Evidence that an APOE ε4 'double whammy' increases risk for Alzheimer's disease

Temporal lobe epilepsy (TLE) is associated with some of the same neuropathological features as those reported for early stages of typical Alzheimer's disease (AD). The APOE ε4 allele is associated with a gene-dose-dependent increase in AD risk and in the severity of amyloid-β (Aβ) pathology. In a study published in the current BMC Medicine, Sue Griffin and colleagues studied markers of brain resilience in the amputated temporal lobes of TLE patients. They discovered compelling evidence that the APOE ε3 isoform in TLE patients is apparently more neuroprotective from Aβ toxicity than is the APOE ε4 isoform, as shown by the reduced levels of neuronal damage, glial activation, and expression of IL-1α in the APOE ε3/ε3 brains. This result points to a new property of APOE isoforms: not only are APOE ε4 alleles associated with increased brain amyloid plaque burden, but these alleles are also apparently inferior to APOE ε3 alleles in conveying resistance to Aβ neurotoxicity. This 'double whammy' result opens up a new direction for studies aimed at elucidating the relevant neurobiological activities of APOE isoforms in the pathogenesis of AD.