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Tau abnormal hyperphosphorylation and the formation of neurofibrillary tangles in the Alzheimer's disease (AD) brain is the result of upregulation of tau kinases. In a group of 729 Spanish late-onset AD patients and 670 healthy controls, we examined variations into a set of 20 candidate genes of kinases involved in tau phosphorylation at AD-related sites (PRKACB; CAMK2A; MARK1, 2, 3 and 4; CSNK1D; CDC2; RPS6KB1 and 2; p38α and β; IB1; JNK1, 2 and 3; MEK1 and 2; ERK1 and 2), to address hypotheses of genetic variation that might influence both AD risk and age at disease onset. There was an increased frequency of RPS6KB2 (intron 2, rs917570) minor allele in patients (50%) versus controls (39%) (OR = 1.52; 95% CI 1.30-1.77; p = 1.24 × 10-5 Bonferroni corrected), and the presence of this minor allele was significantly (p = 4.2 × 10-5) associated with a 3-years later onset of AD (mean age 74.1 years) when compared to age at onset of non-minor allele carriers (mean age 71.1 years). In APOE non-ε4 allele carriers, the combined effect of AD-associated risk alleles from the genes of CDC2, RPS6KB1 and 2, p38α, JNK (1, 2 and 3), MEK2, and ERK2 was significantly (p = 0.002) associated with a late-onset (&gt;76 years) of AD. The CDC2 AGC haplotype derived from SNPs in introns 3 (rs2448347), 5 (rs2456772), and 7 (rs1871447) showed a protective effect against AD in APOE non-ε4 allele carriers (permutation p = 1.0 × 10-4) with a frequency of 9% in cases and 15% in controls. Common genetic variation in the tau kinases pathway does underlie individual differences not only in susceptibility to AD but also in disease phenotype (age at disease onset).

Genetic Variation in the Tau Kinases Pathway May Modify the Risk and Age at Onset of Alzheimer's Disease