The role of genetic factors in modulating ageing-related cognitive change

Alzheimer’s disease (AD) is the major form of dementia. Previous genome wide association studies (GWAS) have indicated that 21 genetic variants contribute to polygenic risk associated with AD as well as Apolipoprotein E (APOE) and brainderived neurotrophic factor (BDNF). Ageing is the major risk factor for AD; however, the relationship between AD-related polygenic risk scores (ADPRS) – computed by AD-related genes identified by GWAS, APOE, BDNF and cognitive changes during brain ageing is unclear. APOE, the strongest genetic factor of AD risk, and BDNF, a gene encoding a multifunction growth factor, are two of the most widely studied genes in relation to cognitive function, but their interactive association with longitudinal change in cognitive function is less studied. We used data from the Tasmanian Healthy Brain Project (TBHP) - an ongoing longitudinal prospective study of healthy older adults who underwent periodic assessment of neuropsychological status and health. This thesis investigated whether APOE and BDNF polymorphisms independently or interactively influence changes in cognitive function (episodic memory, working memory, executive function, language processing) over 36 months in healthy older adults. This thesis also determined the relationship between polygenic risk scores for Alzheimer’s disease with ageing-related changes in cognitive function as well as whether the polygenic risk scores for Alzheimer’s disease are associated with the trajectory of cognitive function in older adults. Five major results were identified by statistical analyses based on linear mixed-effects models (Chapter 2 APOE and BDNF analyses based on 36-month data; Chapters 3-4 ADPRS analyses based on 60-month data). First, in older adults, APOE ε4 was positively associated with episodic memory changes over 36 months. Second, APOE ε4 moderated the effect of BDNF on changes in language processing over 36 months. Third, over 60 months, there was a positive association between the ADPRS (excluding APOE and BDNF) and changes in working memory/executive function, particularly in APOE ε4+ carriers. Similarly, BDNF Met allele may moderate the effect of ADPRS on changes in executive function. Then, two to three distinct groups, including at least 10% of individuals with different trajectory shapes, were identified for four major cognitive domains by using Group-based trajectory modelling. The ADPRS was not associated with the distinctive ageing-related trajectories of cognitive function. These results strongly support that APOE, BDNF, polygenic risk and gene-gene interactions play an important role in ageing-related changes in cognitive function.