In animal models, apoE is induced within hours to weeks after TBI followed by increased neuronal uptake of apoE-containing lipoproteins through the low-density lipoprotein receptor. In mice, apoE deficiency compromises recovery from acute neurological injuries, including TBI. ApoE also regulates b-amyloid metabolism, a function that underlies its genetic association with Alzheimer��s disease. AD is defined neuropathologically by the presence of extracellular amyloid plaques composed of aggregated Ab peptides and intracellular neurofibrillary tangles consisting of hyperphosphorylated tau. The human apoE4 allele increases AD risk and hastens its onset, whereas apoE2 delays onset and reduces AD risk. Recent microdialysis studies demonstrated that apoE genotype modulates the Ab half-life in brain interstitial fluid, with the rate of Ab Folinic acid calcium salt pentahydrate degradation accelerated by apoE2 and prolonged by apoE4 compared to apoE3. Although AD risk and age of onset are indisputably modified by apoE genotype, the relationship between apoE genotype and TBI outcome is complex. Some studies report that apoE4 carriers have significantly poorer outcomes compared to non-carriers, while others find no association. Many variables pose challenges to resolving these uncertainties, including Butenafine hydrochloride relatively short follow-up times after TBI and the diversity of subjects with respect to the age, gender, and injury severity. Despite these challenges, a meta-analysis of 14 studies with 2,527 subjects concluded that apoE4 does not affect initial injury severity but rather may compromise recovery at 6 months post-injury. Several epidemiological studies suggest that TBI may increase the risk of dementia, particularly AD, although this association is not always observed. TBI has also been associated with an earlier onset of AD. Both NFTs and amyloid plaques are found in post-mortem TBI brain tissue. However, the widespread white matter involvement in TBI that is not present in AD results in noteworthy differences in the pattern and distribution of their common neuropathological features. For example, TBI neuropathology is largely that of tau deposition, as only approximately 30% of TBI patients also contain Ab deposits. Ab plaques can appear within hours and remain detectable up to 47 years after a single moderatesevere TBI. NFTs are also detectable after a single TBI and are remarkably prominent in mild, repetitive, concussive injuries. Despite the low prevalence of amyloid deposits in the post-mortem TBI brain, amyloid precursor protein accumulation in damaged axons is a striking histological hallmark of diffuse axonal injury. Increased APP in the post-TBI brain is hypothesized to trigger a burst of Ab production that can deposit in amyloid plaques. Intriguingly, microdialysis experiments in brain-injured humans have demonstrated that ISF Ab levels correlate positively with the patient��s Glasgow Coma Score, suggesting that Ab release is associated with recovery of synaptic function, as has been demonstrated in animals. Improving apoE function may therefore facilitate both neuronal repair and Ab clearance after TBI, thus potentially offering both acute and long-term benefits. One method to enhance apoE function is to promote its lipidation by ATP-binding cassette transporter A1, which is the rate-limiting step in generating apoE-containing lipoprotein particles in the central nervous system. ABCA1 deficiency leads to poorly-lipidated apoE in the CNS, and increases amyloid load in AD mice.