What is the molecular pathology that underlies hippocampal memory decline?

Over a century ago Alois Alzheimer described the importance of neurofibrillary tangles in a woman who died with dementia at the age of 55 years; plaques having already been observed in brains by Blocq and Marinesco. In the 1960s, Martin Roth and colleagues at Newcastle were first to look at the pathological basis of dementia in AD and they identified neuritic plaques and tangles as the key determinants of clinical dementia. Although recent advances have since established the molecular basis for the pathological hallmarks of the disease, several studies have been contradictory in terms of whether it is amyloid or tau pathology that is critical in determining clinical deterioration. Intraneuronal accumulations of tau within the neurofibrillary pathology of AD (tangles, neuritic plaques and dystrophic neurites) are closely linked with the symptoms of dementia, but what initiates the process that leads to these intracellular lesions is uncertain. In some cases, this might be precipitated by abnormal deposition of amyloid -protein while in others, some different factor may be involved. The absence of tools that are sensitive enough to detect subtle clinical changes in key aspects of AD has made it difficult to interpret correlations with global indices of cognitive function.