GWAS studies have provided evidence that in addition to apolipoprotein E (ApoE) gene, CLU and PICALM polymorphisms are associated with risk of Alzheimer’s disease (AD) (Harold et al., 2009; Lambert et al., 2009; Golenkina et al., 2010). Cerebrovascular dysfunction may precede cognitive decline in AD. EEG reactivity to hyperventilation (HV), which depends on hypocapnia-induced cerebral vasoconstriction, is significantly reduced in elderly carriers of AD risk variant ApoE ε4 because of the alterations of neuronal and cerebral reactivity to hypocapnia (Ponomareva et al., 2012). This study was aimed at determining whether the changes of EEG reactivity to HV in normal aging depend on CLU and PICALM polymorphisms. We examined EEG in resting and under HV in 102 healthy volunteers (age range 28-75 years), stratified by CLU (rs11136000) and PICALM (rs3851179) genotypes. The effectiveness of HV was verified by measuring the end-tidal CO2. The effect of ApoE genotype on EEG was controlled. Informed written consent was obtained from all participants. The experimental protocol of this study was approved by the local Ethics Committee. The presence of AD risk variant CLU CC was associated with the reduction of EEG reactivity to HV during aging. In the CLU CC carriers EEG reactivity to HV decreased with age, while in the CLU CT&TT carriers the changes in EEG reactivity were smaller. The relative theta power under HV showed a negative correlation with age in CLU CC but not in CLU CT&TT subjects. The older CLU CC carriers under HV had lower delta and higher alpha relative powers as compared to the older CLU CT&TT carriers. Similar alterations were associated with PICALM polymorphism. In the elderly carriers of AD risk variant PICALM GG, HV-induced changes of EEG were reduced as compared to the noncarriers. The effect of PICALM on EEG was not attributable to the interaction with CLU or APOE genotypes. Our observations suggest altered neuronal and cerebrovascular reactivity to hypocapnia in the elderly carriers of CLU and PICALM AD risk variants. In the CLU CC, as well as in the ApoE ε4 carriers, the EEG alterations may be due to the endothelial dysfunction as a consequence of cerebral amyloid angiopathy and atherosclerosis (Miwa et al., 2005). PICALM is involved in clathrin-mediated endocytosis and regulation of Aβ generation (Xiao et al., 2012). PICALM is predominately present in endothelial cells and may participate in Aβ transport across blood-brain barrier (Baig et al., 2011). These processes may be related to the abnormal cerebrovascular regulation in the older carriers of PICALM risk variant for AD. Impaired cerebrovascular reactivity may irreversibly damage the vulnerable areas of the brains through long-term hypoxemia. The results suggest the involvement of vascular factors in AD pathogenesis.