Inflammation, Amyloid and Atrophy in The Aging Brain: The Borders between Healthy Brain Aging and Neurodegeneration

How the link between aging and Alzheimer's disease should be understood is a major question in contemporary neuroscience. Evidence is mounting that Alzheimer-vulnerable neural systems are highly susceptible to a number of different factors in normal aging, with some being disease related while others are not. The aim of the project is to identify fundamental mechanisms causing these systems to decline also in non-demented elderly, allowing us to address the overarching question of why some people maintain cognitive abilities in higher age while others decline? First, we have used 1100 cross-sectional and more than 200 longitudinal examinations to compute detailed age-vulnerability maps for a range of morphometric brain traits, such as atrophy (tissue loss) and volume of structures of known importance for specific cognitive functions, representing various phenomena. Second, we have started a very intensive study of a smaller sample of participants, where we attempt to understand mechanisms and moderators of the vulnerabilities identified in Part 1. We have selected 200 healthy participants between 20 and 90 years that we follow with comprehensive longitudinal measures of brain structure and function, cognition, genes and life-style factors. The major part of this sample has also been examined with PET (positron emission tomography) to measure the load and distribution of so-called amyloid plaques in the brain, an established risk factor for Alzheimer?s disease. So far, we have discovered that in cognitively healthy older adults with elevated risk for Alzheimer?s disease, neuroinflammation is related to higher incidence of sleep disturbance, while this does not seem to apply for older adults with normal Alzheimer risk. Alzheimer risk was defined by levels of amyloid-beta proteins in the brain. Further, we have found that in participants with high levels of amyloid, there was a relationship between the amyloid levels and brain atrophy - or loss of brain tissue - over a two-year period. Participants with high levels of inflammation in the brain also showed larger cognitive reductions over the same time period. This was especially true for participants with higher levels of amyloid, which represents increased risk for Alzheimer?s disease. Effects of amyloid on brain health in non-demented is a major area of research. We also examine life-style related risk factors for cognitive decline, such as overweight, blood pressure and cholesterol, which we believe can affect the brain, partly through neuro-inflammation. Testing the relationship between these different factors that all may affect brain health has the potential to push the borders of our understanding of brain aging, thereby also opening new venues for intervention.

How the link between aging and AD should be understood is a major question in contemporary neuroscience. Evidence is mounting that Alzheimer-vulnerable neural systems are highly susceptible to a number of different factors in aging, with some being diseas e related while others are not. Our aim is to identify fundamental mechanisms causing these systems to decline also in non-demented elderly, allowing us to address the overarching question of why do some people maintain cognitive abilities in higher age w hile others decline? First, using 1100 cross-sectional and 207 longitudinal examinations, we will compute detailed age-vulnerability maps for a range of brain characteristics representing different neurobiological traits. In Part 2, we will launch the mos t intensive study of normal aging to date in an attempt to understand mechanisms and moderators of the vulnerabilities identified in Part 1. In an independent sample of 200 healthy participants (25-90 yrs), we will obtain extremely comprehensive longitudi nal measures of brain structure and function, cognition, genes and life-style factors. The most novel aspect is that we simultaneously map distribution of amyloid deposition and neuro-inflammation (PET), which has not previously been done. This is strikin g, as there is evidence for a relationship between amyloid and neuro-inflammation from animal studies, and effects of amyloid on brain health in non-demented is a major area of research. Also, life-style related risk factors for cognitive decline, such as overweight, blood pressure and cholesterol, are hypothesized to impact the brain partly through neuro-inflammation. Thus, systematic testing of how amyloid and neuro-inflammation are related to each other and to cerebral and cognitive change in non-demen ted, and the possibly mediating roles played by life-style and genetic risk factors, has the potential to really push the boarders of our understanding of brain aging, thereby opening new venues for intervention.