| Summary: | Hypotension can affect cerebral perfusion and worsen cognitive outcomes. The prevalence of low blood pressure (BP) rises with increasing age. To our knowledge, no study has examined the genetic biomarkers for hypotension-related cognitive impairment (CI) yet. Utilizing the population-based genome-wide study of the Taiwan Biobank containing the data of 2533 healthy aging subjects, we found after adjustments for age, sex, education years, and principal components at a suggestive level of 1 × 10<sup>−5</sup> that minor alleles of <i>leucine rich repeat transmembrane neuronal 4 (LRRTM4)</i> (rs13388459, rs1075716, rs62171995, rs17406146, rs2077823, and rs62170897), <i>proprotein convertase subtilisin/kexin type 5</i> (<i>PCSK5)</i> (rs10521467), and the intergenic variation rs117129097 (the nearby gene: <i>TMEM132C</i>) are risk factors for CI in hypotensive subjects. Except for rs117129097, these single nucleotide polymorphisms (SNPs) were not markers per se for CI or for BP regulation. However, we found a suggestive interaction effect between each of the eight SNPs and hypotension on CI risk. In the hypotensive participants, those carrying minor alleles were associated with a higher incidence of CI in an additive manner than were those carrying major alleles (2 × 10<sup>−4</sup> to 9 × 10<sup>−7</sup>). Intensive BP lowering in elderly patients carrying a minor allele of the eight identified SNPs should raise cautions to prevent a potential treatment-induced neurodegeneration.
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