Arterial aging mediates the effect of TNF-α and ACE polymorphisms on mental health in elderly individuals: insights from IKARIA study

QJM. 2017 Sep 1;110(9):551-557. doi: 10.1093/qjmed/hcx074.


Background: Aging is characterized by an insidious decline in cognitive function. Several genetic and lifestyle factors have been implicated in the increased risk or early onset of dementia.

Aim: We sought to assess the role of tumor necrosis factor (TNF) and angiotensin-converting enzyme (ACE) polymorphisms on the development of impaired mental health in respect to indices of arterial aging in nonagenarian individuals.

Design: 178 consecutive subjects above 75 years that permanently inhabit in the island of IKARIA, Greece were recruited.

Methods: Aortic distensibility (AoD) was calculated and genetic evaluation was performed on the ACE Insertion/Deletion gene polymorphism (intron 16) and the G/A transition (position -308) of the TNF gene. Cognitive function was evaluated using the Mini-mental State Examination (MMSE).

Results: The DD genotype for ACE was independently associated ( b = -0.44, P = 0.007) with AD while AoD remained an independent determinant of mental status (OR = 1.82, P = 0.036). Interestingly though, when a combined genetic index (GI) was calculated for both genes (ACE and TNF), subjects being double homozygous (DD for ACE and GG for TNF) for these loci presented significantly decreased MMSE (adjusted OR = 0.259, P = 0.033). This GI independently associated with AD (beta coefficient = -0.785, P = 0.002). When AoD was included, GI lost its predictive role (OR = 0.784, P = 0.783) towards MMSE. AoD has marginal indirect mediating effect in the association of the GI with MMSE ( P = 0.07).

Conclusion: Vascular aging may modulates the genetic substrate of elderly subjects on the risk for developing dementia.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease* / diagnosis
  • Alzheimer Disease* / epidemiology
  • Alzheimer Disease* / genetics
  • Aorta* / diagnostic imaging
  • Aorta* / pathology
  • Cellular Senescence / physiology
  • Cognition / physiology
  • Echocardiography / methods
  • Endothelium, Vascular / pathology
  • Female
  • Gene Frequency
  • Greece / epidemiology
  • Humans
  • Life Style
  • Male
  • Mental Status and Dementia Tests
  • Peptidyl-Dipeptidase A / genetics*
  • Polymorphism, Genetic
  • Risk Factors
  • Tumor Necrosis Factor-alpha / genetics


  • Tumor Necrosis Factor-alpha
  • ACE protein, human
  • Peptidyl-Dipeptidase A