BETA-AMYLOID DEPOSITION AND OTHER MEASURES OF NEUROPATHOLOGY PREDICT COGNITIVE STATUS IN ALZHEIMERS-DISEASE

The relationship between progressive cognitive decline and underlying neuropathology associated with Alzheimer s disease (AD) is a key issue in defining the mechanisms responsible for functional loss. This has been a subject of much controversy, with separate studies comparing va rious clinical and neuropathological indices in AD. Further, it is dif ficult to compare studies with differences in histochemical staining p rotocols, brain regions examined, and data quantification criteria. Th ere are many difficulties in designing a clinical-pathological correla tive study involving AD patients. It is necessary to control for sever al key parameters. For example, a broad range of cognitively impaired subjects is needed, as well as short postmortem delays, brief interval s between cognitive testing and death, and the most sensitive detectio n and quantification techniques. In this study, we carefully controlle d for each of these parameters to determine if there is a relationship between global cognitive dysfunction and multiple neuropathological i ndices. We selected 20 individuals representing a broad range of cogni tive ability from normal to severely impaired based on the MMSE, Bless ed IMC, and CDR. We counted plaque number, NFT number, dystrophic neur ite number, and the relative extent of thioflavine positive plaques an d neuritic involvement within plaques. We also quantified cortical are a occupied by beta-amyloid immunoreactivity (A beta Load) and PHF-1 po sitive neuropil threads and tangles (PHF Load) using computer-based im age analysis. Interestingly, we found that most pathologic measures co rrelated highly with the severity of dementia. However, the strongest predictor of premortem cognitive dysfunction on all three cognitive me asures was the relative area of entorhinal cortex occupied by beta-amy loid deposition. In conclusion, our data show that in a carefully cont rolled correlative study, a variety of neuropathological variables are strongly correlated with cognitive impairment. Plaque related variabl es may be as strongly related to cognitive dysfunction as other establ ished measures, including synapse loss, cell death and tau hyperphosph orylation, although no correlative study can demonstrate causality. Co pyright (C) 1996 Elsevier Science Inc.