P1-272: Association of a Functional Variant (I89V) in the High Affinity Choline Transporter with Alzheimer’s Disease

The rate–limiting step in the biosynthesis of acetylcholine (ACh) is the uptake of extracellular choline by the high affinity choline transporter gene (ChT–1). Recently a single nucleotide polymorphism (I89V) was identified in a population of Ashkenazi Jews (JBC 277:45315, 2002). Assessment of high affinity choline uptake in I89V ChT–1 expressing mammalian cells resulted in a significant decrease (40–50%) in high affinity choline uptake. The decrease in high affinity choline uptake by I89V ChT–1 was due to a decrease in the velocity of uptake since there was no apparent change in the affinity for choline, sodium, chloride, or hemicholinium–3. Since the neurotransmitter ACh is critical for processing of salient information related to normal memory formation, and high affinity choline uptake is the rate limiting step in ACh biosynthesis, we investigated the allele frequency of the I89V polymorphism in a cohort of AD cases and age–matched controls. A total of 42 patients with AD and 49 nondemented control subjects were included from a Munich AD center in Germany. Genotyping for ChT–1 (I89V) alleles was performed by PCR–based amplification followed by restrictive endonuclease digestion. Statistical analyses were conducted by gender and age group–stratified Mantel–Haenszel odds ratios, CI, and p values. The overall allele frequency of I89V in the population samples was 12%. The frequency of the I89V allele in AD samples was three–fold (18%) versus that which was observed in the control subjects (6%) resulting in a significant association (p=0.02, Chi–Square Association test) of I89V with AD. Although further association studies are needed, these preliminary results suggest that a functional single nucleotide polymorphism in ChT–1 may be associated with late–onset AD.