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Background: Alzheimer’s Disease (AD) is the most common form of dementia and one of the major diseases of old age, causing the impairment of cognitive functions. This disease does not only confront society with financial issues, but also puts severe stress on individuals suffering from AD and their relatives alike. One of the possible symptoms, commonly described in AD, is the impairment of learning as well as the recognition of face-name associations. Beginning at age 60, the chance to develop AD grows exponentially with increasing age, making age a major risk factor. Additionally, the e4 allele of the apolipoprotein E (APOE) polymorphism has been associated with the risk of developing AD when compared to the more common e3 allele. While strong evidence shows a stronger decline in cognitive function with rising age for e4 carriers, some studies demonstrated better cognitive function in e4 carriers at a young age.
This led to the postulation of the hypothesis of antagonistic pleiotropy of the APOE gene, wherein the e4 allele may benefit cognitive function in young carriers, yet leads to a faster decline at a later point in life, encouraging the development of cognitive dysfunction such as AD. Several functional magnetic resonance imaging (fMRI) studies, examining functional activation patterns, found APOE-related differences in key areas of episodic memory, such as the hippocampus, where e4 carriers show aberrant activation similar to AD patients. However, associative memory (encoding and retrieval of face name pairs) has not been well examined for APOE-related differences. Interaction effects of age and the APOE genotype, such as those postulated by the hypothesis of antagonistic pleiotropy, have not been addressed in face-name association tasks either.
Leading Question: Is it possible to detect interaction effects between age and APOE genotype on cognitive performance or neuronal activation patterns in healthy young and old participants during an fMRI face-name association task, supporting the hypothesis of antagonistic pleiotropy of the APOE genotype?
Methods: Participants were stratied by age, and APOE e4 carriers were randomly matched with homozygous e3 carriers. Neuropsychological examination (CVLT and CERAD) was administered. Participants underwent structural MRI analysis via voxelbased morphometry (VBM) as well as fMRI imaging during a face-name association task.
Results: Apart from strong age-related effects in cognitive function detected during neuropsychological testing, the behavioral data from the face-name association task as well as the structural MRI analysis did not show an association with the APOE genotype. Nevertheless, analysis of functional MRI data showed age- as well as APOE-dependent effects on activation patterns for the encoding and retrieval of face-name pairs, in absence of differences in cognitive performance. Further analysis showed eight clusters of significant age X APOE genotype interactions in areas previously associated with working and visual associative memory, including the fusiform gyri bilaterally. These interactions show different patterns, whereas a relative hypoactivation of young e4 carriers together with a hyperactivation of old e4 carriers is the most prominent.
Conclusions: With regard to the leading question, this study successfully found age X APOE interactions in a face-name pair retrieval task, although no interaction effects were present in the encoding task, structural analysis, or cognitive performance. The agemediated effect of the APOE e4 allele on functional activation patterns may be explained by the compensatory hypothesis, describing a relative hyperactivation of old e4 carriers as compensatory, and interpreting a relative hypoactivation of younger e4 participants as reduced effort to achieve the same cognitive performance as non carriers.
These findings present further evidence of an antagonistic pleiotropy of the APOE genotype, showing age-dependent effects of the e4 allele even in healthy carriers. Nevertheless, previously described differences in cognitive performance and brain structure, even in young participants, were not found. On the contrary, functional MRI analysis showed APOE-related differences in young and old participants, suggesting that this modality may be more sensitive in detecting APOE-mediated changes. Among the clusters, demonstrating an interaction effect, the fusiform gyri were most prominent, which might be due to its important role in visual associative memory. As previous studies indicate an early and strong involvement of this area due to AD pathology, this interaction effect of age and APOE genotype in healthy participants underlines the importance of this region in the development of AD, and should be the focus of further research. However, this research is also required to determine, how exactly the APOE genotype influences brain function in healthy humans, and to clarify its relationship to pathological processes facilitating the development of AD.