Title:Rexinoids as Therapeutics for Alzheimer’s Disease: Role of APOE
VOLUME: 17 ISSUE: 6
Author(s):Kevin P. Koster, Conor Smith, Ana C. Valencia-Olvera, Gregory R.J. Thatcher, Leon M. Tai and Mary Jo LaDu
Affiliation:Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago
Keywords:ABCA1, Alzheimer's disease, Aβ peptide, Amyloid, Apolipoprotein E, Bexarotene, Rexinoids, Therapeutic.
Abstract:Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by amyloid
plaques, composed of amyloid-beta peptide (Aβ) and neurofibrillary tangles, composed of aberrantly
phosphorylated tau. APOE4 is the greatest genetic risk factor for AD, increasing risk up to 12-
fold with a double allele compared to APOE3. In contrast, APOE2 reduces AD risk ~2-fold per allele.
Accumulating evidence demonstrates that apolipoprotein E4 (apoE4) plays a multifactorial role in AD
pathogenesis, although the exact mechanisms remain unclear. Further data support roles for apoE4 as a
toxic gain of function or loss of positive function in AD, a discrepancy that has significant implications
for the future of apoE-directed therapeutics. However, recent evidence repurposing retinoid X
receptor (RXR) agonists, or rexinoids, for the treatment of AD demonstrates conflicting, though potentially
beneficial effects in familial AD-transgenic (FAD-Tg) mouse models. Of particular note is
bexarotene (Targretin®), a selective rexinoid previously utilized in cancer treatment emerging as a viable
candidate for AD clinical trials. However, the mechanism of action of bexarotene and similar rexinoids
remains controversial, particularly in the context of human APOE. In addition, rexinoids demonstrate
distinct adverse event profiles in humans that may have greater detrimental effects in an elderly
AD population. Therefore, this special issue review discusses the implications for rexinoiddirected
therapeutic strategies in AD, the potential mechanistic targets, and future directions for the
improvement of rexinoid-based therapies in AD.
