Calcium homeostasis is critical to amyloid beta precursor protein (APP) processing. Na(+)/Ca(2+) exchanger (NCX) proteins play an important role in maintaining intracellular Na(+) and Ca(2+) homeostasis in the brain under physiological and pathological conditions. We sequenced a hyper-variable region in intron 2 of the Na(+)/Ca(2+) exchanger 1 gene (NCX1), and investigated whether insertion/deletion variations in this region are associated with the occurrence for Alzheimer's disease (AD). Examining 413 AD patients and 361 healthy controls, we identified 3 insertion/deletion polymorphisms. No significant differences of the allele and genotype frequencies were observed between the AD cases and the controls for any of the three polymorphisms. However, among the AD patients whose age at onset (AAO) was 65 years or older (n = 299), carriers of a 14 bp insertion showed a lower average AAO (ins/ins and ins/del vs. del/del, 72.49 ± 5.17 vs. 74.28 ± 5.79, p = 0.016). It suggested that this 14 bp insertion/deletion polymorphism might modulate AAO in late-onset AD patients.