Association of variants within APOE, SORL1, RUNX1, BACE1 and ALDH18A1 with dementia in Alzheimer's disease in subjects with Down syndrome.
BACKGROUND
Down syndrome (DS) is caused by either complete or partial triplication of chromosome 21, affecting approximately 1/1000 live births, and it is widely accepted that individuals with DS are more likely to develop dementia of Alzheimer's disease (DAD) compared with the general population. Many studies have investigated genetic susceptibility to AD in the general population, resulting in a number of potential candidate genes that may influence the development of DAD. The majority of these variants, however, have not been investigated in subjects with DS.


OBJECTIVE
The aim of this study was to determine whether genetic variants previously associated with AD in the general population, were also associated with DAD in individuals with DS.


METHODS
Genotyping of 43 SNPs within 28 genes was undertaken in 187 individuals with Down syndrome with and without dementia of Alzheimer's disease, using the SNPlex platform.


RESULTS
Significant associations of SNPs in five genes with DAD in DS were found, namely APOE, SORL1, BACE1, RUNX1 and ALDH18A1. As expected, the most strongly associated SNP was the APOE ɛ4 rs429358 variant (HR=2.47 [1.58, 3.87], p=7.52×10(-5)), although variants within the more recently implicated SORL1 and RUNX1 genes were also strongly associated with DAD in DS (HR=0.54 [0.37, 0.80], p=0.002 and HR=1.61 [1.15, 2.26], p=0.006 respectively).


CONCLUSIONS
Our study demonstrates that a number of variants previously associated with AD in the general population are also associated with DAD in DS. To enable us to determine whether these variants, as well as other more recently revealed AD susceptibility variants, truly contribute to the development of DAD in DS, further multi-centre collaborative studies comprising large number of individuals with DS are needed.
Patel
Ashok
A
Department of Biomolecular and Sport Sciences, Coventry University, West Midlands CV1 5FB, UK. ashok.patel@coventry.ac.uk
Rees
Simon D
SD
Kelly
M Ann
MA
Bain
Steven C
SC
Barnett
Anthony H
AH
Thalitaya
Deepak
D
Prasher
Vee P
VP
D000328:Adult; D000368:Aged; D000444:Aldehyde Dehydrogenase / Q000235:genetics*; D000080924:Aldehyde Dehydrogenase 1 Family; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics*; D053327:Apolipoprotein E4 / Q000235:genetics*; D016282:Aspartic Acid Endopeptidases / Q000235:genetics*; D015331:Cohort Studies; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics*; D003704:Dementia / Q000235:genetics / Q000378:metabolism; D004314:Down Syndrome / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D056726:Genetic Association Studies; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000235:genetics*; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D050697:Retinal Dehydrogenase
D053327:Apolipoprotein E4; D050676:Core Binding Factor Alpha 2 Subunit; D026502:LDL-Receptor Related Proteins; D026901:Membrane Transport Proteins; C493728:RUNX1 protein, human; C102582:SORL1 protein, human; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human