Abstract
Alzheimers disease (AD) is the most common age-related dementia. Among its major challenges is identifying molecular signatures characteristic for the early AD stage in patients with Mild Cognitive Impairment (MCI-AD), which could serve for deciphering the AD pathomechanism and also as non-invasive, easy-to-access biomarkers. Using qRT-PCR we compared the microRNA (miRNA) profiles in blood plasma of 15 MCI-AD patients, whose diagnoses were confirmed by cerebrospinal fluid (CSF) biomarkers, with 20 AD patients and 15 non-demented, age-matched individuals (CTR).To minimize methodological variability, we adhered to standardization of blood and CSF assays recommended by the international Joint Programming for Neurodegenerative Diseases (JPND) BIOMARKAPD consortium, and we employed commercially available Exiqon qRT-PCR-assays. In the first screening, we assessed 179 miRNAs of plasma. We confirmed 23 miRNAs reported earlier as AD biomarker candidates in blood and found 26 novel differential miRNAs between AD and control subjects. For representative 15 differential miRNAs, the TargetScan, MirTarBase and KEGG database analysis indicated putative protein targets among such AD hallmarks as MAPT (Tau), proteins involved in amyloidogenic proteolysis, and in apoptosis. These 15 miRNAs were verified in separate, subsequent subject groups. Finally, 6 miRNAs (3 not yet reported in AD context and 3 reported in AD blood) were selected as the most promising biomarker candidates differentiating early AD from controls with the highest fold changes (from 1.32 to 14.72), consistent significance, specificities from 0.78 to 1 and sensitivities from 0.75 to 1. (patent pending, PCT/IB2016/052440).
Highlights
The most common cause of age-related dementia worldwide is Alzheimer’s disease (AD), a neurodegenerative disorder that affects 47 million individuals globally and is foreseen to increase to about 76 million in 2030 [1]
The results suggest that the 6 miRNAs for diagnosis of early AD (6miR) in the blood are promising candidates that should be verified in future studies in larger cohorts as a possible replacement of invasive cerebrospinal fluid (CSF) markers as identifiers of early AD
The selected 6 best candidate biomarkers for early AD are among the top ones in the differential panel of 15 miRNAs obtained in the pilot screening which were functionally mapped to proteins involved in AD pathology by the two independent in silico searches in databases containing predictive (TargetScan) and validated (MirTarBase) miRNA targets
Summary
The most common cause of age-related dementia worldwide is Alzheimer’s disease (AD), a neurodegenerative disorder that affects 47 million individuals globally and is foreseen to increase to about 76 million in 2030 [1]. The global costs related to AD are similar to the financial burden of heart disease and cancer, placing AD among the major unmet health concerns [2]. The early clinical AD stage occurs not in all, but in some patients with Mild Cognitive Impairment (MCI) [4, 5]. AD progresses from early and mild, through moderate, to the severe, late stage. The recently updated clinical diagnostic criteria allow only for the probable or possible diagnosis of AD in patients with clinical dementia or MCI (MCI attributable to AD; early AD) [6,7,8]. A definite AD diagnosis is presently possible only based on the post mortem histopathological examination of the brain
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