Alzheimer's disease genes are associated with measures of cognitive ageing. 

The advent of large GWAS studies identified a number of novel risk factors for LOAD, including the BIN1, CLU, CR1 and PICALM genes.  Using a large cohort of samples from the LBC1921 (replication set, n=505) and 1936 (discovery set, n=998), we carried out a genetic association study to investigate a total of genetic variants from causal AD genes APP, PS1 and PS2, and risk factor genes BIN1, CLU, CR1, PICALM and an area located on chromosome 19.

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Overall, our results, indicate that gene specific variation and gene-gene interactions may influence cognition (Hamilton et al., 2011).  In particular, we show that a haplotype in TRAPPC6A on chromosome 19 (distinct from APOE) has a role in non-verbal reasoning in individuals that do not carry and APOE ε4 allele.

 

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ECE-1 haplotypes are associated with Alzheimer's disease and non-verbal reasoning.

One contributing cause to the development of AD is thought to be an increase in cellular Aβ species.  Aβ species are increased in all forms of AD and it is possible that proteins involved in the generation and/or degradation of this peptide may influence risk of LOAD, particularly if they contain mutations that affect function.  There are a number of proteins known to have such roles; for example, ECE-1, ECE-2, ACE, PLAU, MME, TF and IDE are known degrading Aβ enzymes.

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We performed genetic association analysis of variants from Aβ-degrading genes using samples from two different cohorts, the LBC1936 and the Genetic and Environmental Risk in Alzheimer's Disease Consortium 1 (GERAD1) cohorts.  We also carried out functional analysis of an ECE-1 promoter variant using in vitro luciferase assays.

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Our results suggest that ECE-1 variation may contribute to non-verbal reasoning scores and AD risk (Hamilton et al., 2012b).  We also show that an ECE-1 promoter polymorphism demonstrates tissue specific expression and that this may contribute to disease risk by decreasing ECE-1 expression (Hamilton et al., 2012b).

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CR1 is a risk factor for LOAD but is also associated with depression.

The advent of large GWAS studies identified a number of novel risk factors for LOAD, one of which was the complement receptor 1 (CR1)  gene.  As part of the Generation Scotland project, we genotyped two CR1 SNPs in 475 individuals with recurrent major depression and 475 individuals negative for DSM-IV mood disorder.  Our results showed for the first time that the minor allele of both CR1 variants were associated with an increased risk of depression in female individuals (Hamilton et al., 2012a).