Accelerated weight loss is not the first symptom that most people focus on in Alzheimer’s disease. However, groundbreaking research shedding light on potential links between brain function and systemic metabolism led by Makoto Ishii, M.D., Ph.D., a physician-scientist at UT Southwestern’s Peter O’Donnell Jr. Brain Institute, has opened the door to an innovative field of study – one that brings accelerated exploration, discovery, and hope to the fight against this degenerative condition.
Makoto Ishii, M.D., Ph.D.
An Alzheimer’s research pioneer
A native Texan with a background in chemical engineering, Dr. Ishii shifted to medical research after transformative experiences at UT Southwestern as an undergraduate and during his pursuit of dual M.D.-Ph.D. degrees at Weill Cornell Medical College and Rockefeller University in the Tri-Institutional M.D.-Ph.D. Program. Dr. Ishii returned to UT Southwestern about a year and a half ago and is a board-certified neurologist. He is the first to demonstrate through his research that amyloid beta, a major pathogenic factor in Alzheimer’s disease, can disrupt specific brain cells in the leptin pathway, an essential regulator of body weight, leading to body weight and metabolic deficits prior to any cognitive dysfunction.
Neurological and neuroscience research was a passion from the start for Dr. Ishii, and his particular interest in Alzheimer's disease was influenced by his studies and personal experiences, specifically his grandmother’s diagnosis of the disease. Even back then, Dr. Ishii noticed unexplained weight loss as the disease progressed, prompting him to consider that although memory loss is the most important clinical manifestation, weight loss potentially had a connection as well.
Toward the end of his neurology residency, he started reading more of the clinical literature on the disease. It was well-documented that weight loss is common in Alzheimer's disease and can occur even before the onset of dementia, but could the brain circuits that regulate body weight be affected and could this lead to much earlier diagnosis and treatment? These queries prompted Dr. Ishii to start investigating the role of the hypothalamus and if the early accumulation of amyloid beta impacts hypothalamic circuits, which are crucial for regulating body weight through appetite and metabolism.
The role of the hypothalamus
“What has been reported in the medical literature and what we and others have observed in our patients is that before significant cognitive decline, some individuals started having problems with weight, others started having problems with sleep, and others started having what we call noncognitive manifestations,” said Dr. Ishii. “This sparked my curiosity about the hypothalamus – a brain region almost the size of an almond, yet it controls nearly every essential function. From fluid regulation and vital neuroendocrine hormones to the pituitary gland, thyroid, sleep and behavior, this tiny powerhouse orchestrates it all.”
As a neurologist, Dr. Ishii knew that many specialties touch upon that region of the brain, and he became increasingly inspired working with his patients and seeing the fascinating things that can happen in neurology and potentially some of the diagnostic and therapeutic treatments that could be done for them. At a basic level, weight loss makes things worse in Alzheimer’s disease. It is associated with a disease that is more aggressive and progresses faster, increasing the risk of morbidity and mortality. Interestingly, the opposite is also true, meaning that if weight is maintained or gained, it seems to be somewhat protective. A lot of epidemiological studies have explored this powerful relationship, but the underlying mechanism was still a mystery.
Exploration and insights
Dr. Ishii had quite a few hypotheses. The hypothalamus regulates so many different areas. Could that be an early target of Alzheimer's disease that just hasn't been studied? By identifying some of those pathways, could that uncover something new about the disease? If the underlying cause of the hypothalamic dysfunction is treated, could it help the patients? It might not be a cure, but if those who lose weight tend to do worse, is it possible to correct that pathway and help them? If the patient is cognitively and relatively in the normal range, what is driving that change in body weight?
With these questions in mind, Dr. Ishii’s team used animal models and clinical studies to determine which circuits might be affected in the brain and that clued them into amyloid beta. Amyloid beta is a naturally occurring peptide in the brain that is believed to be one of the earliest pathogenic factors in Alzheimer’s disease. Once amyloid beta starts abnormally aggregating or clumping together, it starts causing dysfunction in brain cells, specifically neurons. Together with the abnormal misfolding and accumulation of tau, another protein, there is disruption in synaptic function or in the communication between neurons and eventually, the neurons die. The accumulation of amyloid beta and tau over years – often decades – drives neurodegeneration, which refers to the loss of brain cells, ultimately resulting in cognitive decline and dementia.
Early indicators and better treatments
Based on this scientific background, Dr. Ishii hypothesized that if weight loss can occur early in Alzheimer’s disease, before the cognitive decline, could the accumulation of amyloid beta affect brain circuits that control body weight? If so, how? Through a series of experiments in animal models, Dr. Ishii’s team was able to identify that amyloid beta can cause an influx of calcium to enter the neurons in the hypothalamus that are critical for the regulation of body weight by the hormone leptin. As a result, this excess calcium disrupts the function of these neurons associated with significant body weight and metabolic deficits before the memory is affected. Having identified in animal models that the hypothalamus is a target of amyloid beta and that brain circuits regulating body weight are affected as a result, Dr. Ishii’s team is now focused on translating these findings in clinical studies.
It is now possible to detect pathological changes in amyloid beta early in living individuals, before they have cognitive decline. So, those who are at the highest risk, or at the very earliest stages of Alzheimer's disease, can be screened just by measuring spinal fluid with a lumbar puncture or by doing brain scans – before the onset of full dementia symptoms. Utilizing these advancements in detecting Alzheimer’s disease at its earliest stages, Dr. Ishii’s team began studying individuals with pathological evidence of Alzheimer’s disease but who had no or only mild cognitive symptoms. Like the findings in animal models, they found in those individuals at the earliest stages of Alzheimer’s disease that the hypothalamus is a key target of amyloid beta and that changes in body weight and systemic metabolism are an important part of the disease process before the onset of dementia. While a key challenge in applying these findings in the clinical setting is to distinguish metabolic changes in Alzheimer's from normal aging, Dr. Ishii’s work has uncovered critical findings that are leading doctors to develop new avenues of diagnosing and treating these patients before Alzheimer’s takes control of their lives.