Improving Detection of the Earliest Signs of Alzheimer's Disease in the Brain to Help Prevent Memory Loss

Michelle Farrell, PhD
Massachusetts General Hospital (Boston, MA)


Reisa Sperling, MD
Harvard Medical School (Boston, MA)
Year Awarded:
Grant Duration:
July 1, 2019 to June 30, 2021
Alzheimer's Disease
Award Amount:
Grant Reference ID:
Award Type:
Postdoctoral Fellowship
Award Region:
US Northeastern
Michelle Farrell, PhD

Early Consequences of Subthreshold Amyloid for Tau Pathology and Cognitive Decline


Drugs are currently being tested that aim to prevent Alzheimer’s disease by intervening in individuals more than a decade before clinical symptoms appear who have clear evidence of Alzheimer’s pathology. However, little is known about the beginning stages of Alzheimer’s disease and how the two hallmark AD pathologies (amyloid plaques and tau tangles) start to build up in the brain. The proposed project aims to use brain imaging (PET scans) in healthy older adults to visualize the earliest signs of amyloid plaques, and determine how the buildup of these amyloid plaques contributes to the appearance of tau tangles inside brain cells and subtle changes in memory and thinking.  This research will provide urgently needed information about the early stages of development of AD, and help the next generation of prevention trials target individuals who are at an optimal point in the development of AD for successful intervention.


My project is designed to provide crucial information about the earliest stage of Alzheimer’s disease (AD), when the hallmark pathologies (amyloid and tau) first appear and begin leading to subtle changes in memory and thinking.  Due to extensive evidence from autopsy and brain imaging studies that amyloid plays a critical role in initiating a gradual cascade towards dementia in Alzheimer’s disease, I will first examine the earliest signs of amyloid using amyloid PET scans.  These scans use a radiotracer that when injected into the bloodstream binds to amyloid plaques in the brain, allowing us to visualize the location and amount of amyloid plaques in the brains of living persons using positron emission tomography (PET) scans. I will utilize repeated scans from healthy older individuals over the course of several years (collected as part of the Harvard Aging Brain Study), enabling me to observe when and where amyloid first appears and how it spreads throughout the brain.  Next, I will assess how the buildup of these the amyloid plaques contributes to the appearance and spread of the other hallmark AD pathology (tau tangles) inside brain cells. I will utilize recent advances in PET imaging that allow for the visualization of tau tangles using PET scans using a tracer that binds to tau.  Finally, I will assess how both these AD pathologies contribute to the onset of subtle changes in memory and thinking, far in advance of the more severe symptoms observed in dementia. In particular, I aim to identify a pattern of amyloid that precedes the spread of tau tangles and irreversible changes in memory and thinking. Research to date has focused on later stages in the development of AD, when amyloid is already high, to clarify the role of amyloid and tau in the transition towards dementia.  The proposed research shifts the focus to the transition from health to the earliest signs of amyloid and tau, to improve our understanding of the emergence of these pathologies and their effects on the mind and brain.  This research has the potential to play an important role in the design of future clinical trials that aim to prevent Alzheimer’s disease by removing or slowing the accumulation of amyloid, instead of waiting to attempt to treat Alzheimer’s once symptoms appear.  If successful, my research will identify a pattern of amyloid plaques that indicates individuals may be at an optimal point early in the disease course to prevent the spread of tau tangles and changes in memory and thinking. In so doing, I hope my work, with the generous support from the BrightFocus donors, will contribute meaningfully to the race to find a cure for AD.

About the Researcher

I am a cognitive neuroscientist in my second year of postdoctoral training at Massachusetts General Hospital (MGH) with a keen interest in elucidating the earliest stages of the development of Alzheimer’s disease (AD) pathology. I began my training with a bachelor’s degree from the University of California, Berkeley, with a double major in molecular/cell biology and integrative biology.  After college, I worked as a research assistant at the Stanford/VA Aging Clinical Research Center, under the mentorship of Dr. Joy Taylor.  I was involved with two studies during this time, one a healthy aging study examining age-related changes in expertise in pilots, and the second a nationwide, multi-site neuroimaging study of Alzheimer’s disease, the Alzheimer’s Disease Neuroimaging Initiative.  My experience working in the intersection of the healthy aging and Alzheimer’s disease fields led me to undertake a PhD under the mentorship of cognitive aging expert Dr. Denise Park at the University of Texas at Dallas. My graduate work focused on the relationship between amyloid pathology and cognitive decline in cognitively normal adults across the lifespan (aged 30-90 years) from the Dallas Lifespan Brain Study (DLBS). While previous research from the DLBS and other samples had demonstrated that high levels of amyloid were associated with poorer cognition in older adults, I became interested in whether lower levels of amyloid that begin appearing about 2 decades prior to dementia onset might also have subtle consequences for brain and behavior, and provide a window into the study of the earliest stages of AD. After completing my PhD in cognitive neuroscience in December 2017, I had the opportunity and privilege to continue this line of research at Massachusetts General Hospital and Harvard Medical School, under the mentorship of leaders in the field Dr. Reisa Sperling and Dr. Keith Johnson. 

Personal Story

Working with the Alzheimer’s Disease Neuroimaging Initiative before graduate school, I was the primary point of contact for the family members of our participants, fielding their questions. As their spouses and parents had already been living with Alzheimer’s for some time, they were well aware that there is no real treatment to stop Alzheimer’s and were resigned to that truth. Despite this, they were committed to aiding in Alzheimer’s research, out of hope that the research today might, at the very least, save their children from suffering the same fate.  Their dedication inspired me to pursue a PhD in cognitive neuroscience and to focus my research on understanding the earliest stages in the development of Alzheimer’s pathology, when individuals are still healthy. During graduate school, my own grandmother succumbed to Alzheimer’s, and it became my family asking what they could do to prevent a day when they too would be unable to remember their children. This strengthened my resolve to conduct research that could make a tangible contribution to the fight to prevent Alzheimer’s disease. After completing my PhD, I was thrilled to join the labs of Drs. Reisa Sperling and Keith Johnson, whose research into preclinical AD is not only paving the way for prevention trials, but who are also themselves leading multiple clinical trials aimed at intervention before individuals reach dementia. I am honored to complete my postdoctoral training with them, and hope that the research I conduct under the BrightFocus fellowship will aid in the design of their upcoming clinical trials. I truly believe that the work we are doing today will mean that someday when my family asks about what they can do avoid suffering the fate of my grandma and countless others, I can tell them not to worry, there is a cure.  

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