Can a precision medicine approach to Alzheimer’s disease (AD) and other dementias improve outcomes?
That is the theory behind the Dementia Prevention Initiative (DPI). The Florida Atlantic University (FAU) program twists the usual methods used to research and treat AD by employing an “n-of-1” design individualize medicine down to a single patient. Instead of conducting a conventional trial of 100 people who get the same treatment, the program conducts 100 single trials personalized to the individual. The youngest DPI patient is currently 61, and the oldest is 86.
There is increasing evidence that multiple medical conditions increase the risk of neurodegeneration and subsequent development of dementia, according to neuroscientist James Galvin, M.D., who founded DPI at FAU’s Comprehensive Center for Brain Health. It’s also becoming clear that a majority of those risk factors act independently of amyloid and tau proteins, he said. These proteins eventually build up into plaque and tangles in the brain, short-circuiting brain signals and ultimately leading to dementia.
“Because Alzheimer’s disease is heterogeneous in terms of risk factors, age of onset, presentation, progression, and pathology burden, designing a study to treat individuals as a homogenous population requires thousands of patients who have to be followed for years and even decades,” said Galvin, an associate dean at FAU’s Schmidt College of Medicine and a leading expert on Alzheimer’s disease and Lewy Body Dementia. “This approach is very costly and burdensome on clinicians and patients.”
More than 5 million Americans today are affected by AD. If nothing is done to stop this upward trajectory, the Alzheimer’s Association predicts there will be more than 16 million people in the United States and more than 60 million people worldwide with the disease by 2050.
Galvin is developing a best-practice model of personalized care that looks at each individual as the sole unit of observation. The idea is to treat neurodegenerative diseases as a disorder that develops over a lifetime and individualize ways to build a better brain as we age. The ultimate goal is to prevent dementia from happening in the first place. This approach follows a form of personalized treatment similarly used in cancer. It delivers an individualized prevention plan, tailored to each patient’s risk profile based on their genetic traits, biomarkers, socio-demographics, lifestyle choices, and co-existing medical conditions.
An n+1 effort targets the diverse elements of AD by identifying person-specific risk factors and applying a customized intervention directed against this risk profile, Galvin explains in a study in the Aug. 2 issue of the Journal of the American Geriatrics Society. He believes this method will provide more rapid information on whether personalized prevention plans can improve person-centered outcomes.
As Galvin describes in this video, a “whole body” approach is important. They are taking a whole body approach, “because whatever happens below your neck, affects what happens above your neck,” he said in the video. Therefore, a prevention initiative needs to be multimodal and tailored to address individual risks.
Although the single most significant risk factor for AD is age, the disease is not inevitable. By age 85 there’s nearly a 50 percent risk of developing AD, according to the Alzheimer’s Association, which means that 50 percent of older adults do not develop dementia even if amyloid is detected in the brain. The reasons are unknown but may be explained in part by several modifiable and non-modifiable risk factors. As this article describes, up to one-third of AD cases may be preventable through modification of risk factors and behavioral changes.
“We know what’s good for the heart is good for the brain and we are changing people’s blood profiles, controlling blood sugars, reducing inflammation, lowering blood pressure, and changing lipids and cholesterol,” Galvin said. “Our patients say that they are in better overall health, their moods have improved, and they are more physically fit than before.”
Since 2003, every symptom- and disease-modifying agent to treat AD has failed in Phase II or III trials due to safety or efficacy concerns. In the past 25 years, only five symptomatic medications for AD have come to market, and just four are still available. Alzheimer’s Research UK estimates that delaying the onset of AD and related disorders by five years could reduce cases of the disease by a third worldwide.
Even though there are many different interacting factors that can lead to Alzheimer’s Disease (AD), knowing someone’s phenotype doesn’t impact the treatment options they have beyond addressing their comorbidities, so calling this ‘precision medicine’ seems inaccurate. In the study referenced by James E. Galvin, there is an example of a “personalized medicine approach to dementia prevention” (Galvin, 2017) which targets modifiable risk factors for AD and involves extensive medical tests including MRI, EEG, genotyping, neuropsychological testing, gait testing, and blood testing. However, after all of these expensive tests, the recommendations are the same as they would be for almost anyone to keep their body healthy: manage cholesterol and blood pressure, get exercise/physical therapy, eat a healthier diet, and manage mental health.
Also, the term ‘modifiable risk factor’ can be misleading. The MIND diet is recommended to lower risk, but the study that provided evidence for this relationship is observational and does not control for socioeconomic status which is likely highly related to participants’ ability to access the recommended foods (leafy greens, berries, nuts, olive oil, fish, etc.) as well as other health-influencing resources. So, although diet, exercise, and social engagement are ‘modifiable’ in the sense that it is possible for some people with enough resources to choose to change them, they also rely on structural level community issues that individuals often have little control over. In order to improve healthy aging for the whole population, it will be necessary to invest in making ‘modifiable risks’ truly modifiable for all older adults.