The incidence of Alzheimer's disease (AD) is increasing worldwide and imposing enormous economic burdens 
. Alzheimer's disease is the most common form of dementia, presently accounting for 5.5 million cases in the USA, a number projected to double by the end of this decade. Unprecedented advances in the biomedical field, hygiene and nutrition have increased the average life expectancy with an impressive exponential growth in the numbers of those surviving beyond 90 years, defined as the “oldest-old” 
. The general health of aging populations is an urgent issue in terms of the overwhelming and mounting emotional burdens and expenses that the elderly generate. Awareness and intervention are promptly needed given the fact that AD dementia is reaching alarming proportions. Worldwide, there will be 1.3 billion people over the age of 65 years and the numbers of those over age 80 is predicted to increase by 233% by 2040 
Alzheimer's disease is defined by the profuse deposition of amyloid-beta (Aβ) peptides in amyloid plaques and walls of cerebral vessels as well as by the accumulation of intracellular neurofibrillary tangles (NFT). These lesions are accompanied by synaptic depletion, neuronal demise, gliosis, demyelination and severe brain atrophy. The “amyloid cascade hypothesis” suggests that the production and profuse deposition of insoluble fibrillar amyloid and of increased soluble oligomeric forms of Aβ initiates a series of events culminating in neuronal damage, cognitive impairment and ultimately dementia 
. This hypothesis is supported by studies demonstrating higher probability of AD and an increasing number of amyloid plaques and NFT with increasing age 
. The discovery of familial AD mutations in the amyloid precursor protein (APP) coding region, and APP processing genes presenilin-1 (PS-1) and presenilin-2 (PS-2) as well as subsequent work in transgenic mouse models carrying human APP and PS mutations also lent strong support to the amyloid cascade hypothesis 
. Based on these observations, a large number of therapeutic interventions have been designed to prevent the generation of Aβ, reduce its deposition or remove already existing amyloid plaques.
While the amyloid cascade hypothesis is the prevailing mechanism to explain the pathogenesis of sporadic AD, amyloid plaque density has not been shown to robustly correlate with either AD diagnosis or as a measure of disease severity or progression 
. Levels of amyloid/Aβ determined by 11
C-Pittsburgh compound B (PIB)-PET imaging, or altered plasma or CSF Aβ values have not yet been proven to adequately predict AD or cognitive decline, without being combined with other biomarkers of dementia such as tau 
. As many as 30% of elderly individuals with no cognitive impairment have positive PIB/amyloid imaging signals 
. Furthermore, a significant proportion of elderly individuals exhibit sufficient plaque densities warranting a neuropathology-based classification as probable AD, yet were normal by cognitive assessments 
. Some oldest-old individuals are able to remain cognitively intact and endure high amyloid plaque loads for years or even decades 
. These observations cast doubts on the amyloid cascade hypothesis as the sole determinant of dementia and demand an explanation as to why some elderly individuals harbor such high levels of amyloid without cognitive impairment. If amyloid accumulation produces neurotoxicity and dementia, protective mechanisms must be in place to enable these individuals to evade cognitive decline. If, on the other hand, the amyloid cascade mechanism of dementia production is incorrect, why are amyloid plaques produced and what purpose do they serve?
In an attempt to resolve these conundrums, we are initiating a series of systematic studies to determine at the molecular level the differences and similarities between AD and non-demented oldest-old meeting the neuropathological criteria for AD. In the first of these studies, we assessed the neuropathological differences between these two groups. In addition, we quantified by ELISA and Western blots a group of proteins related to APP/Aβ/tau metabolism and other neurotrophic and inflammatory-related molecules that have been found to be altered in neurodegenerative disorders and that are pivotal to brain homeostasis and mental health.