Synergistic Associations of Genetic, Demographic, Health, and Lifestyle Risk Factors on Neurocognitive Performance and Change in Aging

• Author / Creator

  Sapkota, Shraddha

• Objective: Neurocognitive phenotypes observed in aging have been linked to select combinations of candidate genetic polymorphisms and modifiable risk factors. In this dissertation, I test multiple methods and approaches to examine three modifiable risk domains (i.e., demographic, health, lifestyle) and six single nucleotide polymorphisms (SNPs) (i.e., Apolipoprotein E [APOE] Catechol-O-methyltransferase [COMT; rs4680], Brain-derived neurotrophic factor [BDNF; rs6265], Complement receptor 1 [CR1; rs6656401], Clusterin [CLU; rs11136000], and Phosphatidylinositol-binding clathrin assembly protein [PICALM; rs3851179]) on concurrent and longitudinal neurocognitive performance in non-demented aging and Mild Cognitive Impairment (MCI). This dissertation includes three studies. Study 1 tested SNPs, demographic, health, and lifestyle risk factors to build, compare, and validate a multi-domain risk score to predict episodic memory (EM) performance and 9-year change. Study 2 tested independent, interactive, and additive associations of two normal aging SNPs (COMT, BDNF), and as stratified by AD-related SNP (APOE) on EF performance in normal aging. Study 3 examined independent and additive associations of (a) COMT, BDNF, and APOE, (b) COMT and BDNF as separated by APOE risk, and (c) as moderated by age and lifestyle activities groups on EF performance and 9-year change. Method: This dissertation uses data from normal aging older adults and adults classified as MCI from the Victoria Longitudinal Study (VLS): Study 1 (normal aging: n = 568, mean age at baseline = 68.32 years; MCI: n = 69, mean age at baseline = 73.36 years), Study 2 and Study 3 (normal aging: n = 634, mean age = 70.58 years). Study 1 was longitudinal, Study 2 was cross-sectional, and Study 3 followed an accelerated longitudinal design. I used appropriate combinations of confirmatory factor analysis, longitudinal invariance testing, parallel process latent growth models, and receiver operating characteristic curves to test research questions in all three studies. Results: In Study 1, first, I observed that higher risk scores on demographic, health, and lifestyle risk factors predicted worse EM performance at age 75 years and steeper 9-year decline. Second, higher risk scores on independent and additive risk for demographic, health, lifestyle, and genetic factors predicted worse EM performance at baseline and time point 3. Third, independent risk score for demographic and health risk domains distinguished non-demented older adults from those with MCI. In Study 2, I observed that older adults with a high-risk allelic (COMT allelic risk + BDNF allelic risk) combination performed differentially worse on EF compared to their non-risk counterparts (COMT no allelic risk + BDNF no allelic risk). In Study 3, I observed that APOE risk carriers showed a magnified COMT + BDNF risk panel effect on EF performance at age 75 years but this effect was not present in the high lifestyle activities group. Discussion: I used methods and approaches to building a pre-clinical risk score with multiple domains (genetic, demographic, health, and lifestyle risk factors) that were selected to detect cognitive decline in normal aging at a point prior to dementia onset. In addition, select additive versus interactive mechanisms for cognitive aging genes may provide insight into the complex underlying mechanisms and pathways that influence neurocognitive performance in non-demented older adults. Future studies can investigate and address the applicability of our synergistic methods using select risk factors to develop theoretical concepts and identify genetic and modifiable risk factors to inform dementia prevention strategies. Such approaches also have the potential to help identify complex neurobiological and neurogenetic underpinnings of polygenic phenotypes observed in normal aging.

• Subjects / Keywords

  • Aging
  • Neurocognitive Performance
  • Genetic Polymorphisms

• Graduation date

  Spring 2016

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/R3WW7774H

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.