Dysfunction of the serotonergic pathway disrupts normal cognitive functioning and is believed to be the underlying basis for a variety of psychiatric disorders. Two functional polymorphisms within the serotonin transporter (SLC6A4) gene (promoter 44 bp insertion/deletion (HTTLPR) and an intron two 16 or 17 bp variable number tandem repeat (VNTR2)) have been extensively studied in psychiatric conditions but not in the cognitive functioning of normal individuals. We have investigated these two polymorphisms for association with both the level of cognitive abilities and their decline with age using a cohort consisting of over 750 elderly nondemented individuals with a follow-up of up to 15 years. We found that volunteers homozygous for the VNTR2 12 allele had a faster rate of decline for all cognitive tests. This reached significance for both tests of fluid intelligence (novel problem solving) (AH1 P ¼ 0.002, AH2 P ¼ 0.014), the test of semantic memory (P ¼ 0.010) and general cognitive ability (P ¼ 0.006). No association was observed between the HTTLPR polymorphism and the rate of cognitive decline when analysed either independently or in combination with the VNTR2 polymorphism based on their influence on expression in vitro. No associations were observed between the two polymorphisms and the baseline level of cognitive abilities. This is only the second gene that has been reported to regulate the rate of cognitive decline in nondemented individuals and may be a target for the treatment of cognitive impairment in the elderly. Keywords: serotonin transporter; polymorphism; cognition; memory; genes; associationIn an increasingly long-lived population severe cognitive impairment, caused by either the normal ageing process or dementia, is an escalating problem that currently has no effective treatment. Cognitive ability and its rate of decline are highly heritable and both have been shown to predict dementia onset. [1][2][3][4] Of the 13 quantitative trait loci (QTL) currently associated with the level of cognitive ability in normal individuals the most widely reported are located in genes involved in synaptic transmission. 5 These comprise the adrenergic receptor 2A, catechol-O-methyltransferase, dopamine receptor D2, cholinergic muscarinic 2 receptor, brain-derived neurotrophic factor, metabotrophic glutamate receptor 3 and the serotonin receptor 2A. [6][7][8][9][10][11][12][13] To date only the apolipoprotein E e4 allele has been associated with cognitive decline in nondemented individuals and this finding has been challenged. [14][15][16][17][18][19] Serotonin has been shown to play a role in brain development and cognitive functioning. 20,21 There is also a decrease in total brain serotonin with age that may predispose the elderly to depression, dementia and cognitive dysfunction. 22 Despite the importance of serotonin as a modulator of memory and learning the influence of two functional polymorphisms (HTTLPR and VNTR2) in the SLC6A4 gene, which codes for a protein responsible for the reuptake of serotonin, have n...