The observation that aging is regulated by microRNAs (miRNA) and at the same time represents the greatest risk factor for Alzheimer's disease (AD), prompted us to examine the circulating miRNA network in AD beyond aging. We here show that plasma miRNAs in aging are downregulated and predicted to be preferentially targeted to the extracellular vesicle (EV) content. In AD, miRNAs are further downregulated, display altered proportions of motifs relevant to their loading into EVs and secretion propensity, and are forecast to be found exclusively in EVs. The circulating miRNA network in AD, therefore, reflects pathological exacerbation of the aging process whereby physiological suppression of AD pathology by miRNAs becomes insufficient.

1st Department of Neurology St Anne's University Hospital and Faculty of Medicine Masaryk University Brno Czech Republic

Department of Biochemistry Emory University School of Medicine Atlanta Georgia USA

Department of Neurobiology Barrow Neurological Institute Phoenix Arizona USA

Department of Neurology University Hospital Olomouc Olomouc Czech Republic

Department of Neurosciences University of California San Diego La Jolla California USA

Department of Pharmacology and Chemical Biology Emory University School of Medicine Atlanta Georgia USA

Division of Neurology University Medical Centre Ljubljana Slovenia

Institute for Molecular and Translational Medicine Faculty of Medicine and Dentistry Palacky University Olomouc Olomouc Czech Republic

International Clinical Research Centre St Anne's University Hospital Brno Czech Republic

Memory Clinic Department of Neurology 2nd Faculty of Medicine Charles University and Motol University Hospital Prague Czech Republic

Translational Aging and Neuroscience Program Mayo Clinic Rochester Minnesota USA

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