But studies looking into treatments for Alzheimer’s disease have been frustratingly disappointing. Over the last decade, more than 100 human trials aimed at Alzheimer’s disease treatment have been conducted with little success.
“Five available Alzheimer’s disease drugs were all approved by FDA 10 years ago, and they provide only temporary symptomatic relief for an average of six to 12 months,”said Liqin Zhao, assistant professor of pharmacology and toxicology at the University of Kansas School of Pharmacy, part of a team that has published an investigation into human ApoE2, a protective “apolipoprotein” created by the ApoE gene — a gene associated with Alzheimer’s disease risk. The research appears in the Journal of Alzheimer’s Disease 48(2).
“Human ApoE is polymorphic and exists in three major alleles — ApoE2, ApoE3 and ApoE4,” Zhao said. “ApoE2 is a rare form and is considered neuroprotective. ApoE3 is the most common form and considered to play a neutral role in AD. ApoE4 is the greatest genetic risk factor for late-onset sporadic AD — ApoE4 occurs in only about 20 percent of the total population but accounts for approximately 50 percent of the Alzheimer’s disease population.”
According to Zhao, too much previous research has focused on ApoE4 — many of them focused on ApoE4-mediated neurotoxic mechanisms by comparing ApoE4 to ApoE3, or ApoE4 carriers versus non-ApoE4 carriers. By contrast, she said ApoE2 has largely been ignored with only a few published studies that included ApoE2 in their designs — until now.
“We took a different approach and looked from a different angle,” Zhao said. “We asked the question: What makes ApoE2 carriers resistant to Alzheimer’s disease? Our rationale is that if we can figure out the mechanisms that underlie ApoE2-mediated neuroprotective properties, we could translate this molecular understanding into a therapeutic strategy aimed to transform an aging brain — in particular an ApoE4 brain into an ApoE2-like brain. Such a strategy could essentially increase the defense ability of the aging, ApoE4 brain against the development of Alzheimer’s disease.”
The researcher believes several factors could have contributed to the current trend of lost-in-translation from preclinical findings in animal models to trials in humans.
“This could suggest that Alzheimer’s disease animal models that are widely used in preclinical studies — most are early-onset familial Alzheimer’s-disease-related models — don’t accurately model the pathophysiological condition of the majority of human Alzheimer’s disease cases, which is the late-onset sporadic Alzheimer’s disease — the most common form of Alzheimer’s disease representing over 95 percent of the current human Alzheimer’s disease population.”
Thus, Zhao thinks it’s very likely the success derived from familial Alzheimer’s disease-related animal models isn’t replicated in human late-onset sporadic Alzheimer’s disease patients.
Citation: "Human ApoE Isoforms Differentially Modulate Glucose and Amyloid Metabolic Pathways in Female Brain: Evidence of the Mechanism of Neuroprotection by ApoE2 and Implications for Alzheimer’s Disease Prevention and Early Intervention," by Jeriel Thomas-Richard Keeney, Shaher Ibrahimi, and Liqin Zhao, Journal of Alzheimer's Disease, Volume 48, Issue 2, pp 411-424, DOI: 10.3233/JAD-150348.