A message from Kirk R. Daffner, MD, FAAN. Dr. Daffner is the Stephen Muss Clinical Director of the Alzheimer Center, director of the Center for Brain/Mind Medicine, and chief of the Division of Cognitive and Behavioral Neurology at Brigham and Women’s Hospital, and the J. David and Virginia Wimberly Professor of Neurology at Harvard Medical School.
The Alzheimer’s Innovation Fund (AIF) at Brigham and Women’s Hospital provides critical seed funding for promising research projects aimed at Alzheimer’s prevention. Founded by the Vettel family and bolstered by the generosity of many additional supporters, the fund helps novel research ideas become a reality. In fact, support has already helped the team apply for and receive critical additional funding from national organizations. Below are summaries of the work underway, thanks to your generous support.
2019 Project Updates
Development of a Novel Memory Test Smartphone App
Lead Investigator: Kathryn V. Papp, PhD
Clinical Neuropsychologist, Brigham and Women’s Hospital
Assistant Professor, Harvard Medical School
Current measures used to evaluate cognitive and functional changes—such as an individual’s ability to do everyday tasks—are not able to detect the very subtle changes in cognitive processing that may occur over short periods of time in people who are in the preclinical phase of Alzheimer’s. With this in mind, Papp is developing an innovative smartphone app known as Boston Remote Assessment of Neurocognitive Health, or BRANCH, which is designed to help identify those at risk of developing Alzheimer’s and to track treatment effectiveness more quickly.
BRANCH is based on a promising pilot study conducted as part of the Harvard Aging Brain Study (HABS), in which asymptomatic participants were asked to do a series of memory and recognition tasks over several months on an iPad. Initially, there was no difference in performance between participants who had high levels of amyloid beta (Abeta)—a key protein implicated in Alzheimer’s—versus those who had no Abeta or low levels of Abeta in their brains. Within four months, however, those with high levels of Abeta began to perform worse on the tasks than those with low Abeta, suggesting that Abeta had some impact on cognitive performance.
Dr. Papp is currently refining BRANCH and is awaiting approval from the Institutional Review Board for a pilot study in older adults who have no clinical symptoms of Alzheimer’s. With data from her pilot study, Dr. Papp will continue to develop the platform and then use the app in HABS and related observational studies of older adults with Alzheimer’s biomarkers such as Abeta and tau protein.
Thanks to seed funding provided by the AIF, Dr. Papp was awarded a $100,000 Massachusetts Alzheimer’s Disease Research Center (MADRC) Project Award, which will enable her to further develop and validate BRANCH in a wide spectrum of MADRC research participants, from those with memory concerns to patients with mild cognitive impairment.
Assessment of Smartphone Everyday Tasks (ASSET) in Alzheimer’s Disease
Lead Investigator: Gad A. Marshall, MD
Associate Medical Director of Clinical Trials, Center for Alzheimer Research and Treatment,
Brigham and Women’s Hospital and Massachusetts General Hospital
Associate Professor of Neurology, Harvard Medical School
One of the biggest challenges in Alzheimer’s disease prevention efforts is detecting clinically meaningful changes in the earliest stages of the disease that may indicate a transition from normal aging to mild cognitive impairment (MCI). Dr. Marshall is addressing this issue by introducing an innovative smartphone app to help researchers and physicians assess older adults’ ability to perform instrumental activities of daily living (IADL)—tasks such as household chores, driving, managing finances, and managing medical needs. Impairment in IADL is a hallmark of Alzheimer’s disease.
To date, the ASSET pilot study has enrolled 10 young adults and 22 older adults, all with normal cognitive functioning. Participants were asked to perform clinically relevant tasks with a smartphone, including using a patient portal to request prescription refills, making a payment for an emergency room visit, and entering appointments into a calendar. Dr. Marshall found that older adults took longer to complete the tasks and were less accurate than younger adults. Though this finding suggests that cognitively normal older adults may already have subtle changes in their IADL, to truly assess the sensitivity of the app, more research is needed.
With this in mind, Dr. Marshall plans to enroll new study participants as well as follow existing participants to evaluate how their performance on the app changes over time. He will add individuals with MCI to the study and use PET imaging of Alzheimer’s disease pathology to assess how early clinical changes in IADL relate to pathology in the brain. Ultimately, the app may lead to vital insights about clinically meaningful cognitive decline that could help guide Alzheimer’s treatment and prevention strategies.
Thanks to the initial seed funding provided by the AIF, Dr. Marshall has secured an anonymous gift of $100,000, as well as a National Institutes of Health/National Institute on Aging grant, which will enable him to expand his study in the coming year.
Accelerating Laboratory Research on Environmental Enrichment to Slow the Development of Alzheimer’s Disease
Lead Investigator: Huixin Xu, PhD
Former researcher, Brigham and Women’s Hospital
Postdoctoral Research Fellow, Boston Children’s Hospital
Many studies have shown that exercise and environmental enrichment (EE)—creating novel and stimulating physical surroundings—improve cognitive performance. To further understand the biology behind this, and how it may help to protect against the development of Alzheimer’s disease, Dr. Xu and colleagues explored the impact of EE on brain activity in a laboratory animal study.
One group of healthy mice were placed in an enriched environment that included stimulating toys and running wheels for exercise. Over a period of two months, the mice were kept in the cage for eight hours a day and the toys were changed frequently. A second group of littermate healthy mice (siblings) were placed in a cage with running wheels but an otherwise stark environment that didn’t change from day to day.
At the end of 60 days, Dr. Xu and colleagues performed analyses in both groups of mice. In the EE mice, they noted an increase in synaptic activity in the hippocampus—the area of the brain involved with learning, emotions, and the formation of new memories. In Alzheimer’s, the hippocampus is one of the first areas of the brain affected, shrinking over time as amyloid beta and tau proteins accumulate, and manifesting as impaired memory. Moreover, the EE mice showed a considerable resistance to the toxic effects of amyloid beta. In contrast, the mice who had lived in the stark environment had no change in synaptic activity.
These findings suggest that increasing our exposure to novel environments and activities, in addition to exercise, may strengthen the brain’s ability to ward off the effects of amyloid beta and tau, the key causal proteins in Alzheimer’s. Dr. Xu and colleagues published the results of their study in two high-profile scientific journals.
Immune-Related Genetic Markers in Blood in the Harvard Aging Brain Study
Lead Investigator: Hyun-Sik Yang, MD
Associate Neurologist, Cognitive and Behavioral Neurology, Center for Alzheimer Research and Treatment, Brigham and Women’s Hospital
In addition to genes such as APOE4, which are associated with the development of amyloid beta (Abeta) and tau pathology, many other genes are believed to play a key causal role in Alzheimer’s disease—but how these genes affect the Alzheimer’s trajectory is poorly understood. Dr. Yang is investigating the impact of immune cells on the development and progression of Alzheimer’s. In animal models, specific immune cells and their related genes have been linked to Abeta- and tau-related neuronal injury in the brain. However, the role of these immune genes in people, especially in the preclinical stage of Alzheimer’s, is not known. Expanding our knowledge about the relationship between immune genes and Alzheimer’s could lead to novel prevention and treatment strategies.
Thanks to seed funding from the AIF, Dr. Yang launched a pilot study with participants from the Harvard Aging Brain Study. He is collecting blood samples from 300 healthy individuals and will create gene expression profiles of their immune cells. With these profiles, Dr. Yang aims to assess the role of immune genes on Alzheimer’s pathology, neurodegeneration, and cognitive decline. His work holds promise of identifying new molecular targets for treatment and may help to identify appropriate patients for clinical trials. A grant from the National Institutes of Health will help Dr. Yang continue his study in the coming year.
The Brain Health Champion Initiative
Lead Investigator: Seth Gale, MD
Behavioral Neurologist, Brigham and Women’s Hospital
Instructor in Neurology, Harvard Medical School
Though there is clear consensus about the positive impact that behavior and lifestyle changes can have on brain health overall and on reducing the risk of diseases such as Alzheimer’s, there is no proven way for healthcare providers to systematically promote or monitor the adoption of healthy behaviors. Thanks to the AIF, Dr. Gale and colleagues are addressing this issue by evaluating the use of specially trained Brain Health Champions (BHCs) as part of patient care. BHCs help to actively engage patients and their families in adopting healthier lifestyles and participating in activities known to promote brain health.
The team recently reported the results of a six-month pilot study of the Brain Health Champion initiative. On average, participants were in their mid-70s and had been diagnosed with mild dementia, mild cognitive impairment, or subjective cognitive decline. One group worked with a BHC, the other group received standard counseling and education about brain health during routine appointments with their providers.
Results showed that even over this brief, six-month period, patients in the Brain Health Champion group experienced clinically meaningful increases in physical activity, adherence to a Mediterranean diet, cognitive/social activity, and quality of life compared to the group that received standard counseling. Importantly, adopting healthier lifestyles also increased participants’ sense of purpose and value and was closely linked to overall improved quality of life.
Dr. Gale will launch the next phase of this research in the summer of 2019. The team plans to include more diverse populations, such as cognitively normal individuals who are at risk for Alzheimer’s. They also plan to incorporate mobile health platforms and wearable fitness trackers to help patients monitor their progress and to track objective measures of health. Ultimately, Dr. Gale aims to expand the Brain Health Champion initiative to other healthcare settings, and he envisions creating a national model of care that includes brain health coaches.
Thanks to seed funding from the AIF, Dr. Gale was able to generate the pilot data needed to pursue additional funding for the project from the National Institutes of Health, Patient-Centered Outcomes Research Institute, and other government agencies.
Understanding the Impact of Sleep and Activity Levels in Alzheimer’s Disease
Lead Investigator: Jasmeer Chhatwal, MD, PhD
Instructor in Neurology, Massachusetts General Hospital
Assistant Professor in Neurology, Harvard Medical School, Massachusetts General Hospital
Research has shown that poor sleep quality and decreased levels of daytime activity are associated with a greater likelihood of cognitive decline, as well as increased buildup in the brain of both amyloid beta (Abeta) and tau proteins (the defining brain pathologies that underlie Alzheimer’s disease). To assess this association more fully and determine whether individual variations in sleep are related to changes in the brain, Dr. Chhatwal and colleagues from the sleep group at Brigham and Women’s Hospital conducted at-home assessments of sleep and daytime activity in cognitively-normal, older individuals from the Harvard Aging Brain Study (HABS) who are at risk of cognitive decline.
Participants wore special biosensors that tracked their daytime activity and sleep patterns. Additionally, electrographic recordings of sleep were gathered for one night to provide a “gold standard” for sleep assessment and to determine if time in particular sleep stages was a better predictor of how much pathology was present in the brain. Data gathered were combined with PET imaging to measure Alzheimer’s-related proteins in the brain. The study found that chronic poor sleep quality—characterized by less time spent in the deep stages of sleep (REM and slow-wave sleep)—was associated with higher levels of Alzheimer’s-related brain proteins, particularly tau protein. Disturbances in day/night (circadian) rhythm also had associations with the amount of tau protein buildup and with cognitive performance. These findings shed light on the role of poor sleep quality in cognitive decline and may lead to earlier identification and treatment of at-risk patients. These data will also help us understand cognitive changes that take place as part of the normal aging process.
Catalyzed by funding from the AIF, Dr. Chhatwal recently received grants from the National Institutes of Health and the Doris Duke Charitable Foundation to conduct much larger follow-up sleep studies to confirm and extend these results. In addition, based on data from this pilot study, measures of sleep and daytime activity will be incorporated into future and ongoing Alzheimer’s prevention research.
Using Novel Imaging Methods to Identify and Target Toxic Abeta Protein in the Brain
Lead Investigator: Ming Jin, PhD
Investigator, Brigham and Women’s Hospital
Instructor in Neurology, Brigham and Women’s Hospital
Amyloid beta (Abeta) protein is believed to play a key causal role in Alzheimer’s disease, especially at the earliest stages. Though many anti-amyloid antibodies have been developed to neutralize toxic Abeta buildup (“oligomers”) in the brain, only some of these therapies have been evaluated in clinical trials, and almost all have failed. Dr. Jin and colleagues used the IncuCyte Imaging System—a sophisticated new imaging technology that allows researchers to examine living cells in great detail—to assess the efficacy of various Abeta antibodies preclinically, before costly clinical trials.
Dr. Jin applied soluble extracts of Abeta-rich postmortem tissue from Alzheimer’s patients to healthy human brain cells. The IncuCyte system allowed the team to view the gradual breakdown of synapses (the connections between neurons that play an important role in memory formation) in response to human brain-derived Abeta oligomers. Each anti-amyloid antibody was then applied to the cells. Over the course of 72 hours, Dr. Jin used the IncuCyte camera to take time-lapse photos of neuronal connections after the anti-Abeta antibodies were administered. The resulting data provide critical rankings of the effectiveness of each antibody in neutralizing Abeta oligomers, as well as the optimal dose that might be needed. Through this work, the team aims to identify and rank potential new therapeutic antibodies that could be evaluated in clinical trials for treating or preventing Alzheimer’s. Thanks to the AIF, the team has already identified several novel potent antibodies through this project.
A New Model: Improving Care and Fueling Clinical Research
Lead Investigator: Scott McGinnis, MD
Associate Neurologist, Brigham and Women’s Hospital
Assistant Professor of Neurology, Harvard Medical School
Dr. McGinnis and colleagues have made great progress developing the infrastructure for an integrated clinic program to help physicians consistently deliver the highest standard of care for patients with Alzheimer’s. The program includes a Clinical Roadmap to Care through all stages of the disease. Over the last year, the team has synthesized its clinical experience and expertise with existing practice guidelines from the American Academy of Neurology, the Alzheimer’s Association, and other organizations. The resulting care standards that they developed for comprehensive diagnostic formulation, stage-specific management planning, and longitudinal monitoring of symptoms and responses to treatment have been distributed to behavioral neurologists and neuropsychiatrists at the Brigham for pilot testing.
The project has yielded tools to facilitate easy implementation within the Brigham’s electronic medical record. As next steps, Dr. McGinnis and his team are working to improve the coordination of care among the different disciplines in the group (behavioral neurology, neuropsychiatry, neuropsychology, and social work); improve the delivery of information to patients and caregivers, including generating, assembling, and delivering easy-to-understand educational materials; and develop a system for efficiently and consistently creating care plans personalized to patients and caregivers. Ultimately, data collected via these efforts will help to identify patients who are eligible for clinical trials—currently one of the largest hurdles to advancing clinical research.
Thanks to support from the AIF, Dr. McGinnis and his team are paving the way to expert and compassionate care for patients in Boston and beyond.
To learn more about the Alzheimer’s Innovation Fund or how to make a gift—including instructions about giving through your donor-advised fund—please contact Ginny Fuller at email@example.com or 617-424-4329.