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

Date:
April 20, 2022
Source:
University of Texas Health Science Center at San Antonio
Summary:
The International Genomics of Alzheimer's Project (IGAP) analyzed
millions of genetic variants to come up with the latest listing
of 75 variations associated with Alzheimer's disease.



FULL STORY ==========================================================================
21 million. That's the number of genetic variations in the human genome
that researchers are sifting to identify patterns predisposing people
to Alzheimer's disease.


==========================================================================
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.


========================================================================== Story Source: Materials provided by University_of_Texas_Health_Science_Center_at_San_Antonio.

Original written by Will Sansom. Note: Content may be edited for style
and length.


========================================================================== Journal Reference:
1. Ce'line Bellenguez et al. New insights into the genetic etiology of
Alzheimer's disease and related dementias. Nature Genetics, 2022;
54 (4): 412 DOI: 10.1038/s41588-022-01024-z ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/04/220420124903.htm

--- up 7 weeks, 2 days, 10 hours, 51 minutes
* Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1:317/3)