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Spatial navigation and orientation are emerging as promising markers for altered cognition in prodromal Alzheimer’s disease, and even in cognitively normal individuals at risk for Alzheimer’s disease. The different APOE gene alleles confer various degrees of risk. The APOE2 allele is considered protective, APOE3 is seen as control, while APOE4 carriage is the major known genetic risk for Alzheimer’s disease. We have used mouse models carrying the three humanized APOE alleles and tested them in a spatial memory task in the Morris water maze. We introduce a new metric, the absolute winding number, to characterize the spatial search strategy, through the shape of the swim path. We show that this metric is robust to noise, and works for small group samples. Moreover, the absolute winding number better differentiated APOE3 carriers, through their straighter swim paths relative to both APOE2 and APOE4 genotypes. Finally, this novel metric supported increased vulnerability in APOE4 females. We hypothesized differences in spatial memory and navigation strategies are linked to differences in brain networks, and showed that different genotypes have different reliance on the hippocampal and caudate putamen circuits, pointing to a role for white matter connections. Moreover, differences were most pronounced in females. This departure from a hippocampal centric to a brain network approach may open avenues for identifying regions linked to increased risk for Alzheimer’s disease, before overt disease manifestation. Further exploration of novel biomarkers based on spatial navigation strategies may enlarge the windows of opportunity for interventions. The proposed framework will be significant in dissecting vulnerable circuits associated with cognitive changes in prodromal Alzheimer’s disease.

Induction of oxidative stress has been implicated as a causative factor in fetal alcohol syndrome although the source of reactive oxygen species is not clear. One potential source is the microglia, the CNS macrophage, which generate superoxide anion as part of their normal immune function. Our data indicate that chronic exposure to ethanol alters the function of cultured neonatal hamster microglia by inducing superoxide anion production in resting (nonstimulated) cells. An increase in superoxide anion was seen at 24 or 48 hr of ethanol treatment but was not seen during acute exposures of up to 3 hr. This effect was dose dependent and was maximal at 20 mM ethanol. Treatment with ethanol did not directly activate the respiratory burst seen in microglia and did not act as a priming agent to enhance phorbol-ester-stimulated superoxide anion production. Lipopolysaccharide-mediated priming of microglial superoxide anion production was also not affected by exposure to 20 mM ethanol for 24 hr. Ethanol treatment, however, did depress nitric oxide (NO) levels in hamster microglia which had been stimulated to produce NO by polyinosinic:polycytidylic acid (poly I:C). Uptake of latex beads was increased by 24 hr of exposure to ethanol. The overall action of ethanol on neonatal hamster microglia is to shift the balance between the production of superoxide anion and NO. Because NO is protective to mammalian cells, these changes predict that oxidative stress in the CNS would be enhanced.