Identifying How Fat Hormones That Regulate Body Weight Are Affected in Alzheimer's Disease

Makoto Ishii, MD, PhD
Weill Cornell Medicine (New York, NY)
Year Awarded:
Grant Duration:
July 1, 2015 to December 30, 2018
Alzheimer's Disease
Award Amount:
Grant Reference ID:
Award Type:
Award Region:
US Northeastern
Makoto Ishii, MD, PhD

Pathological Role Of Amyloid-Beta On Adipocyte Hormone Signaling


Alzheimer’s disease (AD) is a brain disease that over time causes people to lose memory and have problems with thinking.  However, even before the memory and thinking problems occur, people who develop AD start to lose body weight, for reasons that are not known. Therefore, our main goal is to study whether, early in the course of AD, there are problems in fat hormones that control body weight.  Once we identify the cause of the weight loss in AD, we will see whether this knowledge might help us develop new treatments.


The goal of this project is to understand why Alzheimer’s disease (AD) leads to loss in body weight, particularly early in the disease, and by doing so explore new avenues for developing novel therapeutic targets and diagnostic tools.

Body weight loss is a common feature of AD that worsens as AD progresses. This implies that body weight and metabolic deficits may be an essential part of AD; however, the exact mechanisms underlying the weight loss in AD are not known.  Additionally, weight loss can occur before the cognitive or mental decline, and as such can be one of the earliest manifestations of AD.  In ongoing studies in our laboratory, we use mouse models that have increased amounts of the toxic amyloid-beta (Aβ) peptide, a key pathogenic factor in AD, to identify molecular pathways that may be affected in AD.  Our initial studies found that proteins and hormones produced by fat cells (ie, adipose tissue), that are essential for regulating metabolism and body weight, are abnormally affected early in the mouse models.  For this project, we will examine whether fat-derived hormones and signaling molecules in humans also may be abnormally affected at the earliest stages of AD. To accomplish this, we plan to analyze blood and spinal fluid samples from cognitively intact healthy volunteers who have the earliest pathological signs of AD and comparing those tissues to healthy individual who lack AD pathology.

A major innovation in our project lies in using a two-pronged approach of initially identifying potential targets using mouse models and then validating the targets in a well-characterized human study population.  In addition, the human study population that we are analyzing has several key advantages compared to others.  Importantly, we are investigating AD at the earliest clinical stage, where cognitive and mental functions are intact but pathological signs of AD exist.  Significant evidence already exists to suggest that it may be difficult, at best, to develop an effective therapy or cure once the AD dementia becomes manifest. Thus, identifying and understanding the earliest clinical manifestations of AD is imperative.

Once our study is completed, its foreseeable benefits include the discovery of new targets for possible therapeutic intervention and the potential development of new blood or spinal fluid markers to assess AD at its earliest stages. In addition, our findings will provide important new perspectives and insights into why weight loss occurs in AD. This weight loss contributes to AD morbidity and mortality in important ways that have been clinically recognized for many years; however, the exact reasons for it are unknown. 

About the Researcher

Makoto Ishii is a board-certified neurologist and an assistant professor of neuroscience at the Feil Family Brain and Mind Research Institute at the Joan and Sanford I. Weill Medical College of Cornell University. He studied chemical engineering as an undergraduate at Princeton University before completing the Medical Scientist Training Program at the Tri-Institutional MD-PhD Program (Weill Medical College of Cornell University/Rockefeller University/Memorial Sloan Kettering Cancer Center). In his PhD studies at Rockefeller University, Dr. Ishii studied novel pathways in the brain that regulate appetite and body weight.  After receiving his medical degree from Weill Cornell Medical College, he completed his residency training in neurology at New York Presbyterian Hospital - Weill Cornell Medical Center, where he also was chief resident.  Since finishing his clinical training, he has returned to the research laboratory to combine two of his main academic interests: Alzheimer’s disease and how the brain controls body weight.  His current research program involves investigating the complex interactions between body weight/adiposity and Alzheimer’s disease in the hopes of identifying novel pathways that may shed new light into this currently incurable and devastating disease.  Dr. Ishii is extremely grateful for the research support received from the BrightFocus Foundation and its generous supporters.

"A few years ago, my grandmother was diagnosed with Alzheimer’s disease (AD).  Prior to the disease onset, she was a strong loving woman who lived independently after my grandfather passed away.  She was very talkative and enjoyed having long conversations. When I visited, we talked about everything from her childhood growing up in downtown Tokyo, before the city was known as the electronics capital of the world, to how Japan and the rest of the world had transformed into a global city with cell phones and the Internet making it easier than ever to connect with one another.  Unfortunately, as the disease progressed, she began to require full time care and could no longer live on her own. Our conversations also started to change, as she started to lose track of time, sometimes slipping back to those early childhood years in a Tokyo that no longer exists. 

The most striking aspect of Alzheimer’s clearly is this loss of mental function that cruelly manifests as a simmering, relentlessly progressive dementia, resulting in a loss of identity and independence.  However, I see other manifestations.  I look at a photograph that I took of my grandmother a year before she was diagnosed and compare it to one taken only a couple years later.  My grandmother was never a thin woman, but within a few years of her diagnosis she had lost a significant amount of weight, despite eating what appeared to be her normal amount of food.  What causes this unintended weight loss?  Is it part of the disease?

Talking to my fellow clinicians and reviewing the literature, it is clear that weight loss and the associated metabolic deficits are a central part of the disease process.  Individuals who lose weight later in life appear to be at higher risk for developing AD, and once someone develops AD, weight loss strongly is associated with worsening disease progression and even increased risk of death.  Furthermore, this weight loss can occur early, before mental decline.  Despite overwhelming evidence that weight loss plays a prominent role, the exact significance and contribution of weight loss to the development of AD is not known. 

As a grandson, I feel at times helpless as my grandmother’s dementia continues to worsen.  As a clinician-scientist, I see the potential advances we can make by exploring clinical observations that can help solve the complexities of Alzheimer’s disease. The critical support from the BrightFocus Foundation and its generous donors will enable me to explore this avenue of research. It began as a very personal inquiry, but hopefully now will make a broader contribution to the large community of clinicians, research scientists, tireless family caregivers, and most importantly to the patients like my grandmother, who are all battling this devastating disease."

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