Alzheimer's disease: lesions and their progression.

Alzheimer disease appears to be a stereotyped mode of reaction of the centr al nervous system to various types of aggression such as different mutation s involving various proteins, trisomy 21 or repeated head trauma as in deme ntia pugilistica. Rather than a disease, it appears to be a clinicopatholog ical syndrome due to various causes. Lesions may be considered under 3 head ings: neurofibrillary pathology, A beta peptide deposits and loss (neuronal and synaptic). Neurofibrillary pathology includes the neurofibrillary tang le, the crown of the senile plaque and the neuropil threads. Aii those lesi ons are characterized by the same ultrastructure -i.e. the accumulation of paired helical filaments - and the same immunohistochemistry: they are labe lled by antibodies directed against the tau proteins. The amyloid deposits, present in the core of the senile plaque and in the vascular walls, are ma de of a 40 to 42 amino-acids long peptide, named A beta, derived from the a myloid precursor protein (APP). Antibodies directed against the A beta pept ide also label diffuse deposits that are devoid of the tinctorial affinitie s and of the biochemical properties of amyloid substances. Those diffuse de posits are insufficient to cause dementia since they may be observed in hig h density in aged people without intellectual deterioration. Neuronal loss occurs after neurofibrillary pathology. The role of the synaptic pathology remains discussed. Besides tau proteins, A beta peptide and APP, several ot her proteins may play an important role: apolipoprotein E which could act a s a chaperone protein, inducing or facilitating the formation of amyloid, p resenilins 1 and 2 mutated in some cases of familial Alzheimer disease, alp ha-synuclein which is present in the Lewy bodies found in Parkinson disease and in dementia with Lewy bodies. The A beta deposits are diffusely distri buted in the cerebral cortex; the neurofibrillary changes have a hierarchic al distribution. The progression of the neurofibrillary pathology in the va rious cortical areas follow a stereotyped sequence that may help to grade t he severity of the disease. Progression may take decades. The relations bet ween aging and Alzheimer disease are still poorly understood. Frequency of Alzheimer type lesions in old people could suggest that they are the inevit able burden of age, but this has been discussed.