Analysis of chromosome 12 candidate genes in late-onset Alzheimer disease

Three Alzheimer disease (AD) causing genes: amyloid precursor protein, pres enilin 1, and presenilin 2; and one susceptibility gene, apolipoprotein E, have been identified. Jointly these genes account for approximately 50% of the total genetic effect on AD risk, leaving 50% of the genetic effect unex plained. Studies indicate that one of the most promising locations for a fi fth AD gene is the centromeric region of chromosome 12. This chromosomal re gion contains several genes that are potential candidates for the chromosom e 1 2 AD gene. The Pedigree Disequilibrium Test (PDT) was used to test for allelic association and linkage between AD and nine chromosome 12 candidate genes in a series of multiplex (2 2 AD individuals/family) AD families as diagnosed by NINCDS-ADRDA criteria. The genes examined were the neurotrophi n-3 (NTF3); tumor necrosis factor receptor 1 (TNFR1); human complement comp onent (C1R); oxidized low-density lipoprotein receptor (OLR1); islet amyloi d polypeptide (IAPP); Kirsten rat sarcoma 2 viral oncogene (KRAS2); mitocho ndrial ATP synthase, beta subunit (ATP5B); human brain sodium channel 2 (hB NaC2); and interleukin-4 Stat (IL-4 Stat). These genes are located in an ap proximately 65 cM region spanning 12p 13 to 12q13. PDT p-values were not st atistically significant for any of the candidate genes tested, ranging from 0.23 (IAPP) to 0.94 (KRAS2). These data provide no evidence that any of th e candidate genes examined here is the sought after chromosome 12 AD suscep tibility gene.