The
gene encoding apolipoprotein E (ApoE) called APOE has been shown to provide the
greatest genetic risk to developing late onset AD. (Alagiakrishnan, Gill and
Fagarasanu, 2018) APOE is located on chromosome 19 q13.2 and has also been linked to
increased risk of developing early onset AD. (Cacace, Sleegers and Van
Broeckhoven, 2016) There are 3 different alleles for APOE (?2, ?3, ?4) with
APOE ?4 being the one most linked to development of AD in both early and late
onset AD. It has also been demonstrated that being homozygous for APOE ?4 gives
a much larger risk of AD development than being heterozygous. GWAS studies have
shown that 91% of people diagnosed with AD are homozygous compared to 47% being
heterozygous. Homozygotes also have an earlier median age of onset compared to
heterozygotes. (Kanekiyo, Xu and Bu, 2014) Conversely APOE ?2 has been shown to
have a protective mechanism against AD as it decreases both the risk and age of
onset in late onset AD. (Liu et al., 2013) There is a twofold increase in
carriers of the APOE ?2 allele in the general population than in patients with
AD.

The
protein apoE is involved in mediating the transport and delivery of phospholipids
and cholesterol through cell surface apoE receptors. (Holtzman, Herz and Bu,
2018) ApoE has also been shown to bind A? and to therefore regulate its
metabolism, aggregation and deposition. The ability of apoE to transport A? is
dependent on the isoform with APOE ?4 being less able than ?2 and ?3. (Sun et
al., 2017) It has also been shown that AD patients with the APOE ?4 allele have
higher deposits of A? plaques. Previous studies have also shown that AD
patients with the APOE ?4 allele have decreased glucose metabolism in certain
brain areas as well as increased brain inflammation compared to non ?4
carriers. Both of which are important characteristics in AD. Increased
hippocampal atrophy and decreased synaptic plasticity in AD have also been
linked to the presence of the APOE ?4 allele. (Michaelson, 2014)

More
recent studies have shown direct links between tau and the APOE ?4 allele. A
significant link with APOE and cerebrospinal tau levels was shown in a GWAS
study. Another recent study in mice has also suggested that ApoE directly
affects tau-mediated neurodegeneration with a complete absence of ApoE actually
being protective and with ApoE ?4 leading to more severe degeneration. (Shi et
al., 2017)

APOE ?4 has also been associated with poor
recovery following traumatic brain injury. 

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