The association of APOE genotype, modifiable lifestyle factors, and white matter degeneration during aging.
The high prevalence of Alzheimer's disease (AD), the most common cause of dementia, has become an increasingly significant health concern in the growing elderly population. Apolipoprotein-E (APOE) is the most important genetic factor for late-onset AD (LOAD). APOE e4 allele (APOE4) increases AD risk and is recently shown to be associated with significant blood brain barrier (BBB) breakdown near medial temporal lobe (MTL) regions, corresponding to cognitive status in human participants. Our group recently examined APOE4 carriers' health profiles and revealed more extensive interactions between peripheral blood markers and brain white matter (WM) structural changes compared to APOE4 non-carriers. WM degeneration are potential consequences of increased BBB permeability and are well-established early markers for normal/pathological brain aging. Ours and other groups' findings suggest that an individual's long-term response to environmental or other health factors (i.e. physiological stress, dietary habits, etc.) may vary substantially due to more extensive cross-talks between peripheral circulatory system and central nervous system following BBB breakdown observed in APOE4 carriers. On the other hand, diet, obesity, cardiovascular diseases, hypertension, physical activity and diabetes also increase the risk for LOAD. For instance, a western-style diet (high fat/sugar, and low in vitamins) in combination with a sedentary lifestyle can contribute to a metabolic syndrome, which increases the risk for cardiovascular disease and AD. However, the exact role of APOE in mediating the relationship between peripheral blood markers (e.g. lipid and inflammatory cytokine) with long-term brain structural changes during aging is unknown.
We plan to take advantage of the extensive multidomain longitudinal large human cohort data of UK biobank to examine the relationship between genetic, lifestyle factors and blood biomarkers with changes in brain structure and signs of cognitive changes. This project will provide insight into how APOE genes affect the impact of lifestyle factors on changes to the brain or cognitive decline in those with Alzheimer's. We believe the integration of BBB imaging with biological, genetic and metabolic factors will improve our understanding of their complex interactions for studying aging and dementia. Successful outcome of this project will pioneer a comprehensive model to explain the specific mechanisms by which APOE4 may increase the risk for AD, which will enhance the translational knowledge of CNS and peripheral involvement in the pathogenesis and generate personalized therapeutic strategies for individuals with diverse genetic backgrounds.