Genetic and lifestyle influences on memory, brain structure, and dementia

This doctoral thesis investigated genetic, inflammatory, and lifestyle influences on cognition, brain structure, and dementia. The influence of TOMM40 polymorphisms (Study I), a PICALM, BIN1 and CLU genetic risk score (GRS; Studies II, III), and inflammatory cytokines (Study IV) was assessed, as well as potential interactions with physical activity (Studies II-IV). All studies were based on the Swedish National study on Aging and Care in Kungsholmen (SNAC-K), including a subsample that had participated in magnetic resonance imaging (MRI).

In Study I, the influence of TOMM40 polymorphisms (rs11556505 and rs2075650) on episodic memory and hippocampal volume was investigated. There was no independent influence of TOMM40 polymorphisms on episodic memory and hippocampal volume. However, carriers of an APOE ε4 allele who also harbored TOMM40 risk alleles relied more heavily on hippocampal volume for episodic memory performance. Study II confirmed our hypothesis that high genetic risk (GRS >4) based on Alzheimer’s disease (AD) candidate genes (PICALM rs3851179, rs541458, BIN1 rs744373, and CLU rs11136000) was associated with worse episodic memory performance in non-demented older adults. Interestingly, there was an interaction between physical activity and GRS. The combination of physical inactivity and high genetic risk was most detrimental to memory performance, whereas a high GRS could be compensated for by physical activity. In Study III, we investigated if the same GRS was associated with incident dementia, primarily AD. Despite the associations with memory performance in Study II, there was no effect of GRS on incident dementia during a follow-up period of 6 years. Nonetheless, we did replicate previous work showing that physical inactivity is associated with increased risk of dementia. Study IV investigated the influence of inflammatory cytokines and physical activity on graymatter volume and global cognitive decline. Although there was no relation between inflammatory cytokines and brain volume, high levels of IL-12p40 in individuals who were physically inactive were associated with smaller lateral prefrontal cortex and hippocampal volumes, as well as with global cognitive decline over 6 years. This suggests that levels of inflammation may be especially detrimental for brain and cognitive integrity in individuals who are physically inactive.

In summary, the studies in this thesis suggest that physical inactivity is associated with reduced episodic memory performance, compromised structural brain volume, and dementia risk. Moreover, physical inactivity in combination with a high GRS or systemic inflammation was especially detrimental to episodic memory as well as to frontal and hippocampal volumes, respectively.

List of scientific papers

I. Ferencz, B., Laukka, E. J., Lövdén M., Kalpouzos, G., Keller, L., Graff, C., Wahlund, L. O., Fratiglioni, L., & Bäckman, L. (2013). The influence of APOE and TOMM40 polymorphisms on hippocampal volume and episodic memory in old age. Frontiers in Human Neuroscience. 22(7), 198.
https://doi.org/10.3389/fnhum.2013.00198

II. Ferencz, B., Laukka, E. J., Welmer, A. K., Kalpouzos, G., Angleman, S., Keller, L., Graff, C., Lövdén, M., & Bäckman, L. (2014). The benefits of staying active in old age: physical activity counteracts the negative influence of PICALM, BIN1 and CLU risk alleles on episodic memory functioning. Psychology and Aging. 29(2), 440-449.
https://doi.org/10.1037/a0035465

III. Ferencz, B., Bäckman, L., Fratiglioni, L., & Laukka, E. J. Effects of a genetic risk score and physical inactivity on dementia incidence: A 6-year follow-up. [Manuscript]

IV. Papenberg, G., Ferencz, B., Mangialasche, F, Mecocci, P., Cecchetti, R., Kalpouzos, G., Fratiglioni, L., & Bäckman, L. (2016). Physical activity and inflammation: effects on gray-matter volume and cognitive decline in aging. Human Brain Mapping. 37(10), 3462-3473.
https://doi.org/10.1002/hbm.23252