Cognitive Status, Quality of Life, Brain Structure and Beta-Amyloid Deposition in the Oldest Old

Research over the past twenty years has led to the view that the accumulation of aggregated proteins, which takes place over decades, is the key event in the development of neurodegenerative diseases. The most prevalent neurodegenerative disorder Alzheimer’s disease (AD) is characterized by extracellular deposition of beta-amyloid in the brain parenchyma and blood vessels (the latter also termed congophilic amyloid angiopathy, CAA) along with intracellular accumulation of neurofibrillary tangles (NFT), composed of tau proteins, leading to neuronal degeneration and loss of synapses in hippocampus and neocortical areas (for review see: ((Bercovitz, Decker, Jones, & Remsburg, 2008); (Haass & Selkoe, 2007); (Walsh & Selkoe, 2004))). This view has led to the development of therapeutic strategies aiming at interfering with these accumulation processes. Currently most advanced are strategies to lower brain beta-amyloid in humans, based on passive or active immunization protocols (Morgan, 2006); (Nitsch & Hock, 2008); (Schenk, Seubert, Grundman, & Black, 2005)). Since clinical benefits in pilot active immunization trials against beta amyloid performed in moderate and advanced AD patients were not consistently observed, it was proposed that immunizations should be initiated earlier in the disease process, ideally before the onset of cognitive symptoms (Golde, Schneider, & Koo, 2011). In order to understand the ideal point for administration of these therapeutic strategies, it is crucial to have a profound knowledge on the factors, contributing to progressive brain beta-amyloidosis occurring during normal aging.


Human brain aging occurs both with and without the development of progressive brain beta-amyloidosis. According to the data reported by (Ng, Villemagne, Masters, & Rowe, 2007) and (Mintun et al., 2006) using [11C]PIB, it can be estimated that in ca. 10% to 20% of clinically healthy elderly subjects, PET images will be abnormal because these subjects do have significant amyloid plaque load in the brain. A recent longitudinal study demonstrated a considerable higher risk for developing cognitive impairment for cognitively healthy elderly subjects (HCS) with elevated PiB retention as compared to HCS without (Villemagne et al., 2011). The majority of these imaging studies were performed in patients with an average age 75 years, and only few patients were aged above 90 years, so data on this age group is scarce. A recent publication (Kawas et al. 2012 (online)) found significant correlation between cognitive decline and amyloid plaque load in 13 oldest-old. A post-mortem study did not find such a correlation but identified a different pattern of pathology, especially in the hippocampal formation compared to subjects aged younger than 90 years (Imhof, 2007). This demonstrates the need for additional studies in this population ideally including various biomarkers to elucidate the relationships of beta-amyloid deposition, cognition, genetics, cognitive activity, blood and anatomical markers in oldest old. Of greatest interest would be the identification of biological factors enabling individuals above 90 years to maintain a high level of cognitive functioning and a functional healthy life particular in the in the presence of significant brain-beta-amyloidosis.


In this respect Biomarkers accounting for the many aspects of healthy aging will be collected in this study and compared to data from already on-going studies in younger healthy subjects, MCI and AD Patients in order bring this knowledge into a framework of aging and beta-amyloidosis.



1. To assess brain beta-amyloidosis in at least 40 but up to 100 individuals aged over eighty-five years with preserved activities of daily living. From a statistical point of view at least 40 subjects need to be included, but depending on heterogeneity of the results up to 100 might be needed.

2. To characterize differences in cognitive functioning and quality of life in these subjects with and without brain beta-amyloidosis assessed by PIB Imaging and furthermore to reveal potential differences in distribution pattern compared with younger.

3. To determine whether ApoE genotype or cardiovascular risk factors or specific lifestyle factors are associated with brain beta-amyloidosis in healthy oldest old subjects.

4. To determine whether brain-beta amyloidosis is associated with MRI signs of brain atrophy as well as atrophy rate over time in this age group.

5. To determine the biological indicators of brain-beta amyloidosis by immunological analyses of humoral and cellular immunity.