As an increasing number of individuals survive into advanced age, dementia and milder cognitive impairments takes on growing public health importance. The aetiology of dementia and Alzheimer’s ...disease (AD), which is the most common cause of dementia, is considered to be multifactorial, resulting from both genetic and environmental factors. The present thesis project aimed at obtaining a comprehensive understanding of the role of lifestyle-related factors in the development of dementia and cognitive impairment. Special attention was paid to possible interactions between lifestyle-related and genetic risk factors. The general hypothesis was that a healthy lifestyle could reduce the risk of dementia and cognitive impairment.All five studies were based on the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) project. The participants in the CAIDE project were derived from four independent population-based random samples studied within the framework of the North Karelia Project and the FINMONICA study in 1972, 1977, 1982 or 1987. A random sample of 2000 individuals aged 65-79 years and living in two geographically defined areas in Kuopio and Joensuu in eastern Finland were invited for the reexamination in 1998, and altogether 1449 people (73 %) participated.In study 1, obesity at midlife was associated with an increased risk of dementia and AD. Midlife obesity, high cholesterol, and high systolic blood pressure were all significant risk factors for dementia with ORs of around 2 for each parameter, and they increased the risk additively.In study 2, we observed a U-shaped association between midlife alcohol drinking and the risk of mild cognitive impairment (MCI) in late-life, so that the participants who did not drink alcohol, as well as those who drank alcohol frequently, had a two-fold risk of having MCI when compared with those participants who drank alcohol infrequently. The presence of the apolipoprotein E (ApoE) ε4 allele modified the association between alcohol drinking and dementia: ApoE ε4 carriers showed an increased risk of dementia with increasing alcohol drinking frequency, whereas this was not the case for the ApoE ε4 non-carriers.In study 3, we investigated the relationship of midlife alcohol drinking to cognitive functions in late-life among the non-demented individuals. The participants who did not drink alcohol at midlife, had poorer performance compared to infrequent and frequent drinkers in episodic memory, psychomotor speed, and executive function in late-life.In study 4 low income level in late-life but not at midlife was related to the risk of dementia. Dementia was also associated with decreasing income level from midlife to old age. Low educational level and the ApoE ε4 allele independently increased the risk of dementia.In study 5 we examined whether the association between education and dementia was due to the presence of unhealthier lifestyles or more cardiovascular risk factors among the less educated persons. High education was associated with a lower risk of dementia and AD, and it remained unchanged after adjustments for a wide range of lifestyle factors.In summary, this set of studies showed that unhealthy lifestyle-related factors at midlife, such as obesity, hypertension and hypercholesterolemia increase the risk of developing dementia and AD later in life.
The rare A673T variant was the first variant found within the amyloid precursor protein (APP) gene conferring protection against Alzheimer's disease (AD). Thereafter, different studies have ...discovered that the carriers of the APP A673T variant show reduced levels of amyloid beta (Aβ) in the plasma and better cognitive performance at high age. Here, we analyzed cerebrospinal fluid (CSF) and plasma of APP A673T carriers and control individuals using a mass spectrometry-based proteomics approach to identify differentially regulated targets in an unbiased manner. Furthermore, the APP A673T variant was introduced into 2D and 3D neuronal cell culture models together with the pathogenic APP Swedish and London mutations. Consequently, we now report for the first time the protective effects of the APP A673T variant against AD-related alterations in the CSF, plasma, and brain biopsy samples from the frontal cortex. The CSF levels of soluble APPβ (sAPPβ) and Aβ42 were significantly decreased on average 9–26% among three APP A673T carriers as compared to three well-matched controls not carrying the protective variant. Consistent with these CSF findings, immunohistochemical assessment of cortical biopsy samples from the same APP A673T carriers did not reveal Aβ, phospho-tau, or p62 pathologies. We identified differentially regulated targets involved in protein phosphorylation, inflammation, and mitochondrial function in the CSF and plasma samples of APP A673T carriers. Some of the identified targets showed inverse levels in AD brain tissue with respect to increased AD-associated neurofibrillary pathology. In 2D and 3D neuronal cell culture models expressing APP with the Swedish and London mutations, the introduction of the APP A673T variant resulted in lower sAPPβ levels. Concomitantly, the levels of sAPPα were increased, while decreased levels of CTFβ and Aβ42 were detected in some of these models. Our findings emphasize the important role of APP-derived peptides in the pathogenesis of AD and demonstrate the effectiveness of the protective APP A673T variant to shift APP processing towards the non-amyloidogenic pathway in vitro even in the presence of two pathogenic mutations.
•Decreased levels of sAPPβ and Aβ42 in CSF of protective APP A673T variant carriers•Cortical biopsies of APP A673T variant carriers do not show Aβ pathology•Several differentially regulated targets in CSF of APP A673T variant carriers•APP A673T variant lowers sAPPβ levels in 2D and 3D cell culture models of AD
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