When it comes to the potential for helping patients with Alzheimer’s disease, a field that for decades has been beset by dashed hopes and disappointments, Constantine Lyketsos believes there’s real reason for optimism — optimism that rests in research underway now within the Richman Family Precision Medicine Center of Excellence in Alzheimer’s Disease at Johns Hopkins, which he leads.
For most of the last two decades, Lyketsos explains, researchers have focused on the “amyloid case” — the belief that Alzheimer’s disease is caused by the accumulation of amyloid protein tangles in the brain. A variety of drugs have been developed to diminish those plaques, “and in general, while some of these drugs are pretty good at removing amyloid from the brain, these therapeutics have not been good at improving symptoms,” says Lyketsos, the Alafouzos CIM Scholar, who founded and directs the Johns Hopkins Memory and Alzheimer’s Treatment Center.
He and other researchers at Johns Hopkins are focused on a precision medicine approach. “Alzheimer’s disease and related disorders are not a single disease. We need to take a fresh look and to consider Alzheimer’s and related disorders as a series of diseases that each require a different combination of treatments,” says Lyketsos, the Elizabeth Plank Althouse Professor in Alzheimer’s Disease Research.
The precision medicine strategy is made possible, in part, by technological advances that allow for the analysis of “big data.” Researchers at the precision medicine center have access to more than 130,000 patient records drawn from patients seen at the Memory and Alzheimer’s Center and Johns Hopkins Community Physicians (“under strict oversight,” Lyketsos notes), which they are analyzing to arrive at subgroups of patients who might respond better to different treatments.
One particularly promising area under study homes in on vascular disease in the brain, now widely accepted as a cause for some forms of Alzheimer’s disease. Johns Hopkins researchers are using MRI to measure perfusion (how well blood gets distributed within the brain) in test subjects exposed to a “stress test” — in this case, exposure to carbon dioxide. Brain perfusion is measured before and after the stressor is introduced. “We’re finding that people show a range of responses. Some respond ‘properly,’ with blood flow increasing, while others have reduced perfusion,” says Lyketsos. The latter group, he notes, could represent a subgroup of patients who respond well to individualized, targeted therapies aimed at improving brain blood flow.
Paul Rosenberg, co-director of the Memory and Alzheimer’s Treatment Center Division of Geriatric Psychiatry and Neuropsychiatry, and his team are testing that idea now in animal models, administering cholesterol-reducing atorvastatin to animals with impaired perfusion. “If we can improve perfusion, perhaps we can improve memory loss,” Lyketsos says.
The ability to study and design therapeutic solutions for individual patients has taken a giant leap forward with advances in stem cell technology. It’s now possible, from a single blood sample, for researchers to develop individualized brain cell lines that can then be used in the petri dish to test responses to different drugs or treatments.
“Alzheimer’s disease and related disorders are not a single disease. We need to take a fresh look and to consider Alzheimer’s and related disorders as a series of diseases that each require a different combination of treatments.”– Constantine Lyketsos
Esther Oh, the Sarah Miller Coulson CIM/Human Aging Project Scholar, is doing just that in research examining the role that inflammation plays in the brain since this may be a target of treatments for a subset of patients. In Alzheimer’s disease, immune cells in the brain called microglial cells can get over-activated in some people, producing substances (inflammation) harmful to brain tissue. As part of the Richman Center, Oh collaborates with stem cell engineering expert Vasiliki Machairaki from the Department of Genetic Medicine. Machairaki is developing person-specific microglial cell lines to define and differentiate which individuals are more (or less) apt to have “damaging” inflammatory responses in their brains. These individualized microglial lines can also be used as testing platforms to assess the effect of promising medication that can be used to mitigate these inflammatory responses.
Machairaki is using this same approach to develop a wide variety of different brain cell lines relevant to Alzheimer’s, all derived from the stem cells of individual people (e.g., neurons, astrocytes). Additional, technological advances pioneered by Machairaki now make it possible to develop 3D culture systems, or “organoids,” that are organized in layers almost as in the native brain. These can include many different types of cells and also serve as models to study subtypes of Alzheimer’s.
“Increasingly,” says Lyketsos, “based on the test tube response of 2D and 3D models of an individual’s brain cells, we will be able to predict whether individual therapies are likely to be helpful.” These advances will significantly improve the way clinical trials are performed in the future, he notes. That’s because a promising drug can first be tested using a patient’s cell line, leading to faster selection of a subgroup of patients who are likely to respond positively.
It’s vital work, and time is of the essence. Worldwide today, more than 50 million people suffer from dementia, and nearly 10 million new cases are diagnosed every year. These numbers are projected to double by 2050.
“We still have a long way to go,” says Lyketsos, “but by pursuing precision medicine solutions, I am very excited by the prospect of being able to reach the right patient at the right time with the right treatment.”
