Dendritic spines are postsynaptic sites of excitatory input in the mammalian 
nervous system. Apolipoprotein (apo) E participates in the transport of plasma 
lipids and in the redistribution of lipids among cells. A role for apoE is 
implicated in regeneration of synaptic circuitry after neural injury. The apoE4 
allele is a major risk factor for late-onset familial and sporadic Alzheimer's 
disease (AD) and is associated with a poor outcome after brain injury. ApoE 
isoforms are suggested to have differential effects on neuronal repair 
mechanisms. In vitro studies have demonstrated the neurotrophic properties of 
apoE3 on neurite outgrowth. We have investigated the influence of apoE genotype 
on neuronal cell dendritic spine density in mice and in human postmortem tissue. 
In order to compare the morphology of neurons developing under different apoE 
conditions, gene gun labeling studies of dendritic spines of dentate gyrus (DG) 
granule cells of the hippocampus were carried out in wild-type (WT), human 
apoE3, human apoE4 expressing transgenic mice and apoE knockout (KO) mice; the 
same dendritic spine parameters were also assessed in human postmortem DG from 
individuals with and without the apoE4 gene. Quantitative analysis of dendritic 
spine length, morphology, and number was carried out on these mice at 3 weeks, 1 
and 2 years of age. Human apoE3 and WT mice had a higher density of dendritic 
spines than human E4 and apoE KO mice in the 1 and 2 year age groups (P<0.0001), 
while at 3 weeks there were no differences between the groups. These age 
dependent differences in the effects of apoE isoforms on neuronal integrity may 
relate to the increased risk of dementia in aged individuals with the apoE4 
allele. Significantly in human brain, apoE4 dose correlated inversely with 
dendritic spine density of DG neurons cell in the hippocampus of both AD 
(P=0.0008) and aged normal controls (P=0.0015). Our findings provide one 
potential explanation for the increased cognitive decline seen in aged and AD 
patients expressing apoE4.