GRIN2B genotypes and APOE haplotypes affect the age at onset of Alzheimer's dementia as well as variations in dementia staging according to the use of Memantine.

Background: Memantine antagonizes the N‐methyl‐D‐aspartate (NMDA) type of glutamate receptor leading to possible behavioral improvement and a synergistic effect with cholinesterase inhibitors on slower functional and cognitive decline in Alzheimer's dementia (AD). Some receptor genes can contribute to variable excitotoxicity and pharmacological response. NR2B is a common subunit of functional NMDA receptors, whereas the GRIN2B gene is mapped to 12p12, and rs3764028 has been associated with variable GRIN2B transcription and human susceptibility to AD. We sought to evaluate associations of promoter GRIN2B genotypes and APOE haplotypes with the age at onset of AD and cognitive and functional response to Memantine. Methods: In this prospective pharmacogenetic study, participants with late‐onset AD according to National Institute on Aging – Alzheimer's Association criteria were screened with the Clinical Dementia Rating Sum‐of‐Boxes, the Index of Independence in Activities of Daily Living, Lawton's Scale for Instrumental Activities of Daily Living, the Mini‐Mental State Examination, the Severe Mini‐Mental State Examination, and a 15‐item Clock Drawing Test, and followed for one year. Genotyping was undertaken with TaqMan® Real‐Time Polymerase Chain Reactions for rs429358 and rs7412 (APOE haplotypes), and with Polymerase Chain Reactions for rs3764028 (GRIN2B). Associations of APOE haplotypes and rs3764028 genotypes with the age at dementia onset were assessed and, after stratification according to APOE‐ε4 carrier status, the presence of each genotype of rs3764028 was linked with use of Memantine or not for test score variations, significance at p<0.05. Results: Among 190 consecutive outpatients, 141 used Memantine (74.2%); mean age at dementia onset was 73.23±6.4 years‐old, with 128 women (67.4%) and 62 men (32.6%), 101 APOE4+ carriers (53.2%) and 89 APOE4‐ carriers (46.8%). APOE‐ε4/ε4 carriers had earlier AD onset by almost five years (p = 0.004), whereas the A allele of rs3764028 had a cumulative effect on later onset of AD (p<0.0001). Memantine protected APOE4‐ carriers of the CC genotype of rs3764028 regarding Clinical Dementia Rating Sum‐of‐Boxes variations (p = 0.018), but not regarding other test score variations. Conclusions: Genotypes of rs3764028 and APOE haplotypes are associated with the age at onset of AD, as well as with variations in dementia staging according to the use of Memantine. (Supported by FAPESP grant #2015/10109‐5) [ABSTRACT FROM AUTHOR]