Genomic study lays groundwork for insights into potential biomarkers and therapeutic strategies

New Cleveland Clinic-led research published in Alzheimer’s and Dementia (2025 Jul;21[7]:e70452) describes how a range of post-transcriptional modifications known as RNA editing may serve as an understudied link between aging and neurodegeneration. These modifications, which change the molecules in RNA, may serve as new targets for diagnosing and treating Alzheimer’s disease (AD).

“There is no one factor that determines how likely someone is to develop Alzheimer’s disease,” says first author Amit Gupta, PhD, a postdoctoral fellow in the lab of senior author Feixiong Cheng, PhD, Director of the Cleveland Clinic Genome Center. “Many factors influence the underlying biological processes, including genetics, proteomics, protein-protein interactions, environment, aging, health history and medication use. Such a complex condition requires new and innovative approaches to tackle it, but first we need to understand understudied factors that contribute to disease risk.”

The rationale for studying RNA editing

RNA editing is a process by which cells alter their RNA sequence by adding, removing or changing specific nucleotides. This alteration is important because it helps create variations in proteins, allowing for greater diversity. Additionally, it can influence key cellular functions, such as how stable the RNA is, where it goes in the cell, how it is spliced, how much of it is present, its structure and how efficiently it is translated into proteins.

RNA editing has been linked to neurological conditions including AD, but the landscape specific to genome-wide tissue and its impact on brain regulation remain relatively underexplored. To gain more insight, the researchers thoroughly examined RNA editing across nine distinct areas of the human brain affected by AD. They used RNA sequencing data along with corresponding whole-genome sequencing information from three major human brain biobanks: the Mount Sinai Brain Bank, the Mayo Clinic Religious Order Study and the Memory and Aging Project.

A total of 4,208 RNA-seq samples (1,364 from AD cases and 742 from healthy controls) underwent analysis, which factored in variables such as age, postmortem interval, biological sex and apolipoprotein E4 (APOE4) genetic status. Matched genotyping data from 3,627 samples across all biobanks were also used to examine local genetic variations that influence RNA editing.

(A) Overview of the study. (B) Brain region-specific sample distribution. (C) Circular plot depicting the brain region-specific landscape of RNA editing (cf. Methods) events. Nine circular tracks show editing level and density from different brain regions (CBE, TCX, PHG, IFG, STG, FP, DLPFC, PCC, ACC). The plot highlights 127 genes harboring significant RNA editing loci (p ≤ 5×10-3) that are shared by two or more brain regions. ACC, anterior cingulate cortex; AD, Alzheimer’s disease; CBE, cerebellum cortex; DLPFC, dorsolateral prefrontal cortex; FP, frontal pole; HC, healthy controls; IFG, inferior frontal gyrus; MAYO, Mayo Clinic; MSBB, Mount Sinai Brain Bank; PCC, posterior cingulate cortex; PHG, parahippocampal gyrus; ROSMAP, Rush University’s Religious Orders Study and Memory and Aging Project; STG, superior temporal gyrus; TCX, temporal cortex.

Key findings

The researchers uncovered RNA editing occurrences in both AD brains and aging brains of healthy controls, drawing attention to 127 genes displaying notable RNA editing sites present across multiple cerebral regions. AD brains showed increased RNA editing in the parahippocampal gyrus and cerebellar cortex, with the former exhibiting the greatest number of editing occurrences. The genes identified are primarily involved in neuronal growth, morphogenesis, and processes related to synaptic function and signaling.

The study also identified a collection of RNA editing events markedly connected to sex-specific variations within AD brains, demonstrating significant variability across regions. The parahippocampal gyrus revealed the highest count of sex-linked genes (158) in AD.

Additionally, groupings of RNA editing connected to APOE4 status in AD were identified throughout all nine cerebral regions.

The investigation also revealed 147 instances of colocalization between genome-wide association study (GWAS) signals and local RNA editing quantitative trait loci (cis-edQTLs) within 48 potentially causative genes. Notably, 33 genes displayed important colocalized GWAS and cis-edQTL associations. These colocalized signals showed connections to pathways involving tau protein interaction, amyloid-beta regulation, cell development and immune responses, suggesting how epitranscriptomic processes might influence susceptibility to AD.

Implications and next steps

Together, the findings underscore the importance of post-transcriptional modifications in regulating brain cell function as humans age. Additionally, the identified RNA editing differences may help resolve a longstanding question in AD research by explaining how certain genes can influence brain health more profoundly in some individuals than others, even when the genes themselves are not mutated.

The next step is to functionally validate the most promising findings from this analysis in the lab. Dr. Cheng and his team are investigating how RNA editing influences protein expression, laying the groundwork for identifying novel therapeutic targets for AD and other complex conditions.

“By deepening our understanding of the RNA-edited targets we found and the mechanisms that link these targets to disease risk, we may uncover new biomarkers and therapeutic strategies for Alzheimer’s disease and related dementias,” Dr. Cheng says. “This project reflects our Genome Center’s commitment to developing innovative genomic research strategies that look beyond genes themselves to better understand and treat complex diseases.”

Source – The Cleveland Clinic