Candidate gene association studies of genes involved in neuronal cholinergic transmission in Alzheimer's disease suggests choline acetyltransferase as a candidate deserving further study

Consistent deficits in the cholinergic system are evident in the brains of Alzheimer's Disease (AD) patients, including reductions in the activities of acetylcholine, acetylcholinesterase (AChE), and choline acetyltransferase (ChAT), increased butyrylcholinesterase (BChE) activity, and a selective loss of nicotinic acetylcholine receptors (nAChRs). Accordingly, we have analyzed polymorphisms in the genes encoding AChE, ChAT, BChE, and several of the subunit genes from neuronal nAChRs, for genetic associations with late-onset AD. A significant association for disease was detected for a non-coding polymorphism in ChAT (allele χ₁ ² = 12.84, P = 0.0003; genotype χ₂ ² = 11.89, P = 0.0026). Although replication analysis did not confirm the significance of this finding when the replication samples were considered alone (allele χ₁ ² = 1.02, P=0.32; genotype χ₂ ² = 1.101, P = 0.58) the trends were in the correct direction and a significant association remained when the two sample sets were pooled (allele χ₁ ² = 12.37, P = 0.0004; genotype χ₂ ² = 11.61, P = 0.003). Previous studies have reported significant disease associations for both the K-variant of BChE and the coding ChAT rs3810950 polymorphism with AD. Replication analyses of these two loci failed to detect any significant association for disease in our case-control samples.