Alzheimer’s Disease Consists of Three Distinct Subtypes, According to UCLA Study

(University of California, Los Angeles) Alzheimer’s disease, long thought to be a single disease, really consists of three distinct subtypes, according to a UCLA study. The finding could lead to more highly targeted research and, eventually, new treatments for the debilitating neurological disorder, which robs people of their memories.

The study further found that one of the three variations, the cortical subtype, appears to be fundamentally a different condition than the other two, said Dr. Dale Bredesen, the study’s author, a UCLA professor of neurology and member of the Easton Laboratory for Neurodegenerative Disease Research.

“Because the presentation varies from person to person, there has been suspicion for years that Alzheimer’s represents more than one illness,” said Bredesen, who also is the founding president of the Buck Institute for Research on Aging. “When laboratory tests go beyond the usual tests, we find these three distinct subtypes.

“The important implications of this are that the optimal treatment may be different for each group, there may be different causes, and, for future clinical trials, it may be helpful to study specific groups separately.”

The subtypes are:

  • Inflammatory, in which markers such as C-reactive protein and serum albumin to globulin ratios are increased.
  • Non-inflammatory, in which these markers are not increased but other metabolic abnormalities are present.
  • Cortical, which affects relatively young individuals and appears more widely distributed across the brain than the other subtypes of Alzheimer’s. It typically does not seem to cause memory loss at first, but people with this subtype of the disease tend to lose language skills. It is often misdiagnosed, typically affects people who do not have an Alzheimer’s-related gene and is associated with a significant zinc deficiency.

The findings of the two-year study, which involved metabolic testing of 50 people, appear in the current issue of the peer-reviewed journal Aging.

No effective therapy for Alzheimer’s exists. And scientists have yet to completely identify the cause, although multiple studies have pointed to metabolic abnormalities such as insulin resistance, hormonal deficiencies and hyperhomocysteinemia, a condition characterized by an abnormally high level of an amino acid in the blood.

In a 2014 paper, Bredesen showed that making lifestyle, exercise and diet changes designed to improve the body’s metabolism reversed cognitive decline in nine out of 10 patients with early Alzheimer’s disease or its precursors.

The current finding grew out of an extensive evaluation of the data from last year’s study, and it could eventually help scientists pinpoint more precise targets for treatments — the same approach that has led to major advances in treating other diseases.

For example, Bredesen explained, researchers have recently been able to develop precise treatments for cancer by sequencing tumor genomes and comparing them to the patients’ genomes to better understand what drives the formation and growth of tumors.

“However, in Alzheimer’s disease, there is no tumor to biopsy,” Bredesen said. “So how do we get an idea about what is driving the process? The approach we took was to use the underlying metabolic mechanisms of the disease process to guide the establishment of an extensive set of laboratory tests, such as fasting insulin, copper-to-zinc ratio and dozens of others.”

Going forward, Bredesen and his team will seek to determine whether the subtypes have different underlying causes, and whether they respond differently to potential treatments.

The need for a new approach to treat Alzheimer’s is urgent. It is the most common age-related dementia, and the number of people with the disease in the U.S. is expected to increase to 15 million in 2050, from nearly 6 million today. The cost to treat people in the U.S. with Alzheimer’s and other dementias is expected to be $226 billion in 2015 alone, and could reach $1.1 trillion in 2050.

The study was funded by the National Institutes of Health (AG165070, AG034427 and AGO36975), the Mary S. Easton Center for Alzheimer’s Disease Research at UCLA, the Douglas and Ellen Rosenberg Foundation, the S.D. Bechtel, Jr. Foundation, the Joseph Drown Foundation, the Alzheimer’s Association, the Accelerate Fund, the Buck Institute and Marin Community Foundation, the Michael and Catherine Podell Fund, Craig Johnson, Allan Bortel and Michaela Hoag.


© 2015 UCLA All Rights Reserved.


Cocoa as Novel Dietary Source for the Prevention of Cognitive Deterioration in Alzheimer’s Disease

(Journal of Alzheimer’s Disease) The potential benefits of dietary cocoa extract and/or its final product in the form of chocolate have been extensively investigated in regard to several aspects of human health. Cocoa extracts contain polyphenols, which are micronutrients that have many health benefits, including reducing age-related cognitive dysfunction and promoting healthy brain aging, among others.

Dr. Giulio Maria Pasinetti, MD, PhD, Saunders Family Chair and Professor of Neurology at the Icahn School of Medicine at Mount Sinai, Director of Biomedical Training at J.J. Peters Bronx VA Medical Center, is leading author of a recent paper entitled “Recommendations for development of new standardized forms of cocoa breeds and cocoa extract processing for the prevention of Alzheimer’s disease,” to be published in the Journal of Alzheimer’s Disease. This research suggests that

“there is strong scientific evidence supporting the growing interest in developing cocoa extract, and potentially certain dietary chocolate preparations, as a natural source to maintain and promote brain health, and in particular to prevent age-related neurodegenerative disorders such as Alzheimer’s disease, which is the most common form of age-related dementia affecting an estimated 44 million people worldwide.”

Previous studies from Dr. Pasinetti’s laboratory and others suggest that certain cocoa extract preparations may prevent or possibly delay Alzheimer’s disease in animal experimental models of the disease, in part by inhibiting the generation and promoting the clearance of toxic proteins, including β-amyloid (Aβ) and abnormal tau aggregates, in the brain through mechanisms mediated by polyphenols.

Most importantly, the role of cocoa polyphenols in preventing abnormal accumulation of toxic protein aggregates in the brain would play a pivotal role in preventing the loss of synapses that are critical for functional connection among neurons. Recent clinical studies appear to confirm the potential beneficial role of certain cocoa extracts in delaying cognitive aging. The benefits of cocoa polyphenols in preventing synapse loss and, therefore, in preserving/restoring synaptic function may provide a viable and important strategy for preserving cognitive function and, thereby, protecting against the onset and progression of Alzheimer’s disease.

In spite of the promises of cocoa polyphenols for treating and/or preventing Alzheimer’s disease, Dr. Pasinetti hypothesizes in his new publication that there is a need for multidisciplinary collaborative efforts involving cocoa producers, wholesalers, and the biomedical community if we want to succeed in the development of cocoa extract for health benefits.

For example, there are still major issues relating to the diminishing global supply of cocoa and the lack of consistency and reproducibility of cocoa extract processing, which should be carefully addressed. Changes in growth, climate/conditions, and cocoa plant diseases are decreasing the supply of cocoa.

To address this, new breeds of cocoa, engineered to be fruitful, more resistant to disease, and more flavorful, are currently being investigated. Furthermore, little is known about how cocoa processing may influence the biological effect of cocoa extracts. Evidence suggests that certain procedures used in cocoa processing can significantly influence its polyphenol content, ultimately influencing its biological activity. Interestingly, two of the most common processing techniques for the chocolate we consume have been reported to result in the loss of as much as 90% of the polyphenols in cocoa.

Dr. Pasinetti notes that ongoing interdisciplinary research will provide an unprecedented opportunity to strengthen our understanding of the beneficial roles of cocoa polyphenols and improve cocoa development and processing in order to promote healthy brain aging and possibly prevent Alzheimer’s disease.


This work is supported in part by the 1PO1AT004511-031 Center for Excellence in Research on Complementary Alternative Medicine (Program Director: Pasinetti).

“Recommendations for Development of New Standardized Forms of Cocoa Breeds and Cocoa Extract Processing for the Prevention of Alzheimer’s Disease: Role of Cocoa in Promotion of Cognitive Resilience and Healthy Brain Aging.” Lauren Dubner, Jun Wang, Lap Ho, Libby Ward and Giulio M. Pasinetti. Journal of Alzheimer’s Disease 48(4). DOI: I0.3233/JAD-150536.

Full text of the paper is available to credentialed journalists upon request by contacting Daphne Watrin at +31 20 688 3355 or

About the Journal of Alzheimer’s Disease (JAD) – The Journal of Alzheimer’s Disease ( is an international multidisciplinary journal to facilitate progress in understanding the etiology, pathogenesis, epidemiology, genetics, behavior, treatment and psychology of Alzheimer’s disease. The journal publishes research reports, reviews, short communications, book reviews, and letters-to-the-editor. Groundbreaking research that has appeared in the journal includes novel therapeutic targets, mechanisms of disease and clinical trial outcomes. The Journal of Alzheimer’s Disease has an Impact Factor of 4.151 according to Thomson Reuters’ 2014 Journal Citation Reports. The Journal is published by IOS Press (

About the Mount Sinai Health System
 – The Mount Sinai Health System is an integrated health system committed to providing distinguished care, conducting transformative research, and advancing biomedical education. Structured around seven hospital campuses and a single medical school, the Health System has an extensive ambulatory network and a range of inpatient and outpatient services—from community-based facilities to tertiary and quaternary care.

The System includes approximately 6,100 primary and specialty care physicians; 12 minority-owned free-standing ambulatory surgery centers; more than 140 ambulatory practices throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and 31 affiliated community health centers. Physicians are affiliated with the renowned Icahn School of Medicine at Mount Sinai, which is ranked among the highest in the nation in National Institutes of Health funding per investigator. Seven departments at The Mount Sinai Hospital and one at the New York Eye and Ear Infirmary (NYEE) ranked nationally in the top 25 in the 2015-2016 “Best Hospitals” issue of U.S. News & World Report. Mount Sinai’s Kravis Children’s Hospital also is ranked in seven out of ten pediatric specialties by U.S. News & World Report.

For more information, visit or find Mount Sinai on Facebook, Twitter and YouTube.

Journal of Alzheimer’s Disease is published by IOS Press

Copyright © 2015


Low Vitamin D Among Elderly Associated with Significant Decline in Cognition, Dementia

(University of California – Davis Health System) Vitamin D insufficiency among the elderly is highly correlated with accelerated cognitive decline and impaired performance, particularly in domains such as memory loss that are associated with Alzheimer’s disease and dementia, researchers with the UC Davis Alzheimer’s Disease Center and Rutgers University have found. The effect is “substantial,” with individuals with low vitamin D declining at a rate three times faster than those with adequate vitamin D levels.

The researchers said their findings amplify the importance of identifying vitamin D insufficiency among the elderly, particularly high-risk groups such as African-Americans and Hispanics, who are less able to absorb the nutrient from its most plentiful source: sunshine. Among those groups and other darker-skinned individuals, low vitamin D should be considered a risk factor for dementia, they said.

The research is published online in JAMA Neurology, a JAMA Network journal.

“Independent of race or ethnicity, baseline cognitive abilities and a host of other risk factors, vitamin D insufficiency was associated with significantly faster declines in both episodic memory and executive function performance,” said Joshua Miller, professor in the Department of Pathology and Laboratory Medicine at the time when the research was conducted and now professor and chair of the Department of Nutritional Sciences at Rutgers University.

“This work, and that of others, suggests that there is enough evidence to recommend that people in their 60s and older discuss taking a daily vitamin D supplement with their physicians,” Miller said.

“Even if doing so proves to not be effective, there’s still very low health risk to doing it,” he said.

The large, longitudinal study was conducted in nearly 400 racially and ethnically diverse men and women in Northern California participating in longitudinal research at the Alzheimer’s Disease Center in Sacramento, Calif. Fifty percent of participants were Caucasian and 50 percent were African-American or Hispanic. The participants had a mean age of 76 and were either cognitively normal, had mild cognitive impairment, or dementia.

The participants’ serum vitamin D status was measured at the beginning of the study. Vitamin D deficiency and insufficiency were prevalent among all of the study participants. Overall, 26 percent were deficient and 35 percent were insufficient. Among Caucasians, 54 percent had low vitamin D, compared with 70 percent of African-Americans and Hispanics.

Over five years of follow-up, vitamin D deficient individuals experienced cognitive declines that were two-to-three times faster than those with adequate serum vitamin D levels. In other words it took only two years for the deficient individuals to decline as much as their counterparts with adequate Vitamin D declined during the five-year follow-up period.

“We expected to see declines in individuals with low vitamin D status,” said Charles DeCarli, director of the Alzheimer’s Disease Center.

“What was unexpected was how profoundly and rapidly [low vitamin D] impacts cognition.”

Exposing the skin to sunlight is the major source of vitamin D. Racial and some ethnic minorities are at greater risk of low vitamin D because the higher concentration of melanin that makes their skin darker — and protects against skin cancer in sunny climates — also inhibits synthesis of vitamin D.

Diet is the other major source of vitamin D. Dietary vitamin D is obtained particularly through dairy consumption. The intake of dairy products is especially low among minority groups, with only 6.5 percent of African-Americans and 11 percent of Mexican-Americans nationwide consuming the recommended three daily servings of dairy products, the study says.

“I don’t know if replacement therapy would affect these cognitive trajectories. That needs to be researched and we are planning on doing that,” DeCarli said.

“This is a vitamin deficiency that could easily be treated and that has other health consequences. We need to start talking about it. And we need to start talking about it, particularly for people of color, for whom vitamin D deficiency appears to present an even greater risk,” he said.


Journal Reference:

Charles DeCarli, MD et al. Vitamin D Status and Rates of Cognitive Decline in a Multiethnic Cohort of Older Adults. JAMA Neurology, September 2015 DOI: 10.1001/jamaneurol.2015.2115

© 2015 UC Regents. All Rights Reserved.


Resveratrol Impacts Alzheimer’s Disease Biomarker

(Georgetown University Medical Center) The largest nationwide clinical trial to study high-dose resveratrol long-term in people with mild to moderate Alzheimer’s disease found that a biomarker that declines when the disease progresses was stabilized in people who took the purified form of resveratrol.

Resveratrol is a naturally occurring compound found in foods such as red grapes, raspberries, dark chocolate and some red wines.

The results, published online today in Neurology, “are very interesting,” says the study’s principal investigator, R. Scott Turner, MD, PhD, director of the Memory Disorders Program at Georgetown University Medical Center (pictured).  Turner, who treats patients at MedStar Georgetown University Hospital, cautions that the findings cannot be used to recommend resveratrol. “This is a single, small study with findings that call for further research to interpret properly.”

The resveratrol clinical trial was a randomized, phase II, placebo-controlled, double blind study in patients with mild to moderate dementia due to Alzheimer’s disease. An “investigational new drug” application was required by the U.S. Food and Drug Administration to test the pure synthetic (pharmaceutical-grade) resveratrol in the study. It is not available commercially in this form.

The investigators enrolled 119 participants for the one-year study. The highest dose of resveratrol tested was one gram by mouth twice daily — equivalent to the amount found in about 1,000 bottles of red wine.

Patients who were treated with increasing doses of resveratrol over 12 months showed little or no change in amyloid-beta40 (Abeta40) levels in blood and cerebrospinal fluid. In contrast, those taking a placebo had a decrease in the levels of Abeta40 compared with their levels at the beginning of the study.

“A decrease in Abeta40 is seen as dementia worsens and Alzheimer’s disease progresses; still, we can’t conclude from this study that the effects of resveratrol treatment are beneficial,” Turner explains.

“It does appear that resveratrol was able to penetrate the blood brain barrier, which is an important observation. Resveratrol was measured in both blood and cerebrospinal fluid.”

John Bozza, 80, participated in the study. Five years ago, his wife, Diana, began noticing “something wasn’t quite right.” He was diagnosed with mild cognitive impairment, but only a year later, his condition progressed to mild Alzheimer’s.

Diana, whose twin sister died from the same disease, says there are multiple reasons she and John decided to participate in the resveratrol study, and they now know he was assigned to take the active drug.

“I definitely want the medical community to find a cure,” she says. “And of course I thought there’s always a chance that John could have been helped, and who knows, maybe he was.”

The researchers studied resveratrol because it activates proteins called sirtuins, the same proteins activated by caloric restriction. The biggest risk factor for developing Alzheimer’s is aging, and studies with animals found that most age-related diseases—including Alzheimer’s—can be prevented or delayed by long-term caloric restriction (consuming two-thirds the normal caloric intake).

Turner says the study also found that resveratrol was safe and well tolerated. The most common side effects experienced by participants were gastrointestinal-related, including nausea and diarrhea. Also, patients taking resveratrol experienced weight loss while those on placebo gained weight.

One outcome in particular was confounding, Turner notes. The researchers obtained brain MRI scans on participants before and after the study, and found that resveratrol-treated patients lost more brain volume than the placebo-treated group.

“We’re not sure how to interpret this finding. A similar decrease in brain volume was found with some anti-amyloid immunotherapy trials,” Turner adds.

A working hypothesis is that the treatments may reduce inflammation (or brain swelling) found with Alzheimer’s.

The study, funded by the National Institute on Aging and conducted with the Alzheimer’s Disease Cooperative Study, began in 2012 and ended in 2014. GUMC was one of 21 participating medical centers across the U.S.

Further studies, including analysis of frozen blood and cerebrospinal fluid taken from patients, are underway to test possible drug mechanisms.

“Given safety and positive trends toward effectiveness in this phase 2 study, a larger phase 3 study is warranted to test whether resveratrol is effective for individuals with Alzheimer’s — or at risk for Alzheimer’s,” Turner says.

Resveratrol and similar compounds are being tested in many age-related disorders including cancer, diabetes and neurodegenerative disorders. The study Turner led, however, is the largest, longest and highest dose trial of resveratrol in humans to date.

The research was supported by a grant from the National Institute on Aging (U01 AG010483). Turner reports no personal financial interests related to the study.


Journal Reference:

R. S. Turner, R. G. Thomas, S. Craft, C. H. van Dyck, J. Mintzer, B. A. Reynolds, J. B. Brewer, R. A. Rissman, R. Raman, P. S. Aisen. A randomized, double-blind, placebo-controlled trial of resveratrol for Alzheimer disease. Neurology, 2015; DOI: 10.1212/WNL.0000000000002035

Copyright 2015 Georgetown University


Overweight, Obesity in Midlife Linked to Earlier Onset of Alzheimer’s

(MedicalNewsToday) Individuals who are overweight or obese at the age of 50 may be at greater risk of earlier onset of Alzheimer’s disease, according to new research published in Molecular Psychiatry.

Alzheimer’s disease is the most common form of dementia, affecting around 5.3 million Americans, of whom 5.1 million are aged 65 and older.

Common risk factors for Alzheimer’s include age, a family history of the disease and the presence of certain genes, such as apolipoprotein E-e4 (APOE-e4).

Previous studies have also suggested a link between midlife obesity and increased risk for Alzheimer’s, but study co-author Dr. Madhav Thambisetty, of the Laboratory of Behavioral Neuroscience at the National Institute on Aging (NIA), and colleagues say it was unclear how midlife obesity impacts the age of onset. They set out to assess this association with their latest research.

The study involved the analysis of 1,394 cognitively normal adults who were a part of the Baltimore Longitudinal Study of Aging (BLSA) – one of the longest-running longitudinal studies of aging in the US.

The team assessed participants’ body mass index (BMI) at midlife – defined as the age of 50 – and their development of Alzheimer’s via neurological assessments every 2 years for an average of 14 years. During follow-up, 142 participants developed Alzheimer’s.

The higher BMI is in midlife, the earlier the onset of Alzheimer’s

The researchers found that subjects who were overweight or obese in midlife – defined as having a BMI of 25 or over – were likely to develop Alzheimer’s around 6.7 months sooner than participants of a healthy weight.

What is more, the risk of earlier Alzheimer’s onset rose with each unit increase in midlife BMI. For example, participants with a BMI of 30 in midlife were likely to develop Alzheimer’s a year earlier than those with a BMI of 28.

The researchers also assessed two subsamples from the BLSA, involving 191 deceased subjects who underwent autopsy and neuropathological assessment.

From this, the team found individuals with a high BMI in midlife were more likely to have greater abundance of amyloid proteins in the brain, a hallmark of Alzheimer’s. This was true even for subjects who were free of dementia.

While the researchers are unable to describe the exact mechanisms behind their findings, they believe their results highlight the importance of maintaining a healthy weight in midlife in order to prevent early Alzheimer’s onset. They add:

“Our findings raise the possibility that inexpensive, noninvasive interventions targeting midlife obesity and overweight could substantially alter the trajectory of Alzheimer’s disease, reducing its global public health and economic impact.”

The team notes that further research involving a larger study sample is warranted in order to determine whether there is a specific BMI value at which the risk of earlier Alzheimer’s onset begins to increase.

Last month, Medical News Today reported on a study by Canadian researchers that found an abnormal accumulation of fat in the brain may speed up the progression of Alzheimer’s.


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Diabetes and Brain Tangles May Be Linked Independently of Alzheimer’s Disease

(American Academy of Neurology)  Diabetes may be linked to the buildup of tangles or tau in the brain, separate from Alzheimer’s disease, according to a new study published in the September 2, 2015, online version of Neurology, the medical journal of the American Academy of Neurology.

“Evidence shows that people with type 2 diabetes have double the risk of developing dementia,” said study author Velandai Srikanth, MD, PhD, from Monash University in Melbourne, Australia.

“This interesting development further defines how the diseases may be connected.”

The study involved 816 people with an average age of about 74. Of those, 397 had mild cognitive impairment, which can be a precursor to dementia, 191 had Alzheimer’s disease dementia and 228 people had no memory and thinking problems. A total of 124 of the participants had diabetes.

The study looked at the relationship between type 2 diabetes, the loss of brain cells and their connections, the levels of beta amyloid (a sticky buildup of plaques) and tau or tangles of protein in the spinal fluid of the participants.

The study found that those with diabetes had on average 16 picograms per milliliter greater levels of the tau protein in the spinal and brain fluid irrespective of the diagnosis of dementia. Greater levels of tau in spinal fluid may reflect a greater build-up of tangles in the brain. These tangles may eventually contribute to the development of dementia.

It also found that diabetes was associated with a reduced thickness of the cortex, the layer of the brain with most nerve cells. People with diabetes had cortical tissue that was an average of 0.03 millimeter less than those who did not have diabetes, whether they had no thinking and memory problems, mild cognitive impairment or dementia due to Alzheimer’s disease. The buildup of tangles may contribute to this loss of brain tissue.

“Due to the fact that nerve cells in the brain do not replace themselves, it is extremely important to find ways to reduce the death of current brain cells.

Studies such as ours seek to understand how diseases like diabetes may directly or indirectly affect brain cell death,” said Srikanth.

He noted that because the study looked at participants’ data at one point in time, it does not determine whether there is a cause-and-effect relationship between diabetes and the brain tangles.

The study was based on data from the US Alzheimer’s Disease Neuroimaging Initiative and was supported by the National Institutes of Health.

To learn more about Alzheimer’s disease, please visit

The American Academy of Neurology, an association of more than 28,000 neurologists and neuroscience professionals, is dedicated to promoting the highest quality patient-centered neurologic care. A neurologist is a doctor with specialized training in diagnosing, treating and managing disorders of the brain and nervous system such as Alzheimer’s disease, stroke, migraine, multiple sclerosis, brain injury, Parkinson’s disease and epilepsy.

For more information about the American Academy of Neurology, visit or find us on Facebook, Twitter, Google+ and YouTube.


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Researchers Shed Light on Potential Shield from Alzheimer’s

(Journal of Alzheimer’s Disease) Today, more than 5.1 million Americans live with Alzheimer’s disease, a devastating type of dementia that plagues memory and thinking. That number is expected to triple in the coming decades. Moreover, according to a 2012 survey, Americans fear Alzheimer’s more than any other disease.

But studies looking into treatments for Alzheimer’s disease have been frustratingly disappointing.

“There is no cure for Alzheimer’s disease,” said Liqin Zhao, assistant professor of pharmacology and toxicology at the University of Kansas School of Pharmacy.

“Five available Alzheimer’s disease drugs were all approved by FDA 10 years ago, and they provide only temporary symptomatic relief for an average of six to 12 months.”

Zhao said that over the last decade, more than 100 human trials aimed at Alzheimer’s disease treatment have been conducted with little success.

Now, she’s part of a KU team that has published a breakthrough investigation into human ApoE2, a seemingly protective “apolipoprotein” created by the ApoE gene — a gene associated with Alzheimer’s disease risk. The research appears in the Journal of Alzheimer’s Disease 48(2).

“Human ApoE is polymorphic and exists in three major alleles — ApoE2, ApoE3 and ApoE4,” Zhao said.

“ApoE2 is a rare form and is considered neuroprotective. ApoE3 is the most common form and considered to play a neutral role in AD.”

“ApoE4 is the greatest genetic risk factor for late-onset sporadic AD — ApoE4 occurs in only about 20 percent of the total population but accounts for approximately 50 percent of the Alzheimer’s disease population.”

According to Zhao, too much previous research has focused on ApoE4 — many of them focused on ApoE4-mediated neurotoxic mechanisms by comparing ApoE4 to ApoE3, or ApoE4 carriers versus non-ApoE4 carriers. By contrast, she said ApoE2 has largely been ignored with only a few published studies that included ApoE2 in their designs — until now.

“We took a different approach and looked from a different angle,” Zhao said.

“We asked the question: What makes ApoE2 carriers resistant to Alzheimer’s disease?

“Our rationale is that if we can figure out the mechanisms that underlie ApoE2-mediated neuroprotective properties, we could translate this molecular understanding into a therapeutic strategy aimed to transform an aging brain — in particular an ApoE4 brain into an ApoE2-like brain.”

“Such a strategy could essentially increase the defense ability of the aging, ApoE4 brain against the development of Alzheimer’s disease.”

The KU researcher believes several factors could have contributed to the current trend of lost-in-translation from preclinical findings in animal models to trials in humans.

“This could suggest that Alzheimer’s disease animal models that are widely used in preclinical studies — most are early-onset familial Alzheimer’s-disease-related models — don’t accurately model the pathophysiological condition of the majority of human Alzheimer’s disease cases, which is the late-onset sporadic Alzheimer’s disease — the most common form of Alzheimer’s disease representing over 95 percent of the current human Alzheimer’s disease population.”

Thus, Zhao thinks it’s very likely the success derived from familial Alzheimer’s disease-related animal models isn’t replicated in human late-onset sporadic Alzheimer’s disease patients.

“Another possibility could be that when the disease gets to the mid-to-late stage, the damage in the brain could be too advanced to be altered by the drugs tested in those trials,” she said.

Zhao believes the trend of clinical failures stresses a tremendous need for the development of strategies that can be used for prevention, risk reduction or early intervention at the preclinical stage of the disease, in addition to continuing the effort of finding an effective treatment.

“Alzheimer’s disease is a unique brain disease in that it begins with a very long preclinical development phase — 10 to 20 years — before it can be clinically diagnosed,” she said.

“During this long prodromal period, the brain undergoes many changes including two major ones — decreased glucose utilization and increased amyloid deposition.”

Zhao’s KU colleagues on the study published in the Journal of Alzheimer’s Disease are Jeriel Thomas-Richard Keeney and Shaher Ibrahimi.

“This study essentially opens up a new line of research for us,” Zhao said.

“We’re currently expanding our investigations to further test our hypothesis that bioenergetic robustness could serve as a major mechanism whereby ApoE2 delegates neuroprotection.

If our hypothesis proves true, we can move forward with the idea that a strategy that enhances brain energy metabolism holds great promise for prevention, risk reduction or delaying the onset in an aging brain — in particular an ApoE4 brain — of Alzheimer’s disease.”

The Alzheimer’s Association, NIH-funded KU Alzheimer’s Disease Center and KU general research funds and new-faculty startup funds supported this work.


Journal of Alzheimer’s Disease is published by IOS Press

Copyright © 2015


New Drugs Show Signs of Slowing Alzheimer’s

(WebMD) New results from ongoing clinical trials have fueled hopes for a class of Alzheimer’s drugs that target the buildup of sticky plaque in the brain linked to the disease.

The data, presented Wednesday to a standing-room-only crowd of doctors and patients at the Alzheimer’s Association International Conference 2015, suggest — on paper, at least — that the drugs may slow the decline of people who are treated early in the course of the disease.

But experts who were not involved in the studies say the drugs will likely be pricey, while their benefits appear to be small — perhaps so slight that people with Alzheimer’s might not notice improvements in their ability to think or function in their daily lives.

“Will we get enough bang for our buck?” said Paul Rosenberg, MD, associate director of the Memory and Alzheimer’s Treatment Center at Johns Hopkins Hospital.

But the drugs will continue to be tested, and it could be that larger benefits will become more apparent over time, especially if they can stabilize patients by slowing their decline, said Sam Gandy, MD, PhD, associate director of the Mount Sinai Alzheimer’s Disease Research Center.

“Maybe in 1, 2, or 3 years the treatment will be meaningful, but we can’t know that until longer trials are completed,” said Gandy, who was also not involved in the research.

Five million Americans have Alzheimer’s, and that number is expected to climb as the population ages. Current drugs help symptoms, but their benefits wear off over time as the disease marches on, and people inevitably get worse as the disease gradually lays waste to the brain.

The experimental medications target sticky protein pieces called beta amyloid in the brain. Beta amyloid forms telltale plaques that can be seen on brain scans of people with Alzheimer’s disease.

The idea was that getting rid of some of these protein pieces might slow or even reverse the underlying disease. And the drugs, called aducanumab, gantenerumab, and solanezumab, appear to do exactly what they were designed to do.

The problem is that getting rid of beta amyloid doesn’t seem to hold as much benefit for patients — especially those in the middle and later stages of the disease — as researchers hoped.

Slowing Alzheimer’s in Its Early Stages

In two large clinical trials, solanezumab failed to show any benefits for patients compared to a placebo. But there were hopeful signs in people with mild Alzheimer’s.

Rather than give up on solanezumab, Eli Lilly, the company developing the drug, decided to keep testing it, focusing on people who had earlier stages of the disease when they started taking the medication.

They gave all the mild patients in the two failed studies — both those who had been taking a placebo, and those taking solanezumab — the option to continue to on the study medication.

Those patients, more than 1,300 in total, have now been participating in the studies of the drug for 3 and a half years.

People who had been taking the placebo, but who switched to the drug after 18 months, were considered to have been delayed on their start of the medicine. Researchers were curious to see whether those people would eventually see the same benefits as the patients who had been continuously taking the drug over time.

If the people who were delayed in starting solanezumab never caught up to the benefits in patients who had continuously taken the drug, that would indicate that the medicine had some effect on the underlying biology behind the disease.

After 2 more years, results suggest that the “delayed start” patients don’t catch up, suggesting that the drug alters the course of the disease.

“Think about a disease that has a 10-year span. We’re talking about delaying progression to [a nursing home] or to loss of ability to communicate with family,” said Paul Aisen, MD, director of the Alzheimer’s Therapeutic Research Institute at the University of Southern California.

But the differences for patients were small — about two points or less on tests of thinking, memory, and activities of daily living.

In addition to the conference presentation, the results of the solanezumab study were simultaneously published in the journal Alzheimer’s & Dementia: Translational Research and Clinical Interventions.

“Overall, the changes we’re making are modest. We have to be honest about that,” said Philip Scheltens, MD, PhD, director of the Alzheimer’s Center at the VU University Medical Center in Amsterdam.

Scheltens is testing a drug called gantenerumab that proved to reduce both beta amyloid and another toxic protein called tau in people with Alzheimer’s. But that drug also showed no benefits for patients — they didn’t do any better on tests of thinking and memory or function in their daily lives than people who were taking a placebo. Scheltens thinks that might be because researchers haven’t been testing a high enough dose of the drug.

“On a disease-modifying therapy, people don’t notice that they’re being treated because over time, the gradual differences are so slowly changing, you don’t know how to compare yourself with where you are a year ago,” he said.

Solanezumab is given through a vein (IV) every 4 weeks, and it has some side effects, including headaches and signs of brain swelling that can be detected on brain scans. Those side effects were considered to be manageable, though. Also, the effect of “biologic” drugs like these can also wear off over time if the immune system starts to react to them.

Roughly 50% of patients have dropped out of the study over time. These are people who know they have Alzheimer’s disease — an illness which is ultimately fatal — and are getting a cutting-edge medication for free. Generally, if people are seeing benefits from experimental drugs like these, they clamor to stay in clinical studies so they can continue to have access to the drug.

But researchers disputed that notion. They said the high drop-out rate was to be expected in a clinical trial setting where older patients were being asked to have regular tests and brain scans.

“That is not surprising to us at all. I think it reflects age, other illnesses, and the burden of study procedures that all come together to cause people to drop out,” said Aisen.

When asked if he thought people with Alzheimer’s would be willing to pay large amounts of money to go on a drug that offers little apparent benefit and to stay on that medicine indefinitely, Aisen said, “I do.”

Another drug, called aducanumab, is still in the earliest stages of clinical testing. In those trials, researchers are still trying to determine the best dose to give people.

Similar to solanezumab, aducanumab showed slight benefits on tests of thinking and memory on the highest dose of the drug.

The differences were in the range of one to two points compared to placebo.

On that dose, though, about a third of people reported headaches, visual disturbances, and confusion.

Based on those results, Jeff Sevigny, MD, senior medical director of neurodegenerative disorders at Biogen, the company that’s developing the drug, said the company is already screening patients for longer and larger studies of the drug.


By WebMD Health News

Reviewed by Arefa Cassoobhoy, MD, MPH

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