Missorting of Plasma miRNAs in Aging and Alzheimer’s Disease

Aging is the greatest risk factor for Alzheimer’s disease (AD) 1 , a pervasive cognitive disorder with unsettled etiology. The precise role of aging in AD, however, remains poorly understood. Accumulating evidence documents the dysregulation of circulating microRNAs (miRNA) separately in aging 2,3 and AD 4 . Considering miRNAs play a role in aging and longevity 5,6 , we comprehensively test which aging-associated miRNA changes are observed in AD, and change in AD beyond aging in the circulating miRNA network. Here we show that plasma miRNAs in aging are downregulated and preferentially targeted to extracellular vesicle (EV) content, while in AD, miRNAs are further downregulated and of exclusive EV origin. We further show that miRNAs in AD display altered proportions of motifs relevant to their loading into EVs 7,8 and secretion propensity 9 . Considering endosomes play a role in the genesis of EVs 10,11 and are compromised early in AD 12 , these findings implicate endosomal pathology underlying the AD plasma miRNA profile and its potential as a mechanistic AD biomarker. Striking similarities between plasma miRNA profiles in aging and AD further suggest that the AD miRNA network profile reflects a pathological exacerbation of the aging process whereby physiological suppression of AD pathology by plasma miRNAs becomes insufficient.