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We’re happy to hear good news, but we still need to see the data

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This week, BioArctic Neuroscience, Esai, and Biogen made headlines when they announced via press release the topline and positive results of their Phase 2a study of the anti-amyloid antibody BAN2401. The press release indicated that the drug “demonstrated statistically significant slowing in clinical decline and reduction of amyloid beta accumulated in the brain” in patients with early Alzheimer’s disease.

To be sure, this is welcomed news. Too often headlines for Alzheimer’s disease clinical trials are about “flops” and “failures.” So we should take this good news and embrace it. Unfortunately, there remain many questions to which we need answers before we celebrate too much.

First, this trial was previously considered negative. The investigators from Esai and their partners are to be commended for pushing the envelope. This trial employed a complex modern protocol known as an adaptive design. The adaptive design used numerous planned analyses of data from the ongoing trial to try to “pick a winner” among five doses of the drug, funneling more patients into the best dose. Unfortunately, after enough patients had achieved 12-months of treatment, there was no winner. Despite this, the plan was always to keep the trial going until patients had received the drug for 18-months.

When the trial was analyzed in a more traditional sense, comparing the patients who got drug to the patients who got placebo for the entire 18-months, those receiving the highest dose apparently benefited most. Still, we will need to hear more about all of the groups, including how many patients were in each group and how the groups performed compared to each other. We also need to see the full safety data, though the topline report suggests that the safety profile was as good as some other antibodies in development for Alzheimer’s disease, but worse than some others.

This represents the second time that an investigational agent targeting the fibrillar form of amyloid beta that accumulates in the Alzheimer’s brain has demonstrated promising effects on both brain biomarker and clinical outcomes. These results are heartening. Nevertheless, the secondary nature of the analyses and the need for replication in Phase 3 trials warrant caution, as well as optimism.

Possible link between human herpes viruses and Alzheimer’s disease

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Recent scientific reports, one in the journal Neuron and another coming out in the journal Cell, present some intriguing new data indicating a link between human herpes viruses and Alzheimer’s disease (AD). Because the majority of AD cases cannot be attributed to genetics alone, there has been keen interest in finding other factors that affect the risk of developing AD. Head trauma and infections are two such factors that have received attention by researchers. With regard to infectious agents, speculation has often centered on the herpes viruses, especially herpes simplex virus 1 (HSV1). Human herpes viruses are neurotropic, which means they have an affinity for nerve cells. In fact, UCI MIND Faculty members Drs. David Cribbs, Carl Cotman and Frank LaFerla published a paper in 2000 in the journal Biochemistry where they showed HSV1, which is extremely common and causes cold sores, includes a small region that is very similar to amyloid peptide that accumulates in neuritic plaques in AD brains. Surprisingly, when they tested the virus in laboratory studies, it had many of the properties of amyloid, including killing nerve cells growing in a dish. In the more recent study, increased levels of two human herpes viruses (HHV-6A & HHV-7) were found in AD brain tissue when compared to brains from controls. The authors of those study also found that AD progression correlates with increased virus levels across multiple brain regions.

In the forthcoming Cell publication, investigators have extended the UCI report and shown that herpes virus induces Aβ peptide aggregation into plaque-like structures. Moreover, herpes virus infection rapidly seeds amyloid plaque deposition in a transgenic mouse model of AD and in 3-dimensional human neural cell cultures.

Collectively, these research reports provide support for the hypothesis that herpes viruses may be a risk factor for AD, though many in the field are recommending caution when interpreting these results. In particular, the recent studies in human tissue speak only to an association, not a causal relationship. Understanding who with herpes virus, which many of us do, develops AD and who does not may be a critical question for the field to address.

Light and electron micrographs of the assemblies formed by the Aβ and gB peptides. Aβ and gB peptides are shown on the left and right side, respectively: (a and b) light microscopy-phase contrast view, (c and d) thioflavin S staining of the peptides, and (e and f) electron micrographs of negatively stained peptide assemblies.

References:

Cribbs DH, Azizeh BY, Cotman CW, LaFerla FM. Fibril formation and neurotoxicity by a herpes simplex virus glycoprotein B fragment with homology to the Alzheimer's A beta peptide. Biochemistry. 2000 May 23;39(20):5988-94.

Readhead B, Haure-Mirande JV, Funk CC, Richards MA, Shannon P, Haroutunian V, Sano M, Liang WS, Beckmann ND, Price ND, Reiman EM, Schadt EE, Ehrlich ME, Gandy S, Dudley JT. Multiscale Analysis of Independent Alzheimer’s Cohorts Finds Disruption of Molecular, Genetic, and Clinical Networks by Human Herpesvirus. Neuron 99, 1–19 July 11, 2018

Eimer, William A. and Vijaya Kumar, Deepak Kumar and Shanmugam, Nanda Kumar N. and Washicosky, Kevin J. and Rodriguez, Alex S. and György, Bence and Breakefield, Xandra O. and Tanzi, Rudolph E. and Moir, Robert D., Alzheimer’s Disease-Associated β-amyloid Is Rapidly Seeded by herpesviridae to Protect Against Brain Infection (2018). Available at SSRN: https://ssrn.com/abstract=3155923 or http://dx.doi.org/10.2139/ssrn.3155923

With Mother’s Day in MIND

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Reflections on Mother’s Day by Virginia Naeve and Dr. Rosalyn Laudati, members of the UCI MIND Leadership Council.

I just received an email advertisement from a lovely seaside restaurant stating that they are providing a “Mother’s Day Brunch that your mother will never forget.” I would have loved taking mom there on Mother’s Day, but Alzheimer’s disease forever changed those kinds of plans for us.

Up until about the last four years of mom’s disease, we always loved Mother’s Day. Unfortunately, as her disease progressed, it was heartbreaking for me to realize that Mother’s Day had lost its meaning for her. As I always explain to people, Mom knew that when I walked into the room I was in some way important to her, but she had absolutely no idea that I was her daughter and that she gave birth to me.

That is still a sobering thought. My own mother had no idea that I was her daughter. That fact alone keeps me interested and focused on supporting Alzheimer’s research until a cure is found.

Virginia Naeve

 

 

Mother’s Day for me has been difficult since I lost my mom to Alzheimer’s almost 2 years ago. I miss her terribly and have become more resolved to help find a cure for this scourge.

My mom was physically fit and healthy in all other ways. This disease took her from me too early and I have become more determined to help with the fight to eradicate its devastation for families. I will help by continuing to support the researchers at UCI MIND. I hope you will too.

Dr. Rosalyn Laudati

 

With the research taking place at UCI MIND, there is real hope we can prevent this disease. Please consider supporting this research today by making a gift in tribute to someone special in your life on Mother’s Day.

 

Click here to donate >

The role of exercise in reducing or slowing Alzheimer’s disease

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Contributed by Carl Cotman, PhD, Founding Director of UCI MIND

The role of exercise in reducing or slowing Alzheimer’s disease keeps coming up on headlines. Observational studies like the one in this article suggest that brain health may be different for older adults who exercise versus those who do not.

While the results of studies like this one are intriguing, disease modifying effects need to be demonstrated in a larger and more diverse populations using accessible, cost-effective and sustainable programs that have the potential for implementation in a community setting.

To address this need, UCI MIND and the Alzheimer’s Disease Cooperative Study (ADCS) have partnered with the YMCA of the USA (Y-USA) to conduct a randomized controlled 18-month trial to test whether moderate-high intensity aerobic exercise can positively impact cognitive function and biomarkers of Alzheimer’s disease in  sedentary older adults (65-89 yrs old) with mild memory impairments. Participants complete their exercises at YMCAs under the supervision of a study-certified trainer in the first 12 months, and independently in the final 6 months.

To learn more about this important national study, call 949.824.0008, visit the UCI MIND Clinical Trials webpage, or email research@mind.uci.edu.

Sleepy older adults accumulate amyloid pathology more quickly

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Contributed by Bryce Mander, PhD

As reported in CNN, a new study published in JAMA Neurology indicates that healthy older adults who are excessively sleepy during the day show a greater buildup over time of β-amyloid plaques, a defining brain feature of Alzheimer’s disease, compared to those who are not excessively sleepy.

As we describe in our editorial on this article, this study is an important advance in our understanding of how sleep disturbance in general can result in increased risk for Alzheimer’s disease. Many studies over the past few years, including our own, have linked poor sleep to increased risk for developing Alzheimer’s disease, and many other studies have linked poor sleep to the amount of Alzheimer’s disease markers in the brain. Until now, however, it was not known if symptoms of poor sleep result in long-term increases in Alzheimer’s disease pathology over the course of years. This finding is critical, because Alzheimer’s disease pathology can build up in the brain for a decade before any memory problems and other symptoms begin, and identifying any factors promoting this process may reveal novel therapeutic opportunities to decrease Alzheimer’s disease risk.

While illuminating a relationship between excessive daytime sleepiness and brain amyloid plaques is helpful, the underlying cause remains unknown. Multiple sleep disorders, including sleep apnea and insomnia, can result in excessive daytime sleepiness, as can poor sleep quality in general. A critical next step will be to determine what specific features of sleep are causing both excessive daytime sleepiness and greater Alzheimer’s disease risk. This is now an important research question for multiple researchers at UCI MIND, and is a core research mission for the new UCI Sleep and Circadian Neuroscience (SCN) center sponsored by the UCI Office of Research.

Individuals interested in participating in our upcoming studies of sleep and Alzheimer’s disease can enroll in the UCI Consent to Contact (C2C) registry. It is only through our partnership with volunteers in the community that we can continue to pave the way for new treatments and cures for those suffering from debilitating diseases such as Alzheimer’s disease.

About the Author
Bryce Mander, PhD is an Assistant Professor of Psychiatry & Human Behavior for the School of Medicine at UC Irvine.

His research interests include Sleep, Sleep Deprivation, Sleep Disorders, Cognitive Aging, Alzheimer’s Disease, Memory, and Neurodegeneration.

Love, Marriage, and Alzheimer’s disease

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by Joshua Grill, PhD

Numerous studies have shown links between lifestyle factors and risk for Alzheimer’s disease and other dementias. A new assessment of available studies by investigators at University College in London examines one lifestyle factor, marriage, and finds that people with a spouse may be at decreased risk for Alzheimer’s disease and other dementias. In contrast, widows and people who have been single their whole lives may be at 20-40% increased risk.

At UCI MIND, a variety of studies have explored the implications of spousal status on Alzheimer’s disease clinical trials. In particular, we’ve shown that people with Alzheimer’s who lack a spouse are drastically underrepresented in clinical trials. The requirement of a study partner, a role most often filled by a spouse, is a barrier to enrollment in these clinical trials, but also in clinical trials that test potential preventative therapies in people with no symptoms of cognitive impairment. In a recent article with my colleague Dr. Jason Karlawish at the University of Pennsylvania, I argue that the requirement of a study partner should be continued in these clinical trials for reasons of safety, data integrity, and to ensure the scientific and clinical value of the research.  Click here to read the manuscript.

Perspectives on amyloid PET imaging

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A new study published in JAMA Neurology explored participants’ perspectives on receiving amyloid PET scan results as part of an Alzheimer’s disease prevention clinical trial, the A4 study.  Participants at UCI MIND contributed to this important research, led by investigators at the University of Pennsylvania (read more about the study here).
Amyloid PET is a biomarker test that could someday be used to identify people at increased risk for Alzheimer’s disease who may benefit from preventative or disease-delaying treatments. Biomarker testing such as amyloid PET is being used more and more in the research setting to identify participants appropriate for Alzheimer’s disease prevention trials, like the A4 study. However, before biomarker testing can be used clinically, more research is needed to understand how people interpret results and whether access to this information affects behavioral health and lifestyle choices, making studies like this and findings published earlier this year by Grill and colleagues all the more important.
Researchers, including those at UCI MIND, continue to perform important work, not only to change the way we treat Alzheimer’s disease, but also to instruct the optimal clinical care and public health associated with using such treatments. To learn more about participation in clinical trials or studies like this, call 949.824.0008 and join the UCI C2C Registry.

Today is World Alzheimer’s Day!

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Today, September 21, is WORLD ALZHEIMER’S DAY! Our faculty and staff are spending this day, as they do every other day:

  • In the laboratory performing cutting edge research with molecules, cells, and animal models to unlock the causes of Alzheimer’s disease and identify treatment targets
  • Working with volunteer participants who have donated their time to help us better understand, diagnose, and treat Alzheimer’s disease through research
  • Conducting clinical trials of promising therapies we hope will prevent, reduce, or reverse Alzheimer’s disease

We hope today you will consider doing one or all of the following:

  • ADVOCATE: Write to your local, state, or federal representative and communicate the need for increased funding for Alzheimer’s research and improved support for families with dementia. Click here!
  • DONATE: Make a gift to support Alzheimer’s disease research at UCI MIND. Click here!
  • PARTICIPATE: Take a step toward enrolling in a study at UCI MIND by joining the UCI Consent-to-Contact Registry (C2C). You could be matched to a study that’s right for you. Click here!