The inability to diagnose Alzheimer’s disease, the most common form of dementia in the elderly, at its early stages of molecular pathology is considered a major reason why treatments fail in clinical trials. Previous research to molecularly diagnose Alzheimer’s disease yielded “A/T/N” central biomarkers, based on the measurements of proteins, β-amyloid (“A”) and tau (“T”), and “N” that includes neurodegeneration. A/T/N can be measured in brain tissue, by in vivo brain imaging techniques, and by analyzing cerebrospinal fluid and plasma.
Alzheimer’s disease is thought to be caused by combinations of genetic and environmental risk factors. Blood-based biomarkers such as plasma microRNAs (miRNAs) – molecules that regulate genome-environment interactions and control the expression of genes that control brain functions that deteriorate in Alzheimer’s disease – could offer advantages in terms of cost savings, accessibility and reduced invasiveness.
Two new papers from a team of researchers at Boston University, Indiana University School of Medicine and the Alzheimer’s Disease Neuroimaging Initiative (ADNI), and the German Center for Neurodegenerative Diseases (DZNE) in Goettingen, Germany, published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association shows that evaluating microRNAs in blood can be used not only to diagnose mild cognitive impairment (MCI), but also, critically, to predict the conversion of MCI to dementia due to Alzheimer’s disease. to predict. In addition, the researchers discovered microRNA candidate molecular biomarkers that associate with current amyloid, tau, and neurodegeneration (A/T/N) biomarkers of Alzheimer’s.
“Our articles are the result of a successful collaboration that coupled the technology developed by Professor Andre Fischer at Germany’s DZNE to reliably measure the levels of microRNA in human plasma, and the potency of blood samples obtained from hundreds of ADNI participants who participated in a simulated clinical trial. trial taking place at approximately 60 medical centers in the US and Canada. Our discovery is important because microRNAs, unlike current A/T/N biomarkers, can serve as molecular biomarkers in the blood years before Alzheimer’s disease manifests clinically, thereby identifying the time window for the disease. effective prevention or early intervention to halt the progression of Alzheimer’s disease,” said one of the four senior authors Ivana Delalle, MD, PhD, professor of pathology and laboratory medicine at Boston University Chobanian & Avedisian School of Medicine.
The other senior authors are Andre Fischer, PhD, DZNE speaker and professor of epigenetics of neurodegenerative diseases at the University Medical Center Goettingen, Germany; Kwangsik Nho, PhD, professor of radiology and imaging sciences at the IU School of Medicine; and Andrew J. Saykin, PsyD, Raymond C. Beeler Professor of Radiology and director of the Center for Neuroimaging and the Indiana Alzheimer’s Disease Research Center at the IU School of Medicine. The work was funded by the National Institute on Aging multisite project RF1AG078299 of the National Institutes of Health. “MicroRNAs as Diagnostic and Prognostic Biomarker of Alzheimer’s Disease” that supports teams of researchers at multiple institutions.
The researchers examined the miRNA expression in the plasma samples of three diagnostic groups of participants: cognitively normal, mildly cognitively impaired and dementia due to patients with Alzheimer’s disease. They found that, in combination with neuropsychological testing, plasma microRNAome assessment helps predict which aging individuals concerned about cognitive decline will develop Alzheimer’s disease.
These findings provide a path toward better understanding the molecular mechanisms that drive plaques, tangles, and atrophy, and may provide clues to next-generation therapeutic targets.”
Andrew J. Saykin, Indiana University
While these are exciting times for new therapies for Alzheimer’s disease to enter clinical care, the researchers note that these therapies will only work in practice if at-risk patients are identified as early as possible.
“MicroRNAs are ideal biomarkers because they are not only very stable, but also control entire molecular pathways and therefore guarantee cellular homeostasis. As such, one microRNA can simultaneously control many proteins belonging to a particular pathway,” Fischer said. “Therefore, the analysis of a few microRNAs can provide information about complex pathological changes that reflect multiple pathways, such as neuroinflammation, metabolic changes or synapse dysfunction. Thus, we need biomarkers that enable screening in a point-of-care setting.” are an important step in this direction.”
“We have laid the foundation for further research into the role of microRNAs in the pathogenesis of Alzheimer’s disease,” said Nho. “We anticipate that once specific miRNA signatures are further confirmed, the analysis of blood miRNAs will be transitioned to simple assay formats that enable the adoption of blood miRNAome analysis into clinical practice.”
The researchers said that improved tools for the early detection of Alzheimer’s disease are indispensable for developing prevention and treatment strategies for the disease that causes enormous suffering and burdens healthcare systems around the world.
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Journal references:
Kruger, D.M. et al. (2024). The plasma miRNAome in ADNI: signatures supporting the detection of at-risk individuals. Alzheimer’s and dementia. doi.org/10.1002/alz.14157.