues in the American Academy of Neurology sought to examine the role of personality in midlife to late life dementia examining data from a well established longitudinal study of women in Gothenburg, Sweden.

The Prospective Population Study of Women in Gothenburg, initiated in 1968 in Sweden, is a cohort study of 800 women who were born in 1914, 1918, 1922 and 1930. The cohort was made up of 111 women aged 38 years, 309 women aged 46 years and 290 women aged 50 years. A total of 677 (85%) participated in the first follow up cycle, with subsequent follow up rates ranging from 87% to 67% over the years (decreased rates were noted due to losses, mainly due to death. A screening phase occurred in 1968 with administration of two inventories: Eysenck Personality Inventory – an inventory that measures personality dimensions of neuroticism stability and extraversion/introversion traits that were assessed with yes /no (dichotomous) answers. The neuroticism scale assesses emotional reactivity, anxiety and psycho-somatic concerns, guilt proneness and ego strength, while the extraversion scales assessed the positive effect and sociability of the participants. Other types of assessments performed in this cohort during their study visits included a dementia assessment with the use of data from neuropsychiatric examinations, information interviews, medical records and the hospital discharge records(if available).

Self reported distress was assessed at the examinations conducted in 1968, 1974, 1980, 2000 and 2005. Typical questions asked were: “Have you experienced any period of stress (one month or longer) in relation to circumstances in everyday life, such as work, health or family situation?" Stress was defined as irritability, tension, nervousness, fear, anxiety or sleep disturbances. Ratings were based on a scale of 0 to 5, with 0 = have never experienced any period of stress to 5 = have experienced constant stress during the last five years.

The entire cohort of 800 people were followed from 1986 to 2006 and during that time, 19% of the women developed dementia, 104 developed AD, 35 developed vascular dementia and 14 developed other dementia. The mean time between baseline examinations in 1968 to dementia was 29 years and the mean age of dementia onset was 78 years. Higher scores of neuroticism were associated with increased risk of AD dementia, but not with all types of dementias or vascular dementia. Even after controlling for APOe4 allele status in a subsample of 306 women, these findings did not change.

Further AD dementia was two times higher for the women with the highest levels of neuroticism compared to those with lower levels. Longstanding distress appeared to weaken the association between neuroticism and AD dementia, whereas extraversion was not associated with risk of developing dementias. Women with high neuroticism / low extraversion had an increased risk of developing AD dementia, compared to women with low neuroticism and high extraversion in the aged adjusted models.

What do these findings mean for women? Two takeaways can be gleaned from this report. First, the association between neuroticism and AD dementias diminishes after adjusting for longstanding distress, suggesting that the association between AD dementia and neuroticism is at least partially mediated by a lifelong proneness to experience everyday life stressors in a negative way as well as stressor-related situations. Efforts to reduce stress could be beneficial to the cognitive health and prevention of the development of dementia and Alzheimer’s disease.

Second, the combination of low extraversion/high neuroticism had the highest risk of AD – as noted in other studies - and suggests that certain early and midlife personality traits could put one at risk of developing cognitive decline and dementia later in life. Some studies have shown that personality may influence the individual’s risk of dementia perhaps through poor behavioral and lifestyle choices. Other studies have suggested that people with low neuroticism more often have lifestyles with healthier metabolic, cardiovascular and inflammatory risk profiles. Biomarker studies are now reporting changes in structural imaging findings associated with neuroticism/stress, in that high levels of glucocorticoids (as seen in people who are stressed) have detrimental effects on hippocampal size, and increased numbers of tangles in the brain have been noted in people with high levels of neuroticism.

More research is needed to conduct intervention studies focusing on the role of modifying behaviors in women with these types of characteristics. Practically from a physician point of view - a discussion with women patients on how personality/behavior impacts health and wellness and how positive lifestyle changes can impact cognitive functioning in late life, is critically important.
Want to read more? Here are 3 articles you can refer to and learn more about personality and Alzheimer’s Disease in Women.

Johansson L, Guo X, Duberstein PR et al. Midlife Personality and Risk of Alzheimer’s Disease and Distress: 38 year follow up. Neurology 2014: 83: 1538-1544

Kendler KS, Gardner CO, Prescott CA. Personality and the experience of environmental adversity. Psychol Med 2003: 33: 1193-1202

Terracciano A, Iacono D, O’Brien RJ, et al Personality and resilience to Alzheimer’s Disease neuropathology: a prospective autopsy study. Neurobiol Aging 2013-:34: 1045-1050

Thanks for reading.


Neelum T. Aggarwal, MD
Steering Committee Member, ADCS
Site Principal Investigator ( RUSH) - ADCS
Rush Alzheimer’s Disease Center
Chicago, IL






 
Author: Neelum Aggarwal MD at 9:15 AM 0 Comments

Thursday, October 30, 2014

Possible Beneficial Effect of Flavanols on Memory


Dear Readers,

Previous research has shown that changes in a specific part of the brain, the hippocampus, are associated with age-related memory decline. Until now, however, the evidence in humans showed only a correlational link, not a causal one. To see if the hippocampus is the source of age-related memory decline in humans, researchers tested whether compounds called cocoa flavanols can improve the function of this brain region and improve memory. Flavanols extracted from cocoa beans had previously been found to improve neuronal connections in the brains of mice.

In the latest study, published in the journal Nature Neuroscience, 37 healthy volunteers, ages 50 to 69, were randomized to receive either a high-flavanol diet (900 mg of flavanols a day) or a low-flavanol diet (10 mg of flavanols a day) for three months. Brain imaging and memory tests were administered to each participant before and after the study. The brain imaging measured blood volume in the hippocampus, a measure of metabolism, and the memory test involved a 20-minute pattern-recognition exercise designed to evaluate a type of memory controlled by the hippocampus. Participants on high-dose flavonols showed improvements both on imaging and in memory performance.

Certainly larger and longer studies are needed to better understand the role of flavanols as potential therapies, but this was a well controlled study that should serve as motivation to conduct larger scale studies on dietary compounds that may reduce the risk for developing dementia by keeping the hippocampus healthy.



Thanks for reading,


Michael Rafii, MD, PhD
Director, Memory Disorders Clinic
Medical Core Director
Alzheimer’s Disease Cooperative Study
University of California San Diego
 
Author: Michael Rafii MD, PhD at 9:04 AM 0 Comments

Thursday, September 18, 2014

Technology to the Rescue


Guest post by Gregory A. Jicha, M.D, Ph.D
Professor of Neurology
University of Kentucky Alzheimer's Disease Center


Science fiction often portrays a future where intelligent robots take over menial tasks and make people’s lives easier. In yet another example of life imitating art, many researchers are studying artificial intelligence as a means to improve in home care for impaired elders and lessen the burden on their caregivers. Several groups are designing interactive talking devices or crude robots to guide cognitively impaired people through simple household tasks. Such machines are still in a primitive stage, nowhere near the level of sophistication of fictional movie androids. While the dream of caregiving robots is likely decades away from fruition, simple, readily available, technological tools exists today that can help avoid some of the major disasters memory loss can create every day and improve the quality of life for us all. Such devices include the common Blackberry or I-POD for those with only mild memory problems as well as “simple” phones and automated pill dispensers for the more severely impaired.

For those of us (like myself) that commonly forget appointments, the common smartphone can be a lifesaver. Keeping a calendar and providing alarms for taking medication and upcoming appointments can keep us functional, despite life’s daily distractions. Yet, even smartphones may pose challenges to those of us that find it hard to learn to use a new electronic device. Learning to use such a device
before the onset of memory problems can help maintain independence once a memory problem emerges, but such devices are essentially useless if adopted after the onset of memory problems.

Technological developments and good old American ingenuity have created a host of devices that are easy to use and can be mastered by even those in the early stages of Alzheimer’s disease or dementia. These include “simple” phones, originally designed for children that have a few simple programmable buttons, or even a single button to help them contact you when needed. These devices can be used by even those with moderate impairment that may struggle with the complexity of even the simplest cell phone designed for normal adults. These devices almost universally include a trackable GPS service that can help us find a lost or displaced loved one.

Programmable, alarmed pill dispensers can also be a lifesaver for those with memory decline. These devices can be programmed with dispensing times as frequent as four times daily and are preloaded weekly. Such devices can help ease the burden of daily medication oversight for those with dementia. While such devices could never replace a human caregiver/friend/family member, currently, they can be a valuable tool that lessens caregiver burden and helps those with memory problems remain as independent as possible for as long as humanly (or technologically) possible.
 
Author: Jeffree Itrich at 10:07 AM 0 Comments

Wednesday, September 03, 2014

Normal Brain Function Without Any Form of ApoE


Dear Readers,

As many of you will recall, ApoE is a protein that binds to and transports cholesterol throughout the body, including the brain. Since 1993, researchers in the Alzheimer’s field have known that one form of ApoE, called ApoE4 significantly increases the risk for developing AD and brings the disease on at an earlier age. People with one copy of ApoE4 are eight times more likely to develop AD, and those with two copies of ApoE4 are about 12 times more likely. About 20 percent of the general population has at least one copy of ApoE4.

The ApoE protein actually exists in three major forms (ApoE2, E3, E4) and the risk for getting AD differs with each form, E4>E3>E2. ApoE4 is thought to bind directly to beta-amyloid, forming a complex molecule. Work published a few years ago showed that the binding of ApoE4 to beta-amyloid shifts the removal of beta-amyloid out of the brain from a rapid export pathway, to a very slow pathway, resulting in poor beta-amyloid clearance from the brain, and hence, its accumulation within the brain. Furthermore, researchers showed that not only does ApoE4 lead to accumulation of beta-amyloid in the brain, but it also seems to be specifically routing beta-amyloid to synapses, connections between neurons, where it leads to additional injury. Other mechanisms exist in the brain to also remove beta-amyloid and are independent of this ApoE mechanism. Because of this, some treatments being developed for AD target ApoE and aim to alter its function.

Earlier this month, researchers at UC San Francisco reported on a 40 year old patient whose body produces no ApoE protein whatsoever. The condition, called dysbetalipoproteinemia is characterized by high blood levels of cholesterol as a consequence of poor clearance from the blood. The researchers conducted extensive neurological tests and found his cognition to be essentially normal. They performed MRI scans of the patient’s brain which revealed normal brain size, with no signs of the atrophy, or shrinkage in the hippocampus, a key finding that characterizes AD. They also measured levels of AD-related proteins such as beta-amyloid and Tau in his cerebrospinal fluid, which were also normal.

What do these results mean? Perhaps the most important take away message is that one can have normal brain function without any form of ApoE protein. Certainly other mechanisms are at work removing beta-amyloid out of the brain, and ApoE is just one component. But the notion that completely blocking ApoE, particularly in patients with ApoE4, to reduce the risk of AD may be worth examining further.



Thanks for reading,


Michael Rafii, MD, PhD
Director, Memory Disorders Clinic
Medical Core Director
Alzheimer’s Disease Cooperative Study
University of California San Diego
 
Author: Michael Rafii MD, PhD at 3:42 PM 0 Comments

Thursday, August 07, 2014

Can Vitamin D Affect the Risk of Alzheimer's?


Dear Readers,

A few years ago, (July 2010), I wrote about a study that raised the possibility of a relationship between vitamin D and Alzheimer’s disease (AD). In that study, researchers reported a possible link between vitamin D deficiency and an increased risk of cognitive impairment and dementia later in life. They had analyzed data from 3,325 people aged 65 and older who lived in Tuscany, Italy over a period of six years. They measured the participants’ vitamin D levels from blood samples, and compared them with their performance on cognitive function measures such as memory tests, orientation in time and space, and ability to maintain attention. Those who scored in the lowest 10 percent were classified as being cognitively impaired. The study found that the risk of cognitive impairment was 42 percent higher in people who were vitamin D deficient, and 394 percent higher in those with severe vitamin D deficiency. This association remained after adjusting for potential confounders.

Now, researchers in the United Kingdom report that individuals with a moderate vitamin D deficiency have about a 50 percent higher risk of some form of dementia, including Alzheimer’s dementia, and a doubling of their increased risk of AD if they are severely deficient.

The researchers analyzed data from a study of vitamin D blood levels in 1,658 people age 65 and older who were cognitively normal. They were followed for about six years, using MRI brain imaging and cognitive tests. The researchers also report that the risk of dementia appears to be significantly increased in people with vitamin D blood levels below 25 nanomoles per liter, while vitamin D levels above 50 nanomoles appear to lead to a reduced risk.

Vitamin D is a steroid hormone that is involved in bone health, but also acts in the brain. Vitamin D deficiency is common in the elderly because of the skin’s reduced capacity to synthesize it with age and because of decreased sun exposure, which is necessary for the synthesis of the vitamin.

Still more work is needed to look at vitamin D and any direct effects on AD risk. For example, could it be possible that there is a reciprocal relationship, that is, could very mild AD lead to dietary changes or diminished outdoor activities that then leads to less sun exposure and hence lower vitamin D levels? It is still recommended that anyone who is considering changing their diet to include vitamin supplements, but before doing so, should speak to their doctor. These vitamin D findings need to be replicated in placebo controlled studies before such recommendations can be made.




Thanks for reading,


Michael Rafii, MD, PhD
Director, Memory Disorders Clinic
Medical Core Director
Alzheimer’s Disease Cooperative Study
University of California San Diego
 
Author: Michael Rafii MD, PhD at 9:37 AM 0 Comments

Wednesday, July 16, 2014

Biomarkers and Further Progress on a Blood Test for AD


Dear Readers,

Many of you have read or heard the term Biomarker. In this blog, I would like to review a recent discovery in AD biomarkers and provide the context for its meaning and potential value. A biomarker may be measured in a sample (as a blood, urine, or biopsy), it may be a recording obtained from a person (blood pressure, ECG), or it may be an imaging test (brain MRI or echocardiogram.

Biomarkers can indicate a variety of disease characteristics. For example, they can indicate the level of exposure to a toxic environmental factor, such as lead levels in the blood; or the presence of cancerous cells, such as in a pap smear looking for cervical cancer; or the genetic susceptibility for a disease, such as the BRCA1 DNA mutation for breast cancer. Thus, a simple way to think about and classify biomarkers is as 1) indicators of disease risk 2) indicators of disease state (is the disease present), or 3) indicators of disease rate (progression). One of the best known biomarkers is LDL cholesterol and the risk it imparts for heart disease.

A commonly used analogy when discussing biomarkers for Alzheimer’s disease is that of cancer. An individual may have a biomarker that indicates increased risk for breast cancer: positive BRCA1 gene mutation. Years later, that individual might have an abnormal mammogram showing a small tumor (disease state), and if left untreated she might develop metastatic disease with tumors in the lungs as seen by PET scan (disease progression.

In Alzheimer’s dementia, a genetic mutation, such as PSEN1 is a biomarker that indicates increased risk for developing AD. A positive amyloid PET scan can indicate presence of amyloid plaques (indicating increased risk and disease state). Finally, an MRI demonstrating brain atrophy, or shrinkage, can indicate neurodegeneration (which shows disease progression). A major effort in the field has been to find an accurate, reliable, practical and inexpensive biomarker for AD. The discovery of a blood test for AD would truly represent a watershed moment in the field, and likely be second in importance only to the discovery of a disease modifying drug.

In the most recent development, a paper published last week in the journal Alzheimer’s and Dementia, described a panel of 10 proteins in the blood. The researchers looked at blood samples from 1,148 subjects: 476 with AD dementia, 220 with MCI, and 452 elderly controls with no dementia. The researchers have identified a panel of plasma biomarkers that correlate closely with other biomarkers of AD, specifically, neuroimaging measures of disease and cognitive measures of memory functioning. Moreover, the 10 protein biomarkers can accurately predict disease conversion from MCI to AD dementia within a year of blood sampling. At the AAIC meeting in Copenhagen we have heard about a retinal measure of amyloid as a potential biomarker, as well as a simple smell test, which also seems to correlate with AD pathology in the brain.

As with other biomarker studies, we need to better understand if this protein panel, retinal scan and smell test will serve as an indicators of disease risk, disease state and disease progression. However, with this recent work, we are getting much closer to that possibility.



Thanks for reading,


Michael Rafii, MD, PhD
Director, Memory Disorders Clinic
Medical Core Director
Alzheimer’s Disease Cooperative Study
University of California San Diego
 
Author: Michael Rafii MD, PhD at 8:56 AM 0 Comments

Friday, May 30, 2014

New AD Mice Models


Dear Readers,

In a recent study published in Nature Neuroscience, researchers at the Riken Brain Science Institute in Japan have reported after a 12 year effort, the creation of two new mouse models of Alzheimer’s disease that may better mirror the disease in humans.

As readers will recall, many compounds that work in mice have not translated to new drugs in human studies. Some of the difficulty is the inadequacy of current mouse models to replicate the same conditions of Alzheimer's disease that would allow for an understanding of the underlying mechanisms that lead to dementia. Specifically, the current mouse models overproduce the protein amyloid precursor protein, or APP, which gives rise to the amyloid-beta (Abeta) peptides that accumulate in the brain, eventually leading to the neurodegeneration that characterizes Alzheimer's disease. However, in mice the overproduction of APP gives rise to additional effects which are not seen in human Alzheimer's disease.

The mouse model developed (NL-F/NL-F) was ‘knocked in’ with two mutations found in human familial Alzheimer's disease. These mice show early accumulation of beta-amyloid peptides, and importantly, were found to undergo cognitive dysfunction similar to the progression of AD seen in human patients. Inflammation accumulated around the amyloid plaques in the mouse brains as also seen in the brains of people with AD. And looking at the hippocampus, the knock-in mice also lose synapses in the same areas. Beginning at 18 months, NL-F mice also had trouble learning, which is seen in humans after plaques and tangles have developed. A second model, with the addition of a further mutation that had been discovered in a family in Sweden, showed even faster initiation of memory loss which occurs at six months.

These two mouse models represent a heroic effort to more closely model human AD and will undoubtedly help advance our search for early diagnostics and effective treatments.


Thanks for reading,


Michael Rafii, MD, PhD
Director, Memory Disorders Clinic
Medical Core Director
Alzheimer’s Disease Cooperative Study
University of California San Diego
 
Author: Michael Rafii MD, PhD at 8:46 AM 0 Comments

Friday, May 09, 2014

Young Blood and Old Brains


Dear Readers,
In a study published last week in the journal Nature Medicine, researchers at Stanford University School of Medicine looked at changes in the brains of old mice given the blood of young mice. They also compared how the old mice performed on standard tests of memory after they had received infusions of plasma – the cell-free part of blood – from young mice, versus no plasma at all. By transferring young plasma into an old mouse once every three days for three weeks, they found that old mice injected with plasma from young mice outperformed untreated old mice in two separate memory tests. Specifically, after a day of training, the mice treated with plasma from young mice averaged about 25 percent better than those of mice injected with aged plasma. Moreover, the treated mice also showed more neurogenesis (new brain cell production), synaptic density (brain cell communication) and less inflammation.

In a separate study published the same day in the prestigious journal Science, work from the Harvard Stem Cell Institute demonstrated that young blood reinvigorated blood vessels in the brains of old mice. In the treated old mice, the volume of blood vessels in the brain almost doubled. They formed new branches and allowed more blood to flow through them towards various brain regions. This, in turn, led to an increase in the number stem cells in the brain.

From the studies, it appears that young blood contains ‘pro-youthful’ factors that can reverse age related brain impairments while old blood may contain ‘pro-aging’ factors that lead to age-related brain impairment.

Surely, these findings are very exciting and could represent potential targets for intervention with regards to age-related brain disease. Still, much work is needed to understand the factors within plasma that are exerting such changes after transfusion and for how long. It is also important to keep in mind that the studies were conducted in mice, not humans, and that neither study looked at the type of cognitive impairment that is seen in Alzheimer’s disease or in animal models of Alzheimer’s disease. Only through well designed, placebo-controlled clinical trials in humans would the benefits of such treatments be fully understood.




Thanks for reading,


Michael Rafii, MD, PhD
Director, Memory Disorders Clinic
Medical Core Director
Alzheimer’s Disease Cooperative Study
University of California San Diego
 
Author: Michael Rafii MD, PhD at 8:58 AM 0 Comments

Thursday, March 27, 2014

What is Gender Medicine and why is it important to Alzheimer’s disease?



By Neelum Aggarwal, M.D.
Rush Alzheimer’s Disease Center

Prior to the mid-1900s, there was very little discussion about gender medicine. However, with the establishment of the Partnership for Gender Specific Medicine at Columbia University (1997), the Karolinska Institute (2002), and the Charité -Universitätsmedizin Berlin (2003), studies began to systematically examine comparisons between women and men. Over the last 20 years research has slowly but steadily begun to demonstrate the extent of these sex differences, but have also produced advancements in treatment, prevention and diagnosis. The result of this progress led to the 2010 Institute of Medicine declaration that being a woman or a man significantly affects disease course and should be considered in both diagnosis and therapy.

What is the difference between sex and gender and how is it related to medicine?
Gender medicine aims to improve treatment for women as well as for men, and differs from women’s health, because it also focuses on men’s health.

Gender medicine deals with the effects of sex, including biological differences between females and males. Examples of sex differences can include different concentrations of sex hormones, different expression of genes on X and Y chromosomes, or simply reporting a higher percentage and deposition of body fat in women.

Gender however, is the result of socio-cultural processes. Associated with behavior, stress, and lifestyle-related diseases, gender has been shown to determine access to health care, help-seeking behavior, and even individual use of the health care system. Recent studies have shown that gender largely determines one’s compliance with preventative measures, and whether one follows up on referrals or accepts invasive strategies like a pacemaker implant, heart transplant, or other surgeries.

Although the definitions of sex and gender appear straightforward, in medicine, it isn't always that easy to separate the influence of sex and gender on disease. For example, clinical manifestations of prevalent diseases have been shown to differ in women and men; with the question remaining, how much of these differences are due to sex differences in disease mechanisms? One area of medicine that has made great strides in this area is in cardiovascular diseases. Cardiovascular disease risk factors, disease and symptoms of atrial fibrillation, myocardial infarction, and heart failure all have been shown to have sex and gender differences, and have resulted in separately developed suggested treatment plans for men and women.

Alzheimer’s disease ( AD) is the latest medical condition to be put front and center in the sex and gender discussion. Data suggests that the risk for AD and memory decline appear to increase in women after menopause.

Reports have noted that a woman’s overall lifetime risk of developing AD is almost twice that of a man – a statistic not solely due to the fact that women live longer than men. Other areas of study are demonstrating notable sex and gender differences in basic brain structure and function between men and women. In addition, specific AD related risk factors that include cardiovascular disease, genetics (APOE 4 genotype) and depression all have shown to have sex and gender differences and could account for these observations.



Dr. Aggarwal is a cognitive neurologist at the Rush Alzheimer’s Disease Center in Chicago and a Steering Committee member of the Alzheimer’s Disease Cooperative Study.


 
Author: Neelum Aggarwal MD at 2:33 PM 0 Comments

Thursday, March 20, 2014

New Protein Implicated as Central to Alzheimer’s Disease


Dear Readers,

As many of you are aware, a major puzzle in the Alzheimer’s field has been the issue of how it is possible that some patients can have amyloid plaques and neurofibrillary tangles in the brain, but not show symptoms of dementia, while other patients are fully symptomatic. For years, researchers have explained that this observation is a result of ‘cognitive reserve,’ that is, some protective ability in certain individuals that provides resilience despite the presence of brain pathology.

Now, we have another possible explanation as to why some individuals are protected while others are not. Researchers at Harvard Medical School have published a monumental effort in the journal Nature, showing that a protein called RE1-Silencing Transcription factor (REST), that functions as a gene regulator during fetal brain development, switches back on later in life to protect aging neurons from various stressors, including the toxic effects of abnormally accumulating proteins such as beta-amyloid.

To understand REST's functions, the team genetically engineered mice that lacked REST only in their brains and watched what happened as they aged. Intriguingly, as the mice grew older, neurons in their brain started to die in the same places as in Alzheimer's patients. The research team also studied the REST protein in the worm C. elegans and found that it is necessary to protect against toxicity, thereby suggesting REST’s protective function in the aging brain is shared across species.

The team further showed that the REST protein was abundant in normal aging human brains. The brains of people who developed mild cognitive impairment, by contrast, showed an early decline in levels of REST. The affected brain regions of people with Alzheimer's were nearly devoid of the REST protein. The findings were also noted in the brains of patients with other neurodegenerative diseases that cause dementia, including frontotemporal dementia (FTD) and dementia with Lewy bodies (DLB). It appears that the toxic protein in each circumstance, beta-amyloid in AD, Tau in FTD and alpha-synuclein in DLB, bind to and inactivate REST, prohibiting its ability to perform its normal functions.

Getting back to the question about cognitive reserve and why some patients don’t exhibit dementia symptoms despite pathology, the researchers examined brain tissue gathered as part of the Religious Orders Study. Participants in the study were clergy who had detailed annual cognitive assessments performed and donated their brains for study after death. The team sorted the samples into two groups. One group had Alzheimer's pathology and experienced symptoms of dementia. The second group had the same amount of Alzheimer's pathology but did not have dementia. The researchers found that the group with no dementia had at least three times more REST protein within key brain areas. Furthermore, REST levels were highest in the brains of people who lived into their 90s and 100s and who remained cognitively intact. And, the levels were high specifically in the brain areas that are most vulnerable to Alzheimer's disease.

So what do all of these findings mean?

The human body has an incredible capacity for healing, and aging is, in essence a balance between damage and repair. In the liver, cells contain various proteins that process compounds and other molecules, including toxins to maintain health. And so it appears that the brain has its own detoxification system, one that involves the REST protein, a gene regulatory protein that turns on a host of other proteins to help protect neurons from age-related toxicities, including the accumulation of beta-amyloid.

The identification of REST as an endogenous neuroprotection system, so intimately involved in AD, identifies it as a prime target for intervention and drug development. One can imagine that by somehow increasing REST levels in the brain, we could increase resilience and reduce the occurrence of the brain dysfunction we call dementia that results from neurodegenerative disease. Undoubtedly, we will see more research following up on this important discovery.





Thanks for reading,


Michael Rafii, MD, PhD
Director, Memory Disorders Clinic
Medical Core Director
Alzheimer’s Disease Cooperative Study
University of California San Diego
 
Author: Michael Rafii MD, PhD at 12:18 PM 0 Comments

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The Alzheimer's Disease Cooperative Study (ADCS) was formed in 1991 as a cooperative agreement between the National Institute on Aging (NIA) and the University of California, San Diego. The ADCS is a major initiative for Alzheimer's disease (AD) clinical studies in the Federal government, addressing treatments for both cognitive and behavioral symptoms. This is part of the NIA Division of Neuroscience's effort to facilitate the discovery, development and testing of new drugs for the treatment of AD and also is part of the Alzheimer's Disease Prevention Initiative.

The ADCS was developed in response to a perceived need to advance research in the development of drugs that might be useful for treating patients with Alzheimer's disease (AD), particularly drugs that might not be developed by industry.