Fig. 2

Could age-related changes to mitochondria alter ApoE biology? Neurons do not typically express the APOE gene to produce ApoE protein, but may begin to express it in the setting of an age-related decline of mitochondrial function or mtDNA copy number. The ApoE protein that is produced, or a cleavage product of ApoE, may then interact with mitochondria. If the APOE isoform is APOE4, this may confer a toxic effect that further perturbs mitochondrial function and pushes the brain from a state of compensated to uncompensated brain aging, a state equivalent to AD. While this illustration presents a dramatically simplified scenario, it conceptualizes a series of events through which biological changes typically associated with aging could transition into biological changes typically associated with AD