NRG1/ErbB4 signaling and its role on the development and progression of Alzheimer's disease

Abstract

AbstractBackgroundAlzheimer’s disease (AD) is a complex disease; various etiopathogenic mechanisms, like genetics and cognitive reserve, affect its development and progression across the continuum. Neuregulin‐1 (NRG‐1) /ErbB4 signaling has been recently studied regarding its possible role in the development of AD. To our knowledge, the schizophrenia (SZ) risk SNPs rs6994992 (NRG‐1) and rs839523 (ErbB4) have never been explored in association to AD, but the risk alleles have been associated with structural, functional and cognitive alterations in SZ and healthy individuals. Some of these alterations are similar to those experienced by AD patients, over 40% of which evolve to experience psychotic symptoms. This subset of patients experience a more rapid cognitive decline, greater functional impairment, etc., which contribute to a greater level of distress for family and caregivers.MethodThe sample consisted of 584 Spanish individuals: 161 were diagnosed with mild cognitive impairment (MCI; age = 76.66±5.37). The remaining 423 were healthy controls (HC; age = 65.88±8.80).Participants underwent a neuropsychological evaluation, a MEG scan, a magnetic resonance imaging scan, and were genotyped for the rs6994992 and rs839523 SNPs.ResultPreliminary results show a significant interaction between the NRG1 risk allele and the diagnosis in the MMSE score (figure 1); the risk allele had no effect in HC, but in MCI those with the risk allele had a significantly worse performance. Linear models were performed for the prediction of the MMSE score, including either the NRG1 or ErbB4 SNP, the diagnosis, cognitive reserve and age. Significant interactions with the SNPs were found for both, including a three‐way interaction between the diagnosis, cognitive reserve.ConclusionThese preliminary findings could indicate that the SZ risk alleles have a negative influence in the AD continuum over cognition and, potentially, over structural and functional parameters. This effect could be modulated by cognitive activity across the lifespan.