Biological determinants of cognitive change in normal aging and dementia

Summary

Alzheimer's disease (AD) is one of the most frequently reported degenerative disorders in the elderly. It is characterized by the gradual accumulation of plaques and tangles. Correlative clinico-neuropathological studies have found a close relationship between cognitive decline and the density of neurofibrillary changes, but not the extent of extracellular deposits of amyloid protein within the plaques. Furthermore, studies of experimental ‘models’, such as those with implants and APP transgenic mice, failed to support the role of an ‘amyloid cascade’ in generating the AD phenotype. Biochemical studies based on measurements of tau protein, the constituent of paired helical filaments (PHF), indicate that there is redistribution of tau protein from soluble into insoluble, PHF-bound forms in AD. The level of PHF-tau protein increases with the progression of the disease. In the initial stages of AD, the measurements of PHF-tau derive predominantly from tangle-bearing neurons, whereas in the later stages, from the dystrophic neurites. At the same time, there is gradual loss of normal tau protein during the course of the disease. The PHF-tau accumulation on its own may not be sufficient to result in cognitive impairment, unless it is accompanied by significant loss of normal tau protein, as is seen in elderly Down's syndrome individuals. In contrast, normal aging is characterized by decline in normal tau protein, especially in the fronto-temporo-parietal neocortical areas, that might be directly linked to the development of various age-associated (non) cognitive changes. Prospective studies on individuals with different extents of cognitive impairment are needed in order to address in more detail the biological mechanisms leading to cognitive impairment in both aging and AD.