The apolipoprotein E4 allele (ApoE4) plays a pivotal role in processes as disparate as Alzheimer’s disease (AD), cardiovascular disease, Lewy body dementia, longevity, recovery from traumatic brain injury and stroke, hominid evolution, and inflammation. The mechanism(s) by which such disparate effects are achieved has been unexplained, since the function of ApoE has been limited to its role as a lipid-carrying protein. However, we have recently discovered that ApoE also functions as a transcription factor, binding with high affinity to double-stranded DNA, including the promoter regions of 1700 different genes (Theendakara et al., J Neurosci 2016). These results have important implications for the evolving comprehensive therapeutic program we developed to reverse cognitive decline in SCI (subjective cognitive impairment), MCI (mild cognitive impairment), and early AD (Bredesen, Aging 2014), as well as for the ancestral-modern lifestyle mismatch.
