Abstract
Polymorphisms in the apolipoprotein E (APOE) gene have been associated with individual differences in cognition, brain structure and brain function. For example, the ε4 allele has been associated with cognitive and brain impairment in old age and increased risk of dementia, while the ε2 allele has been claimed to be neuroprotective. According to the ‘antagonistic pleiotropy’ hypothesis, these polymorphisms have different effects across the lifespan, with ε4, for example, postulated to confer benefits on cognitive and brain functions earlier in life. In this stage 2 of the Registered Report – https://osf.io/bufc4, we report the results from the cognitive and brain measures in the Cambridge Centre for Ageing and Neuroscience cohort (www.cam-can.org). We investigated the antagonistic pleiotropy hypothesis by testing for allele-by-age interactions in approximately 600 people across the adult lifespan (18–88 years), on six outcome variables related to cognition, brain structure and brain function (namely, fluid intelligence, verbal memory, hippocampal grey-matter volume, mean diffusion within white matter and resting-state connectivity measured by both functional magnetic resonance imaging and magnetoencephalography). We found no evidence to support the antagonistic pleiotropy hypothesis. Indeed, Bayes factors supported the null hypothesis in all cases, except for the (linear) interaction between age and possession of the ε4 allele on fluid intelligence, for which the evidence for faster decline in older ages was ambiguous. Overall, these pre-registered analyses question the antagonistic pleiotropy of APOE polymorphisms, at least in healthy adults.
Highlights
Apolipoprotein E (APOE) is a protein that plays an important role in lipid metabolism and has been implicated in synaptogenesis, repair of injured nerve tissue and the modulation of beta-amyloid plaques and neurofibrillary tangles that characterise Alzheimer’s disease (AD)
None of the Cambridge Centre for Ageing and Neuroscience (CamCAN) participants had a diagnosis of dementia or mild-cognitive impairment at recruitment; all reported themselves to be in good cognitive health, and all scored above conventional cut-offs for dementia on the mini-mental state examination (MMSE) and Addenbrooke’s cognitive examination – revised (ACE-R) screening tests
For resting-state functional MRI (fMRI) connectivity, we focused on (5) mean connectivity within the default mode network (DMN), following the optimised pre-processing pipeline described in Geerligs et al (2017)
Summary
Apolipoprotein E (APOE) is a protein that plays an important role in lipid metabolism (including cholesterols) and has been implicated in synaptogenesis, repair of injured nerve tissue and the modulation of beta-amyloid plaques and neurofibrillary tangles that characterise Alzheimer’s disease (AD) (for review, see Belloy et al, 2019; Rocchi et al, 2003).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
