In the race to solve Alzheimer's disease, scientists find more needles in the haystack

It's a huge haystack, and Alzheimer's-related genetic variations, like needles, are miniscule in comparison. Sudha Seshadri, MD, and other faculty at The University of Texas Health Science Center at San Antonio (UT Health San Antonio) readily attest to the deep gulf between what is known about Alzheimer's genetics and what is yet to be discovered.

Dr. Seshadri, Habil Zare, PhD, and colleagues at the university's Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases are investigators on a global project to answer the many Alzheimer's riddles. Dr. Seshadri is a founding principal investigator of the International Genomics of Alzheimer's Project, commonly called IGAP. Glenn Biggs Institute faculty contributed data for the newest research from IGAP, published April 4 in Nature Genetics, and helped craft the discussion on implications of the findings, Dr. Seshadri said.

Large sample

Genomic data of half a million people were used in this latest IGAP study, including 30,000 people with confirmed Alzheimer's disease and 47,000 people categorized as proxies. Researchers could not be sure that proxy participants had Alzheimer's clinically, but they were included based on conversations with their children.

"In Alzheimer's disease research you need many samples, because some of these variants are very rare, and if you want to detect them, you need to study many, many people," said Dr. Zare, assistant professor of cell systems and anatomy in the Joe R. and Teresa Lozano Long School of Medicine and an expert in computational biology and bioinformatics. "The only way to get there is through collaboration between centers and consortia, and IGAP was established for such kind of collaboration."

IGAP conducts genome-wide association studies. These studies reveal areas of the genome, the encyclopedia of human genes, that vary between people who have Alzheimer's disease and people who don't.

"We are looking for the genetic basis so as to better understand all the different types of biology that may be responsible for Alzheimer's disease," said Dr. Seshadri, founding director of the Biggs Institute and professor of neurology in the Long School of Medicine. "As we include data from more and more people, we are able to find variants that are fairly rare, that are only seen in about 1% of the population."

Sea change

In 2009, the year of the first genome-wide association studies, researchers knew of one gene, called APOE, associated with late-onset Alzheimer's disease. Before the April 4 journal publication, researchers had a list of 40 such genes. The new paper confirmed 33 of them in a larger population sample and added 42 new genetic variants not described before.

"We've doubled the number of genes that we know are associated with Alzheimer's disease," Dr. Seshadri said. "Each of these genetic variants is a route to understanding the biology and a potential target for treatment."

Emerging pathways of Alzheimer's biology suggest the involvement of inflammation, cell senescence, central nervous system cells called microglia, and many others. Finding genetic variations will shed light on these pathways.

"A certain percentage of them are what are called druggable targets," Dr. Zare said. "Some are considered more likely to yield drugs."

Diversity needed

The study published in Nature Genetics is confined to certain people groups, which makes it impossible to generalize the gene variations worldwide.

One of the challenges with this paper, as well, is it is largely in persons of European ancestry," Dr. Seshadri said. "So, we hope to bring, over the next few years, a much larger sample of Hispanic and other minority populations to further improve gene discovery."

The South Texas Alzheimer's Disease Research Center (ADRC), a collaboration of the Glenn Biggs Institute, UT Health San Antonio and The University of Texas Rio Grande Valley, is on a mission to bring the region's sizable Hispanic population into genetic studies and other initiatives such as clinical trials. ADRCs are National Institute on Aging Centers of Excellence.

Older Hispanic adults are estimated to be at 1.5 times greater risk of Alzheimer's and other dementias than non-Hispanic whites. Dementia is costing individuals, caregivers, families and the nation an estimated $321 billion in 2022, according to the Alzheimer's Association.

"Our South Texas ADRC is here to treat people and make discoveries that lead to better treatments," Dr. Seshadri said.

The needles in the haystack are being located, and this is having results.

"We are part of this international team and are finding a lot of needles in this huge haystack of 21 million variants," Dr. Zare said.

Partners are crucial

Dr. Seshadri said a gene called SP1 is being considered for drug development by industry. SP1 was identified in an earlier study conducted by IGAP.

"That was a clue discovered years ago and now we have more clues, and hopefully we will have more promising targets in the near future," Dr. Zare said.

As the quest to end the suffering endured by individuals and families continues, the researchers acknowledge the partners who play significant roles.

"We would like to thank each of the collaborators within IGAP, and all the patients and families that join such studies, and the National Institute on Aging, which is our funder," Dr. Seshadri said.

New insights into the genetic etiology of Alzheimer's disease and related dementias

Researchers listed in the paper and affiliated with the Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases at UT Health San Antonio are Bernard Fongang, Xueqiu Jian, Claudia L. Satizabal, Habil Zare, Maryam Bahadori, Monica Goss, Timothy Hughes, Debora Melo van Lent, Sudha Seshadri and Alfredo Ramirez.