Alzheimer's disease (AD) is the most frequent cause of dementia. Misfolded protein pathological hallmarks of AD are brain deposits of amyloid-β (Aβ) plaques and phosphorylated tau neurofibrillary tangles. However, doubts about the role of Aβ in AD pathology have been raised as Aβ is a common component of extracellular brain deposits found, also by in vivo imaging, in non-demented aged individuals. It has been suggested that some individuals are more prone to Aβ neurotoxicity and hence more likely to develop AD when aging brains start accumulating Aβ plaques. Here, we applied genome-wide transcriptomic profiling of lymphoblastoid cells lines (LCLs) from healthy individuals and AD patients for identifying genes that predict sensitivity to Aβ. Real-time PCR validation identified 3.78-fold lower expression of RGS2 (regulator of G-protein signaling 2; P=0.0085) in LCLs from healthy individuals exhibiting high vs low Aβ sensitivity. Furthermore, RGS2 showed 3.3-fold lower expression (P=0.0008) in AD LCLs compared with controls. Notably, RGS2 expression in AD LCLs correlated with the patients' cognitive function. Lower RGS2 expression levels were also discovered in published expression data sets from postmortem AD brain tissues as well as in mild cognitive impairment and AD blood samples compared with controls. In conclusion, Aβ sensitivity phenotyping followed by transcriptomic profiling and published patient data mining identified reduced peripheral and brain expression levels of RGS2, a key regulator of G-protein-coupled receptor signaling and neuronal plasticity. RGS2 is suggested as a novel AD biomarker (alongside other genes) toward early AD detection and future disease modifying therapeutics.

Adams Super Center for Brain Studies Sagol School of Neuroscience Tel Aviv University Tel Aviv Israel

Bioinformatics Unit George Wise Faculty of Life Sciences Tel Aviv University Tel Aviv Israel

Department of Biomedical Sciences University of Cagliari Cagliari Italy

Department of Cell and Developmental Biology Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel

Department of Human Molecular Genetics and Biochemistry Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel

Department of Pediatrics and Adolescent Medicine 1st Faculty of Medicine Charles University Prague and General University Hospital Prague Prague Czech Republic

Department of Physiology and Pharmacology Sackler Faculty of Medicine Tel Aviv University Ramat Aviv Tel Aviv Israel

The Genomic Analysis Laboratory Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel

Unit of Clinical Pharmacology University Hospital of Cagliari Cagliari Italy

Erratum v

Transl Psychiatry. 2017 Feb 14;7(2):e1035. doi: 10.1038/tp.2016.228. PubMed

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