JDFAF has just funded a breakthrough research project integrating the expertise and resources of researchers at three University of California campuses.

The John Douglas French Alzheimer's Foundation has just funded a breakthrough research project integrating the expertise and resources of researchers at three University of California campuses. 

Researchers at UCSF (led by Bruce Miller, MD), UCLA (led by Giovanni Coppola, MD and Daniel Geschwind, MD, PhD), and UCSB (led by Kenneth Kosik, MD) will employ three different forms of the very latest genomic technologies to probe variation across the entire genome to identify patterns of gene expression that define the varied types and stages of neurodegeneration, and to evaluate repertoires of immune cells at the single-cell level to allow better tracking of disease progression and inter-individual variation in disease.

The entire project will be under the direction of the Foundation's Chief Medical Officer, Bruce L. Miller, MD, who was recently elected to the National Academy of Medicine.

These groundbreaking studies leverage and integrate the unique expertise of the research teams at the three universities, and are driven by new advances in technology that have brought new tools to the study of genomics, while dramatically driving down the costs for these studies.  

Simultaneously, the massive and creative efforts at UCSF to collect large numbers of healthy elders and patients in the preclinical, early and more advanced stages of differing dementias, and the detection of new isolated populations in the Basque-country in Spain, and Columbia, South America will make these studies unique, powerful and transformative.  

Variation across the genome provides the biological foundation from which brain health is maintained and disease occurs during aging. By understanding the genetic contributions to specific forms of early-onset forms of frontotemporal lobar degeneration (FTLD) and Alzheimer’s disease (AD) we can gain a better understanding of the biological changes that promote risk for these diseases across the lifespan. Conversely, by characterizing individuals who benefit from healthy cognitive aging we can gain insight into factors that may protect the aging brain and promote better function. 

Studying patients from both groups will enable better identification of individuals at risk for neurodegeneration and will provide new biological targets for treating disease. Although genes that cause familial forms of FTLD and AD have been identified, most of the genetic contribution to these disorders remains unknown. In addition to genes encoding proteins directly involved in disease pathology, evidence is mounting to support the role of immune dysregulation and inflammation as important contributors to both neurodegeneration and healthy cognitive aging. 

New Research Project to Examine the Role of Microglia in Alzheimer’s Disease Using Cellular Reprogramming

The John Douglas French Alzheimer's Foundation has funded an important new research project under the direction of Justin Ichida, PhD, of the University of Southern California, Department of Stem Cell Biology and Regenerative Medicine. 

The research project—Examining the Role of Microglia in Alzheimer’s Disease Using Cellular Reprogrammingapplies new techniques to enable researchers to gain a better understanding of how genetic differences affect the functioning of Microglia, and the risk for Alzheimer’s disease.

Microglia are a type of immune cell that make up about 15% of the cells in the brain. Microglia scavenge throughout the central nervous system removing infectious agents, damaged neurons, and plaques. Interestingly, recent studies suggest that genetic differences that increase the risk of developing Alzheimer’s disease (AD) may do so by altering microglial function rather than nerve cell function. This is because many of the genes or gene control regions that have been recently linked to AD are predicted to predominantly affect microglia. 

However, studying how AD-associated genetic changes affect human microglial function has been challenging because obtaining microglia from biopsies is difficult. To address this problem, Dr. Ichida and his team have developed a method called “cellular reprogramming” that enables the generation of human microglia from biopsied skin or blood cells. This approach has been used to produce functional nerve cells and other cell types from patients, but not microglia. Dr. Ichida’s team will couple this procedure with a technique called CRISPR that allows the introduction of genetic changes that increase AD risk into microglia in a petri dish. 

The research project will test the hypothesis that genetic differences that increase AD risk do so in part by altering microglial function. They will do this by examining microglial function in the presence or absence of two different genetic changes that are strongly associated with AD. The impact of this study will be to 1) determine if AD-associated genetic changes cause disease-relevant alterations in human microglial function and 2) establish this approach as a powerful platform for studying the role of microglia in AD.

Bruce L. Miller, MD, Chief Medical Officer of The John Douglas French Alzheimer's Foundation, has been elected to the National Academy of Medicine.

Bruce L. Miller, MD, Chief Medical Officer of The John Douglas French Alzheimer's Foundation, has been elected to the National Academy of Medicine.  

Election to the National Academy of Medicine is one of the highest honors in the fields of health and medicine, recognizing individuals who have demonstrated outstanding professional achievements and commitment to service in the medical sciences, health care and public health — in Dr. Miller’s case, as a contrarian who believed the type of disease causing dementia symptoms in a patient could be determined while the patient was still alive. 

Dr. Miller, who is the A. W. and Mary Margaret Clausen Distinguished Professor in Neurology and Director of the UCSF Memory and Aging Center, is principal investigator of the NIH-sponsored Alzheimer’s Disease Research Center, co-director of the Global Brain Health Institute, and leader of two philanthropy-funded research consortia, the Tau Consortium and the Consortium for Frontotemporal Research. 

He has received numerous awards including the Potamkin Award from the American Academy of Neurology, the Raymond Adams Award from the American Neurological Association and the Wallace Wilson Distinguished Alumni Award from the University of British Columbia. 

We are proud to note that Dr. Miller has served as the Chief Medical Officer of The John Douglas French Alzheimer's Foundation since it was founded in 1983.  In that time, Dr. Miller has overseen several hundred research projects funded by the Foundation.  We congratulate Dr. Miller on this recognition of his enormous talent, deep dedication, and true compassion.

Practical Strategies for Reducing Your Risk for Cognitive Decline.

A new book by Ken Kosik, MD, Outsmarting Alzheimer's, lays out practical strategies for helping people reduce their risk for developing Alzheimer's disease.

Dr. Kosik recommends four activities based on solid research evidence.  He says that people who regularly do these activities have a lower risk of developing cognitive decline.

1. Get Physical
Dr. Kosik says physical activity is the most potent Alzheimer's protection agent, stating that study after study has shown that people who exercise at least three times a week for a minimum of 15 to 30 minutes a sessions were less likely to develop Alzheimers disease, even if the disease ran in their family.

2. Eat Antioxidant-Rich, Anti-Inflammatory Foods
Dr. Kosik cautions that there is no single dietary pattern, food, or supplement that leads to optimum brain health, he says that one thing those that are effective have in common is an abundance of plant-based foods and a minimum of processed food.  He cites a new diet, developed by researchers at Rush University Medical Center in Chicago, as an an example of a the kind of approach to eating that can significantly lower the risk for developing Alzheimers.

The MIND (Mediterranean-DASH Intervention for Neurodegenerative Delay) diet is a hybrid of two other diet regimens (the Mediterranean and DASH (Dietary Approaches to Stop Hypertension) diets) previously found to reduce the risk of cardiovascular conditions, like hypertension, heart attack and stroke.  

Read more about the MIND diet Here, Here, and Here.

3. Make Time For Friends
Dr. Kosik points to a research study at Rush Alzheimer's Disease Center in Chicago that showed that adults who frequently spent time with others—being part of a book club, or a card game, having dinner dates with their friends, visiting familky had a 70 percent lower rate of cognitive decline over 12 years than did seniors with fewer interactions.

4. Exercise Your Brain
Dr. Kosik says one long-term study showed that older adults who frequently did stimulating leisure activities were less likely to develop dementia over 21 years, compared with those who did so less often. Reading, playing board games, practicing musical instruments, and working on puzzles at least several times a week may encourage the growth of new brain cells and connections between them. Even people who were carriers of a gene linked to Alzheimer's postponed the development of the disease by almost a decade by immersing in intellectually enriching activities throughout their lives.

This is not the first book to focus on ways individuals can adjust their lifestyle to reduce the risk of cognitive decline (Alzheimer's), but this book is noteworthy not only for it's research-backed guidance; it's noteworthy because of its author.

Ken Kosik, MD is one of the world's leading Alzheimer's researchers.  Dr. Kosik's work focuses on gaining an understanding of the fundamental causes, risk factors, and workings of Alzheimer's disease. 

After completing a B.A. and M.A. in English literature from Case Western Reserve University in 1972 and an M.D. from the Medical College of Pennsylvania in 1976, he served as a resident in neurology at Tufts New England Medical Center and was Chief Resident there in 1980. Beginning in 1980 he held a series of academic appointments at the Harvard Medical School and achieved the rank of full professor there in 1996. He also held appointments at McLean Hospital, Brigham and Women's Hospital, the Massachusetts General Hospital and the Dana-Farber Cancer Institute. In 2004, Kosik became the Harriman Professor of Neuroscience Research and Co-Director of the Neuroscience Research Institute at the University of California, Santa Barbara. He founded and serves as Medical Director of the non-profit center, Cottage Center for Brain Fitness (CCBF).

Dr. Kosik is probably best known for the ground-breaking research he has conducted in and around Medellin, Columbia.  JDFAF was a supporter of Dr. Kosik in his research in Columbia.

Dr. Kosik and his fellow researchers discovered an extended family, spread over this region of Colombia who have passed a particular Alzheimer gene from generation to generation, and Kosik says the family members who carry the Alzheimer's gene will definitely get the disease. The family represents the largest cluster of familial Alzheimer's disease in the world. In each generation, affected family members get the disease in their mid-40's.

Kosik explained it is possible to test people in the Colombian families for the gene, and predict who will get the disease and who will be spared. The ability to predict who and when family members will get the disease raises the possibility of developing clinical trials to find out whether or not certain drugs and other therapies are effective in delaying the disease in those family members who have the gene.

"We have the opportunity to treat this disease before it strikes," said Kosik. "We would be able to find out if drugs really work."

Clinical drug trials are now underway among this population.

Read more about Dr. Kosik's research Here and Here.

New diet shown to significantly reduce the risk for Alzheimer's.

A new study, reported in Alzheimer's & Dementia: The Journal of the Alzheimer's Association, finds that adhering to a new diet, developed by researchers at Rush University Medical Center in Chicago, can significantly lower the risk for developing Alzheimers.

The MIND (Mediterranean-DASH Intervention for Neurodegenerative Delay) diet is a hybrid of two other diet regimens (the Mediterranean and DASH (Dietary Approaches to Stop Hypertension) diets) previously found to reduce the risk of cardiovascular conditions, like hypertension, heart attack and stroke.  

The study shows that the MIND diet lowered the risk of AD by as much as 53 percent in participants who rigorously adhered to the diet, and by about 35 percent in those who followed it moderately well.

“One of the more exciting things about this is that people who adhered even moderately to the MIND diet had a reduction in their risk for AD,” said Martha Clare Morris, PhD, a professor, assistant provost for Community Research, and director of Nutrition and Nutritional Epidemiology at Rush. “I think that will motivate people.”

The MIND diet is also easier to follow than, say, the Mediterranean diet, which calls for daily consumption of fish and three to four daily servings of each of fruits and vegetables, Morris said.

The MIND diet has 15 dietary components, including 10 “brain-healthy food groups” — green leafy vegetables, other vegetables, nuts, berries, beans, whole grains, fish, poultry, olive oil and wine — and five unhealthy groups that comprise red meats, butter and stick margarine, cheese, pastries and sweets, and fried or fast food.

The MIND diet includes at least three servings of whole grains, a salad and one other vegetable every day — along with a glass of wine. It also involves snacking most days on nuts and eating beans every other day or so, poultry and berries at least twice a week and fish at least once a week. Dieters must limit eating the designated "unhealthy" foods, especially butter (less than 1 tablespoon a day), cheese, and fried or fast food (less than a serving a week for any of the three), to have a real shot at avoiding the devastating effects of Alzheimer's, according to the study.

"Even moderate adherence to the MIND diet showed a statistically significant decreased risk of developing Alzheimer's disease," says study author Martha Clare Morris, a professor of epidemiology at Rush University in Chicago. "Neither the Mediterranean diet or DASH had that benefit with moderate adherence."

Learn more about the MIND Diet here, here, and here

New Studies suggest women's brains are more vulnerable to Alzheimer's than men’s.

Two-thirds of all individuals in the US diagnosed with Alzheimer’s are women — a circumstance long explained by scientists by the fact that women live longer than men. 

Two new studies presented at the 2015 Alzheimer's Association International Conference (AAIC) in Washington, DC suggest there may be more to the story.

The studies indicate that women's brains may in fact be more vulnerable to the degenerative effects of Alzheimer's disease than men’s, and that these differences may also cause them to experience memory loss and other declines in cognitive function twice as fast as men.

The first study conducted at Duke University used data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to study how the cognitive abilities of about 400 seniors (141 women, 257 men) with Mild Cognitive Impairment (MCI) changed over the course of up to eight years.

They found the cognitive abilities of the women declined twice as fast as men's.

“The bottom line is, more and more we think there are some differences,” said Kristine Yaffe, a professor of psychiatry, neurology and epidemiology at the University of California at San Francisco. “It’s not just that women are living to be older — that’s true, and that drives some of this. But there’s something else going on in terms of biology [and] environment for women compared to men that may make them at greater risk or, if they have some symptoms, may change the progression.”

Katherine Amy Lin who reported on the study said, "Our findings suggest that men and women at risk for Alzheimer's may be having two very different experiences."  "Our analyses show that women with mild memory impairments deteriorate at much faster rates than men in both cognitive and functional abilities. These results point to the possibility of as yet undiscovered gender-specific genetic or environmental risk factors that influence the speed of decline. Uncovering those factors should be a high priority for future research."

The second study conducted at University of California at San Francisco used PET (positron emission tomography) scanning to measure levels of amyloid (the substance that forms sticky plaques in the brains of Alzheimer's patients) in about 1,000 people, including many with cognitive impairment or Alzheimer's disease. 

“This study shows women have more amyloid in their brain than men in general, and especially once the women are in the late stages where they’re having dementia,” said Michael W. Weiner, a radiology professor at UC San Francisco and principal investigator of the Alzheimer’s Disease Neuroimaging Initiative.

As to why women have more amyloid in their brain, Weiner says the answer is still unclear—it may be a function of genetics, or caused by hormonal differences (women have estrogen, men have testosterone) or lifestyle differences; diet, exercise, childbearing.

Learn more about this research Here.

New study shows a form of age-related cognitive decline—tied to an immune-system molecule—can be reversed in mice.

Two studies published in 2014 and 2015 — the product of a collaboration between Saul A. Villeda, PhD, a Faculty Fellow at University of California San Francisco (UCSF) and Tony Wyss-Coray, PhD, professor of neurology at Stanford University — provide important insights into the cause of one type type of cognitive decline—and the possibility of reversing its effects. (note: Dr. Wyss-Coray has been previously funded by JDFAF. Read his profile here.)

The research teams found that a blood-borne molecule (beta-2 microglobulin, or B2M, a component of a larger molecule called MHC) which plays an important role in the adaptive immune system, greatly increases as we age, and can act adversely in the brain, in ways not related to immunity—blocking the regeneration of brain cells, thus promoting cognitive decline.

In 2014 study, Villeda and Tony Wyss-Coray showed that connecting the circulatory system of a young mouse to that of an old mouse could reverse the declines in learning ability that typically emerge as mice age.

Over the course of their research, however, the researchers noted an opposite effect—blood from older animals appears to contain the "pro-aging factors" that suppress neurogenesis--the formation of new brain cells in regions important for memory--which when introduced into younger animals can contribute to cognitive decline.

In a new study, published online on July 6, 2015 in Nature Medicine, Villeda and  Wyss-Coray followed up on these findings, as well as other studies correlating high B2M blood levels with cognitive dysfunction in Alzheimer's disease, HIV-associated dementia, and as a consequence of chronic dialysis for kidney disease.

The researchers observed that when B2M was administered to young mice, either via the circulatory system or directly into the brain, the mice performed poorly on tests of learning and memory compared to untreated mice, and neurogenesis was also suppressed in these mice.

These experiments were complemented by genetic manipulations in which some mice were engineered to lack a gene known as Tap1, which is crucial for the MHC I complex to make its way to the cell surface. In these mice, administration of B2M in young mice had no significant effect, either in tests of learning or in assessments of neurogenesis.

The group also bred mice missing the gene for B2M itself. These mice performed better than their normal counterparts on learning tests well into old age, and their brains did not exhibit the decline in neurogenesis typically seen in aged mice.

Villeda emphasized that the effects on learning observed in the B2M-administration experiments were reversible—30 days after the B2M injections, the treated mice performed as well on tests as untreated mice, indicating that B2M-induced cognitive decline in humans could potentially be treated with targeted drugs.

"From a translational perspective, we are interested in developing antibodies or small molecules to target this protein late in life," said Villeda. "Since B2M goes up with age in blood, cerebrospinal fluid (CSF), and also in the brain itself, this allows us multiple avenues in which to target this protein therapeutically."

Read more about this research.

First Alzheimer's Drug Shown in Early Stage Clinical Trial to Remove Beta Amyloid Plaque and Slow Cognitive Decline.

As of the end of last year (2014), more than two-hundred forty-four Alzheimer's drug compounds have been tested, with failure rate that exceeds 99 percent.  

But a new treatment is showing real promise in early stage clinical trials.

The results of a new early-stage trial, reported at the AD/PD 2015: International Conference on Alzheimer's and Parkinson's Diseases, and a further analysis of subgroup treatment response presented at the recent American Academy of Neurology (AAN) 67th Annual Meeting, showed that a monoclonal antibody, aducanumab (formerly known as BIIB037), developed by Biogen Inc., significantly reduced amyloid plaque in the brain over the 1 year study period and slowed cognitive decline.

"Treatment with aducanumab results in a dose-dependent and time-dependent effect that is consistent across APOE ε4 carriers and noncarriers, and among subjects with both mild and prodromal disease," lead author Jeffrey Sevigny, MD, Biogen Inc, stated.  

This is significant as more than 50 percent of people with AD are APOE ε4 carriers.

Scientists are cautiously optimistic, in light of a history of other drugs which have shown promis in early stages, only to fail in later, larger scale trials.

Based on these early-stage results, Aducanumab will now move directly to phase III trials.

Learn more about aducanumab here, here, and here