APOE is a gene found on chromosome 19 in humans, which encodes a protein (ApoE) which is involved in lipid transport. ApoE is the main lipid transport protein in the brain.There are 3 known variants of APOE: epsilon2, epsilon3 and epsilon4. epsilon4 is thought to be the ancestral allele of APOE(Mahley et al 2000), but in the UK population the expected frequencies of epsilon3, epsilon4 and epsilon2 are 0.78, 0.14 and 0.08 respectively.(Abdollahi et al 2006) These variants are the single of single nucleotide polymorphisms at two locations: T2060C(Cys112Arg) and C2198T (Arg158Cys).(Ensembl) The epsilon3 allele has cysteine and arginine in these two positions, the epsilon2 allele has cysteine in both and the epsilon4 allele has arginine in both.(Weisgraber et al 1981)

Possession of an e4 allele has been robustly shown to increase the risk of late onset Alzheimer's disease (Corder et al 1993). It is now known that ApoE is involved in neuronal repair, with E4 being the least efficient isoform (White et al 2001) and that APOE genotype influences outcome following head injury (Teasdale et al 1997).

Positive pleiotropy of the e4 allele has been investigated over the last 10 years with mixed results (e.g. Hubacek et al 2001, Bunce et al 2011). There is no effect of e4 on IQ (Taylor et al 2011), but several fMRI studies have been reported as showing more efficient memory activation in young adult e4 carriers (e.g. Scarmeas et al 2005). Working memory and e4 has been little studied, but there are suggestions from small imaging studies that e4 may be beneficial for working memory in young adults (Rusted et al 2013). Conversely studies of middle aged and older adults have found a deleterious effect of e4 on working memory (Reinvang et al 2010, Greenwood et al 2005)) A study of 445 people of mixed ages found no effect (Alexander et al 2007)

Defects in working memory have been reported as one of the earliest deficits seen in Alzheimer's disease (McKhann et al 1984). I therefore aim to study the relationship between APOE genotype and working memory in a large community sample of young adults.

Hypotheses

1) Null hypothesis: APOE genotype does not influence working memory performance

2) APOE genotype influences working memory performance, either positively or negatively.

Exposure Variable

APOE genotype

Outcome Variables

Working memory performance, specifically performance on the n-back test aged 18 with accuracy across the 2 and 3 back levels being the primary outcome.

Confounding Variables

In genetic studies it is often difficult to identify confounders as they have to have an independent relationship with both the genotype and the outcome of interest. Head injury outcome is known to be associated with APOE genotype and such injuries can have a wide range of adverse neuropsychological effects. APOE genotype is known to influence LDL levels. I would like to use this as a proxy means of checking genotyping accuracy as is routinely done in this field. Higher LDL levels have also been linked to increased cognitive problems in later life. I would like to investigate a number of other variables likely to modify working memory performance to see if they have any effect on my results.