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Monday, March 16, 2015

Stem Cells Elucidate Genetic Mechanism for Protection from Alzheimer’s


Dear Readers,

Genes come in different versions or variants. That is, the gene for eye color may be slightly different from one person to another (green, blue, etc). These variations typically impart differences in the functions of the proteins that are encoded by their genes (type of pigment in the iris). In the last few years, many gene variants have been discovered that are considered risk factors for AD. One of these is the gene SORL1, which encodes a protein called sortilin-related receptor-1 that is highly enriched in neurons. Previous studies have shown that certain variants of the SORL1 gene confer some protection from AD, while other variants are associated with about a 30 percent higher likelihood of developing the disease.

In a recent study led by Larry Goldstein at UCSD, researchers took skin cells from 13 people, seven of whom had AD and six of whom were healthy control subjects, and reprogrammed the skin cells into stem cells. These stem cells were coaxed to differentiate into neurons, and the neurons were cultured and then treated with a Brain Derived Neurotrophic Factor (BDNF), an endogenous protein that helps keep neurons healthy. BDNF is in fact being studied as a potential therapy for AD.

The researchers found that neurons carrying the disease-protective SORL1 variants responded to the BDNF therapy by reducing their baseline rate of beta amyloid peptide production by an average 20 percent. But the neurons carrying the risk variants of the SORL1 gene showed no change in beta amyloid production. These results demonstrate that BDNF reduces beta-amyloid production in neurons by boosting the activity of SORL1 and that the SORL1 should be of a certain variety in order to be responsive in the first place.

This kind of stem cell study also further supports the idea that levels of beta-amyloid production are important for the development of AD. It also clarifies the mechanism by which variants of SORL1 impart risk for or protection against AD. And finally, this type of work allows researchers to identify exactly how a person’s genetic background might determine their response to potential treatments, in this case to BDNF.



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 12:03 PM 0 Comments

Friday, February 13, 2015

New Tracer Allows Direct Visualization of Tau


Dear Readers,

At the recent Human Amyloid Imaging Conference, researchers presented results from brain imaging studies using a new tracer called AV1451 that allows for direct visualization of tau, the key component of neurofibrillary tangles. As readers of this blog will recall, tangles are one of the two main brain changes in Alzheimer’s disease, the other being amyloid plaques. The results from the latest studies indicate that that tangles actually correlate more strongly than amyloid with brain shrinkage and memory decline in Alzheimer’s disease. Together, the data strengthen the notion that while amyloid and tau pathology begin independently in separate brain areas, the presence of amyloid somehow accelerates the spread of tau leading to brain cell injury and eventual brain cell death. Tangles are seen in many other forms of dementia, including frontotemporal dementia, progressive supranuclear palsy, and chronic traumatic encephalopathy, which has been reported in former athletes who have sustained repetitive concussions.

With brain imaging capabilities for both amyloid plaques and tau tangles, researchers hope to soon understand the relationship between amyloid and tau. The data presented at this meeting from people who have had both amyloid and tau imaging strengthens the concept that almost everyone develops some tangles with age, the presence of which impairs memory slightly but does not cause full blown dementia. However, in those people who also develop amyloid plaques, the neurofibrillary tangles somehow increase and spread throughout the brain.

Tau imaging is an extremely powerful tool and quickly being added to numerous clinical studies, including interventional trials with new treatments. By including both amyloid and tau imaging, we will be able to capture the progression of AD on a molecular level over time in patients and better understand the ideal timing for beginning interventions.



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 4:19 PM 0 Comments

Wednesday, January 14, 2015

Alzheimer’s Disease: 2014 Year in Review


Dear Readers,

It is hard to believe that this installment marks the fifth annual Year in Review for the ADCS blog. As I have done previously, I would like to review some of the highlights of what has happened in the AD research world in the past year and discuss some of the new directions that we will likely be heading towards in 2015.

But first, I would like to provide you with a backdrop of AD research in the past five years to present a context in which developments are occurring. Without question, the onward progression towards earlier identification of AD with non-invasive biomarkers has been the area in which the greatest strides have been made. Specifically, the ability to identify the presence of amyloid plaques and neurofibrillary tangles through the use of PET imaging has allowed numerous improvements to be realized in AD research. This includes earlier identification of disease decades before the onset of symptoms. In addition, it permits for making a more accurate diagnosis, which is of paramount importance in clinical drug development. Finally, the study of these imaging capabilities in individuals with genetic forms of AD that is familial (early-onset) and Down syndrome, provide the best opportunity for discovering new biomarkers of Alzheimer’s disease in its earliest stages.

Despite this advance, clinical drug development is only now benefitting from and incorporating these techniques into clinical trial designs in order to select appropriate study participants. In the past five years, we have witnessed the launch of clinical trials for prodromal Alzheimer’s disease where patients have mild cognitive impairment, and most recently preclinical Alzheimer’s disease, where patients are completely asymptomatic. This movement towards intervention early in the course of disease, combined with more accurate diagnosis will undoubtedly pave the way towards finding treatments that work.

Trials and Tribulations

At the end of 2014, we saw the halting of the Phase 3 trial of the investigational antibody gantenerumab in prodromal Alzheimer’s disease due to a lack of benefit compared to placebo. As readers of this blog will recall, antibodies against beta-amyloid are being tested as treatments for AD because they remove beta-amyloid from the brain. The trial, called SCarlet RoAD, was the first Phase 3 study that used the new guidelines for diagnosing prodromal AD using biomarkers. In mid 2014, the Phase 2 trials of crenezumab failed to meet primary endpoints of cognition and function. Much like solanezumab, this antibody showed some evidence of a cognitive benefit at the highest dose in the mildest patients. Both the gantenerumab and crenezumab trials were well designed and properly conducted. Clinical trials of BACE inhibitors, drugs that actually prevent production of beta-amyloid, as opposed to removing it as antibodies do, continue to move ahead in mild AD and prodromal AD clinical trials and hold great promise.

Brain Imaging

Just as important as the research world, in 2014, the FDA approved the third PET imaging tracer to allow for imaging amyloid plaques in the brain in the clinics. This means that florbetaben, florbetapir and flutemetamol are approved for the evaluation of amyloid plaques in patients. A negative scan essentially rules out AD. Researchers continue to actively gather data to show the meaning and usefulness of a positive amyloid scan in clinical practice. As readers of this blog will recall, the Centers for Medicare & Medicaid Services does not recommend reimbursement of amyloid PET scans in clinical settings. In the meantime, more data from large studies continue to add to the evidence that people with amyloid in their brains are much more likely to suffer cognitive decline in subsequent years and develop AD dementia.

Young Blood

In a study published in 2014 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 of 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. Researchers continue to look at these exciting studies as indication that unknown factors in blood may affect AD, raising the possibility that new treatment modalities may exist.

Funding

In 2014, the Accelerating Medicines Partnership, a group consisting of NIH and 10 industry partners, pledged nearly $130 million to study biomarkers in AD. At the same time, the U.S. Congress set aside an additional $80 million for the NIA, part of a total of about $500 million to be spent on AD research. Although these are fantastic developments, research funding for AD still pales in comparison with many other diseases such as cancer, which garners ten times as much, $5 Billion per year.

So, where are we headed in 2015?

The ongoing Anti-Amyloid in Asymptomatic Alzheimer’s disease (A4) clinical trial is actively enrolling participants in a landmark study aimed at preventing cognitive symptoms in AD. This project will also help answer questions about amyloid’s role in AD and when treatments should be administered. In 2015, much more work on blood–based tests for AD is anticipated, particularly confirmation of protein panels reported in 2013 and 2014 that may reflect brain amyloid status. Imaging of tau, the main component of neurofibrillary AD tangles, will also be a major target. Researchers will look at its usefulness in predicting cognitive decline, as will clinical trials of new compounds targeting tau specifically.

We look forward to keeping you updated on the world of Alzheimer’s research in the upcoming year and are optimistic that there will be great developments in 2015. Stay tuned.



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 2:29 PM 0 Comments

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

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About Us

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.