Literature internship: Molecular mechanisms of reserve in Alzheimer’s Disease.
Research on external factors that reduce the likelihood to develop AD have received more and more attention. A higher education and more social and physical activities are associated with a later onset of the disease (Stern, 2012; Perneczky et al., 2019; Zhu et al., 2019). Observations from several longitudinal aging cohorts have indicated a disjunction between degree of AD pathology and its clinical manifestations. During post-mortem neuropathological assessments, individuals characterized as cognitively normal were found to have advanced AD pathology (Price & Morris, 1999; Neuropathology, 2001; Riley et al., 2002). These findings led to the hypothesis that some individuals might have reserve that allows them to cope with neuropathology and therefore remain cognitively intact. It has been hypothesized that certain individuals are generally subjected to a similar progression of AD pathology while lifelong experiences like education or social contacts allow them to cope better with disease-related changes. How the brain acquires a reserve during the lifespan of an individual is not well understood.
The current evidence for reserve in AD has mainly come from clinical epidemiological studies. In these studies, the status of the brain, like the amount of pathology, cognitive outcomes and a measure of reserve, like a proxy or a functional brain measure, is used to demonstrate that the proposed proxy influences the relationship between neuropathology and cognitive status (Stern et al., 2018). However, considerable heterogeneity has been found in studies focusing on putative brain substrates of reserve (Ewers, 2020). Moreover, such an approach does not imply any mechanistic link, imposing a black box on the exact underlying mechanisms. In order to find the mechanism behind reserve, we have to study the brain tissue itself.
In this specific literature thesis, a few molecular mechanisms and/or pathways which could potentially explain the molecular mechanisms of reserve will be further explored. Also, different methods on how to study molecular mechanisms of reserve and how to translate findings from animal models to humans will be explored.
For more information, please contact Luuk de Vries
- Neuropathology, G. (2001). Pathological correlates of late-onset dementia in a multicentre, community-based population in England and Wales. Neuropathology Group of the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS). Lancet (London, England), 357(9251), 169.
- Perneczky, R., Kempermann, G., Korczyn, A. D., Matthews, F. E., Ikram, M. A., Scarmeas, N., . . . Ewers, M. (2019). Translational research on reserve against neurodegenerative disease: consensus report of the International Conference on Cognitive Reserve in the Dementias and the Alzheimer’s Association Reserve, Resilience and Protective Factors Professional Interest Area working groups. BMC medicine, 17(1), 47.
- Price, J. L., & Morris, J. C. (1999). Tangles and plaques in nondemented aging and “preclinical” Alzheimer’s disease. Annals of Neurology: Official Journal of the American Neurological Association and the Child Neurology Society, 45(3), 358-368.
- Riley, K. P., Snowdon, D. A., & Markesbery, W. R. (2002). Alzheimer’s neurofibrillary pathology and the spectrum of cognitive function: findings from the Nun Study. Annals of neurology, 51(5), 567-577.
- Stern, Y. (2012). Cognitive reserve in ageing and Alzheimer’s disease. The Lancet Neurology, 11(11), 1006-1012.
- Zhu, Q.-B., Bao, A.-M., & Swaab, D. (2019). Activation of the brain to postpone dementia: a concept originating from postmortem human brain studies. Neuroscience bulletin, 35(2), 253-266.