McFall, G. P. | Search bioRxiv

bioRxiv2019

Mitonuclear interactions influence Alzheimer’s disease risk

We examined the associations between mitochondrial DNA haplogroups (MT-hg) and their interactions with a polygenic risk score based on nuclear-encoded mitochondrial genes (nMT-PRS) with risk of dementia and age of onset of dementia (AOO). Logistic regression was used to determine the effect of MT-hgs and nMT-PRS on dementia at baseline (332 controls / 204 cases). Cox proportional hazards models were used to model dementia AOO (n=1047; 433 incident cases). Additionally, we tested for interactions between MT-hg and nMT-PRS in the logistic and Cox models. MT-hg K and a one SD larger nMT-PRS were associated with elevated odds of dementia. Significant antagonistic interactions between the nMT-PRS and MT-hg K and T were observed. Individual MT-hg were not associated with AOO; however, a significant antagonistic interactions was observed between the nMT-PRS and MT-hg T and a synergistic interaction between the nMT-PRS and MT-hg V. These results suggest that MT-hgs influence dementia risk, and that variants in the nuclear and mitochondrial genome interact to influence the age of onset of dementia.\n\nHighlightsO_LIMitochondrial dysfunction has been proposed to influence dementia risk\nC_LIO_LIMT-hg K and T interacted with a genetic risk score to reduce dementia risk\nC_LIO_LIMT-hg T and V interacted with a genetic risk score to influence dementia age of onset\nC_LI

genetics↗

bioRxiv2018

Alzheimer’s environmental and genetic risk scores are differentially associated with ‘g’ and δ

IntroductionWe investigated the association of the Australian National University Alzheimers Disease Risk Index (ANU-ADRI) and an AD genetic risk score (GRS) with cognitive performance.\n\nMethodsThe ANU-ADRI (composed of 11 risk factors for AD) and GRS (composed of 25 AD risk loci) were computed in 1,061 community-dwelling older adults. Participants were assessed on 11 cognitive tests and activities of daily living. Structural equation modelling was used to evaluate the association of the ANU-ADRI and GRS with: 1) general cognitive ability (g) 2) dementia related variance in cognitive performance ({delta}) and 3) verbal ability, episodic memory, executive function and processing speed.\n\nResultsA worse ANU-ADRI score was associated with poorer performance in g, {delta}, and each cognitive domain. A worse GRS was associated with poorer performance in {delta} and episodic memory.\n\nDiscussionThe ANU-ADRI was broadly associated with worse cognitive performance, validating its further use in early dementia risk assessment.\n\nHighlightsO_LIAn environmental/lifestyle dementia risk index is broadly associated with cognitive performance\nC_LIO_LIAn Alzheimers genetic risk score is associated with dementia severity and episodic memory\nC_LIO_LIThe environmental risk index is more strongly associated with dementia severity than genetic risk\nC_LI\n\nResearch in ContextO_ST_ABSSystematic ReviewC_ST_ABSThe authors reviewed the literature using online databases (e.g. PubMed). Previous research has highlighted the need for dementia risk assessment tools to be evaluated on outcomes prior to dementia onset, such as cognitive performance. The relevant citations have been appropriately cited.\n\nInterpretationThe Australian National University Alzheimers Disease Risk Index (ANU-ADRI) was more broadly associated with cognitive performance than Alzheimers genetic risk. For the ANU-ADRI, stronger effects were observed for dementia-related variance in cognitive task performance that for variance in general cognitive function. This suggests that ANU-ADRI is more specifically associated with dementia-related processes and further validates its use in early risk assessment for dementia.\n\nFuture DirectionsAccordingly, future studies should seek to evaluate the association of the ANU-ADRI and genetic risk with AD biomarkers and longitudinal cognitive performance to evaluate differential trajectories in g and {delta}.

genetics↗