A large, multidimensional study, led by University of Miami Miller School of Medicine researcher Amanda Myers, Ph.D., has identified a potential therapeutic target for late-onset Alzheimer’s disease — a protein called HSPA2.
Published in the journal Brain, the study combined genomics, transcriptomics, and proteomics to gain a more complete picture of the molecular changes happening in Alzheimer’s patients. Also, the study shows how comprehensive systems approaches like this one can help answer some of the most difficult biological questions.
“Alzheimer’s disease is a huge health problem around the world,” said Dr. Myers, an associate professor of psychiatry and behavioral sciences and senior author on the paper. “By 2030, as many as 82 million people will suffer from dementia, and at least 60 percent will have Alzheimer’s disease. Even advancing the age of risk by five to 10 years, or slowing down disease progression, would greatly impact care.”
For decades, Alzheimer’s research has been focused on reducing amyloid protein plaques and tau protein tangles in patients’ brains. Unfortunately, these targets have not produced effective therapies, as drugs that target amyloid and tau have consistently failed in human clinical trials.
To better understand the biology, dozens of researchers from the U.S. and Europe joined this comprehensive effort to map the human “brainome.” The researchers studied two collections of brain samples, including more than 300 from people suffering from mild to intense Alzheimer’s disease and an additional 320 controls.
Because Alzheimer’s is highly influenced by genetics, the group studied DNA variations, but that was only the beginning. Genes are transcribed into RNA, which is translated into the proteins that do most of the work in cells. By examining these pathways, scientists can better understand the molecules that may be driving Alzheimer’s disease.
“We map genetic changes and what those changes are doing downstream,” said Dr. Myers. “Unlike other classic genetic approaches, we can capture group relationships and look at how targets are acting in concert with other molecular hits. This helps us understand the pathways and increases the pool of therapeutic targets.”
This intensive approach analyzed about 5.2 million DNA variants, 15,000 RNA transcripts, and 2,000 proteins to identify HSPA2 and five other potential targets. HSPA2 is a heat shock protein — part of a family of molecules that help cells respond to stress — and was the most significant hit from the screen. This particular molecule is part of a group called the chaperonin complex, which shuttles key proteins to their appropriate places in the cell. On a disease level, HSPA2 may contribute to amyloid and tau accumulation.
The study also outlines how intensive omics could potentially identify patients before they show symptoms, providing new opportunities to pursue earlier treatments.
“This approach can enable early interventions by mapping the patient’s genetic risk, as well as the output from that genetic risk,” said Dr. Myers. “DNA changes are stable throughout a person’s lifetime, so those can be used to sort individuals early on. We are also measuring the expression outputs from those DNA changes, which can be measured throughout life. We can ensure we are helping people at the appropriate time when expression changes due to risk variation reach critical levels.”
Because this work is hypothesis-free, it gives researchers the flexibility to go where the science takes them, providing new opportunities to identify novel molecular variations that drive Alzheimer’s disease.
“The field has been wholly focused on therapeutic avenues for the same targets,” said Dr. Myers. “Our study nominates different targets, which will open up new therapeutic approaches.”