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      APOE and Alzheimer’s Disease: Evidence Mounts that Targeting APOE4 may Combat Alzheimer’s Pathogenesis

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          Alzheimer's disease.

          Alzheimer's disease is the most common cause of dementia. Research advances have enabled detailed understanding of the molecular pathogenesis of the hallmarks of the disease--ie, plaques, composed of amyloid beta (Abeta), and tangles, composed of hyperphosphorylated tau. However, as our knowledge increases so does our appreciation for the pathogenic complexity of the disorder. Familial Alzheimer's disease is a very rare autosomal dominant disease with early onset, caused by mutations in the amyloid precursor protein and presenilin genes, both linked to Abeta metabolism. By contrast with familial disease, sporadic Alzheimer's disease is very common with more than 15 million people affected worldwide. The cause of the sporadic form of the disease is unknown, probably because the disease is heterogeneous, caused by ageing in concert with a complex interaction of both genetic and environmental risk factors. This seminar reviews the key aspects of the disease, including epidemiology, genetics, pathogenesis, diagnosis, and treatment, as well as recent developments and controversies.
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            Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database.

            The past decade has witnessed hundreds of reports declaring or refuting genetic association with putative Alzheimer disease susceptibility genes. This wealth of information has become increasingly difficult to follow, much less interpret. We have created a publicly available, continuously updated database that comprehensively catalogs all genetic association studies in the field of Alzheimer disease (http://www.alzgene.org). We performed systematic meta-analyses for each polymorphism with available genotype data in at least three case-control samples. In addition to identifying the epsilon4 allele of APOE and related effects, we pinpointed over a dozen potential Alzheimer disease susceptibility genes (ACE, CHRNB2, CST3, ESR1, GAPDHS, IDE, MTHFR, NCSTN, PRNP, PSEN1, TF, TFAM and TNF) with statistically significant allelic summary odds ratios (ranging from 1.11-1.38 for risk alleles and 0.92-0.67 for protective alleles). Our database provides a powerful tool for deciphering the genetics of Alzheimer disease, and it serves as a potential model for tracking the most viable gene candidates in other genetically complex diseases.
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              ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models.

              Alzheimer's disease (AD) is associated with impaired clearance of β-amyloid (Aβ) from the brain, a process normally facilitated by apolipoprotein E (apoE). ApoE expression is transcriptionally induced through the action of the nuclear receptors peroxisome proliferator-activated receptor gamma and liver X receptors in coordination with retinoid X receptors (RXRs). Oral administration of the RXR agonist bexarotene to a mouse model of AD resulted in enhanced clearance of soluble Aβ within hours in an apoE-dependent manner. Aβ plaque area was reduced more than 50% within just 72 hours. Furthermore, bexarotene stimulated the rapid reversal of cognitive, social, and olfactory deficits and improved neural circuit function. Thus, RXR activation stimulates physiological Aβ clearance mechanisms, resulting in the rapid reversal of a broad range of Aβ-induced deficits.
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                Author and article information

                Journal
                Molecular Neurobiology
                Mol Neurobiol
                Springer Nature
                0893-7648
                1559-1182
                July 21 2018
                Article
                10.1007/s12035-018-1237-z
                30032423
                2046562f-f822-48a9-a195-b0e419b6232a
                © 2018

                http://www.springer.com/tdm

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