Late-onset Alzheimer's disease is a debilitating, progressive neurodegenerative disease that affects about 7 million Americans, a figure that is expected to nearly double by 2050, according to the Alzheimer's Association. While there is no cure for the disease, early detection and treatment can preserve brain function for longer.

A study by researchers at The University of Texas Health Science Center at San Antonio (UT Health San Antonio), published in Springer Nature's Molecular Neurodegeneration, discovered a specific protein-coding transcript that may contribute to Alzheimer's disease risk across all genetic types of apolipoprotein E (APOE).

Understanding APOE and its variants

All humans have APOE protein in their genetic makeup, and the main forms, called alleles, are ε2, ε3 or ε4. Each person inherits two APOE alleles - one from each parent - resulting in one of six combinations. APOE ε3 is the most common and is seen as neutral, and APOE ε2 is believed to provide some protection against Alzheimer's disease. Having one or two APOE ε4 alleles is linked to a higher risk of Alzheimer's disease. However, the presence of APOE ε4 does not mean a person will develop Alzheimer's disease, and this has led researchers to explore other genetic factors.

"Despite over three decades of dedicated research, the precise mechanism by which the APOE ε4 allele elevates the risk of Alzheimer's disease and related dementias remains elusive. The complex regulation of APOE gene expression across various bodily systems, organs, tissues and cell types is believed to be pivotal in understanding its multifaceted role in chronic human conditions, including dementia," said co-investigator Agustin Ruiz, MD, PhD, professor and director of the Biological Core Laboratory at the Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases and the Pat V. Orme Endowed Chair in Alzheimer's and Neurogenerative Diseases at UT Health San Antonio.

Liang Ma, PhD, awarded prestigious grant to advance Alzheimer's research

This study was supported by a grant awarded to lead researcher Liang Ma, PhD, assistant professor with the Biggs Institute and the Joe R. and Teresa Lozano Long School of MedicineDepartment of Pharmacology. Out of 154 proposals from 34 centers, Ma was chosen to receive a New Investigator Award from the Alzheimer's Association and the National Alzheimer's Coordinating Center.

"I'm so fortunate to be one of only 13 researchers awarded this prestigious funding. This will allow me to move my Alzheimer's research forward significantly. There are many Alzheimer's centers, and I'm hopeful we can collaborate to pool our data and samples. By combining our resources, we can create a large, comprehensive dataset to uncover the best paths for advancing this critical work. With the right data and funding, we can make real progress in understanding and treating this devastating disease," Ma said.

Insights from diverse brain studies

Recent large-scale genetic studies uncovered variants in the APOE region that may be linked to greater risk for Alzheimer's disease. Still, the challenge remained to discover which APOE elements these variants affected in the brain.

Ma's research team analyzed five datasets from more than 1,000 postmortem human brains of European and African ancestry. They focused on three regions of the brain, particularly the prefrontal cortex - a critical center for learning, memory and executive function. The inclusion of brains from diverse ancestries is critical, as Alzheimer's disease prevalence, progression and risk factors may differ across populations. Studying multiple ancestries helps identify risk factors that are specific to certain groups or factors that may be universally applicable.

"We need brain data from other populations so we can compare it to data we have for Europeans. Hopefully in the future, we'll be able to obtain data from Asian, Hispanic and other populations so we can get a more comprehensive understanding. But for now, we have a better understanding of some risk factors shared between African and European ancestries," Ma said.

What are transcripts and single nucleotide polymorphisms?

Genes, such as APOE, produce messenger RNA, or mRNA, which act like an instruction book telling cells how to make proteins. Changes in mRNA, or how much is expressed, can influence disease risk. This study found that certain variants potentially cause changes to mRNA in the brain that increase the risk of developing Alzheimer's disease.

An mRNA transcript is a nucleotide sequence formed during alternative splicing to create a protein. Variations in how RNA segments come together can affect how a protein is made or alter its function. The research team discovered that dysregulation of a certain APOE transcript (jxn1.2.2) in the prefrontal cortex was particularly associated with Alzheimer's disease risk. This link correlated in both European and African brain samples regardless of APOE allele type (ε2, 3 or 4).

Single nucleotide polymorphisms appear normally in human DNA and are the most common genetic variation. They occur when there is a difference in one nucleotide - the most basic unit of DNA. Most of these variations are harmless, but some can affect how genes function. In the study, two single nucleotide polymorphisms (rs157580 and rs439401) are believed to be Alzheimer's-causative genetic variants for impacting expression of APOE transcript jxn1.2.2 and their effects were consistent across European and African samples.

When compared with the genomic databases, these polymorphisms were associated with amyloid-beta and phosphorylated tau proteins - both significant biomarkers for Alzheimer's disease. In people with Alzheimer's disease, amyloid-beta proteins break down and clump together to form plaques between brain cells, while tau proteins become dysregulated, creating tangles that block the transport of nutrients and signals to neurons, ultimately causing their death.

"Fortunately, the data shows that the risk factor, gene expression changes and polymorphisms are consistent between European and African ancestries. This suggests these are common risk factors across both populations. That's good news, because if we develop a drug, we can potentially use it to treat both populations," Ma said.

Discovery opens new avenues for diagnosis, treatment

By expanding understanding of genetic risk factors beyond APOE ε4, research comes closer to identifying additional biomarkers and therapeutic targets for Alzheimer's disease. The discovery of APOE transcript jxn1.2.2 and its association with Alzheimer's risk across diverse populations provides a promising avenue for developing diagnostic tools for earlier detection and intervention. Understanding how these genetic elements influence disease progression may pave the way for innovative treatments that address underlying mechanisms, offering hope for more effective prevention and management of Alzheimer's disease.

"This discovery not only enhances our comprehension of [APOE] function in the brain but also paves the way for novel research avenues into the underlying mechanisms of Alzheimer's disease. Deciphering the physiological role of this transcript and its potential contribution to disease progression is a current challenge that holds promise for the development of innovative therapeutic strategies," Ruiz said.

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