Association of single-nucleotide polymorphisms implicated in Alzheimer's disease with cognitive phenotypes

Introduction:

Late onset Alzheimer's disease (LOAD) is a chronic and progressive neurodegenerative disorder affecting the elderly and is accompanied by severe cognitive decline. Genetics is supposed to be one of the key factors for the susceptibility to the disease. Several loci have been associated with an increased risk of developing Alzheimer's disease in genome-wide association studies (GWAS). The aim of this study was to investigate whether 9 previously confirmed AD associated single-nucleotide polymorphisms (SNPs) affect cognition in a population of healthy subjects. In addition, we selected one of the allocated genes, CD2-asscociated protein (CD2AP), for a detailed analysis.

Methods:

We selected 2147 unrelated healthy subjects of German descent as part of the PAGES sample. Psychiatric disorders were excluded using the Structured Clinical Interview for DSM-IV (SCID 1 and SCID 2). Family history was recorded to exclude a positive family history for psychiatric disorders. The Mini Mental Status Examination (MMSE) was conducted for every subject older than 60 years, to exclude possible cognitive impairments. Cognitive performance was assessed via the German version of the Wechsler Adult Intelligence Scale, Revision 1991 (WAIS-R). Genotype data was obtained using chip technology and imputation. Nine variations previously implicated in AD were selected for analysis. In addition, 385 SNPs located in the CD2AP gene clumped into 20 LD-independent loci were analysed. Analysis was calculated using an additive linear regression model.

Results:

In the first analysis screening for an influence of AD associated SNPs on cognition one SNP (rs983392) on MS4A6A gene showed significant association (p = 1.92 × 10 – 4) with the subtest verbal information after correction for the amount of SNPs tested. For the CD2AP based analysis 3 index SNPs were significantly associated with different subtests after correction for the amount of independent regions (p < 0.0025). The variation of CD2AP known to be associated with AD (rs10948363) was part of an associated LD region but failed significant association on its own.

Conclusion:

Results of this study indicate an influence of LOAD associated variations on cognitive performance in healthy controls. Additionally, 3 index SNPs of an allocated gene, CD2AP, which acts as a major intracellular signalling molecule coordinating axon-sprouting and structural plasticity in humans showed significant associations. These findings could help to improve the knowledge of the pathophysiology and genetics of cognitive decline. However, further research is needed to validate these associations and detect the functional relevance of the affected genes and variations.