13 March 2013. In the first genomewide association study (GWAS) based on amyloid imaging, researchers have uncovered single nucleotide polymorphisms near the genes encoding butyrylcholinesterase (BChE) and ApoE, the strongest genetic risk factor for sporadic AD. The two loci account for 15 percent of the genetic risk for amyloid deposition. “For a genetics study, that’s a pretty powerful effect,” said Andrew Saykin, Indiana University School of Medicine, senior author on the paper, which was published online February 19 in Molecular Psychiatry. The results reveal clues about the genetics behind plaques specifically, and may point to future therapeutic targets, Saykin told Alzforum.
Since amyloid imaging became available, scientists have wanted to use it in GWAS, but they were hampered by limited tracer availability, which restricted sample sizes. Widespread use of florbetapir has made it possible to recruit enough people for this type of study, said Saykin. First author Vijay Ramanan and colleagues gathered scans and genomic DNA from 555 participants in the multisite Alzheimer’s Disease Neuroimaging Initiative (ADNI) GO and ADNI 2 cohorts. They checked for genetic variants that predicted a higher florbetapir binding in the brain.
Unsurprisingly, florbetapir uptake strongly correlated with ApoE4, which accounted for 10.7 percent of the variation in cortical amyloid deposition. An unexpected association, accounting for 4.3 percent of the variance, appeared about 450 kilobases upstream of the BChE gene in a region previously associated with variation in serum BChE enzyme activity (see Benyamin et al., 2011).
BChE regulates synapse acetylcholine levels in the brain. Previous studies have linked the enzyme to dementia in various ways: A particular genetic variant of the esterase (the K variant) increases risk for AD (see Lehmann et al., 1997); the enzyme is enriched in postmortem AD plaques (see Darvesh et al., 2003) and may facilitate their formation (see Guillozet et al., 1997); and the esterase was found in tangles (see Carson et al., 1991). However, the GWAS finding suggests a stronger association with an AD-related phenotype than any other study has so far.
“For 20 years now, it’s been known that plaques and tangles can be chock full of butyrylcholinesterase—it’s one of the only substances present in both pathologies,” said Marsel Mesulam, Northwestern University Feinberg School of Medicine, Chicago, Illinois. While research on the enzyme never completely evaporated, the field’s overall interest waned because no one could figure out what it did, he told Alzforum. “Suddenly, this GWAS has brought it back to center stage.”
Since this study links a variant of BChE specifically to cerebral amyloid, “it begs the question, What are they detecting that you wouldn’t in a very large AD GWAS?” said Lindsay Farrer, Boston University, Massachusetts. He suggested amyloid burden may produce a better signal-to-noise ratio.
With a sample size of 500 people, “this demonstrates that if the quantitative phenotype is strong, one can detect associations in a study that would be considered modestly sized for a GWAS,” said Saykin. In fact, the study revealed trends for association in other genes as well. If the sample was larger, those few loci that hinted at a plaque association might reach full significance, wrote the authors. Those variants turned up in proinflammatory microglial genes, and in genes that may disrupt insulin signaling in the AD brain. ADNI scientists have conducted florbetapir scanning on many more participants, and will soon sequence their genomes. By the end of this year, the sample size will have doubled, said Saykin. The researchers will then reanalyze the plaque association. They also want to know if rivastigmine, a BChE inhibitor, has differential effects on people carrying the BChE SNPs compared to those who do not.
It would also be interesting to look at the association between BChE genotype and cognition, said Taher Darreh-Shori, Karolinska Institutet, Stockholm, Sweden. He believes BChE is key to AD development. “That would give us more information about what happens even before deposition,” he told Alzforum.
In the meantime, researchers with the Alzheimer’s Disease Genetics Consortium are probing neuropathologic and GWAS data from several thousand deceased to find links between genes and amyloid deposition. “That will be one way to see if this finding holds up,” said Farrer.
"This article is timely," wrote Nigel Greig, National Institute on Aging, Bethesda, Maryland, to Alzforum in an e-mail, as a few more BChE-related developments are underway. Based on preclinical studies that show cognitive- and disease-modifying benefits of blocking BChE in animal models (see Greig et al., 2005, and Furukawa-Hibi et al., 2011), the NIA began a Phase 1 trial of a selective BChE inhibitor (bisnorcymserine) last November, with a view to testing it in AD. In addition, Sultan Darvesh, Dalhousie University, Halifax, Nova Scotia, plans to image BChE-binding ligands to determine if BChE-positive plaques could be used as a diagnostic indicator (see Darvesh, 2012).—Gwyneth Dickey Zakaib.
Ramanan VK, Risacher SL, Nho K, Kim S, Swaminathan S, Shen L, Foroud TM, Hakonarson H, Huentelman MJ, Aisen PS, Petersen RC, Green RC, Jack CR, Koeppe RA, Jagust WJ, Weiner MW, Saykin AJ. APOE and BCHE as modulators of cerebral amyloid deposition: a florbetapir PET genomewide association study. Mol Psychiatry. 2013 Feb 19. Abstract