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Alzheimer disease appears to be a stereotyped mode of reaction of the central nervous system to various types of aggression such as different mutations involving various proteins, trisomy 21 or repeated head trauma as in dementia pugilistica. Rather than a disease, it appears to be a clinicopathological syndrome due to various causes. Lesions may be considered under 3 headings: neurofibrillary pathology, A beta peptide deposits and loss (neuronal and synaptic). Neurofibrillary pathology includes the neurofibrillary tangle, the crown of the senile plaque and the neuropil threads. All those lesions are characterized by the same ultrastructure--i.e. the accumulation of paired helical filaments--and the same immunohistochemistry: they are labelled by antibodies directed against the tau proteins. The amyloid deposits, present in the core of the senile plaque and in the vascular walls, are made of a 40 to 42 amino-acids long peptide, named A beta, derived from the amyloid precursor protein (APP). Antibodies directed against the A beta peptide also label diffuse deposits that are devoid of the tinctorial affinities and of the biochemical properties of amyloid substances. Those diffuse deposits are insufficient to cause dementia since they may be observed in high 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 other proteins may play an important role: apolipoprotein E which could act as a chaperone protein, inducing or facilitating the formation of amyloid, presenilins 1 and 2, mutated in some cases of familial Alzheimer disease, alpha-synuclein which is present in the Lewy bodies found in Parkinson disease and in dementia with Lewy bodies. The A beta deposits are diffusely distributed in the cerebral cortex; the neurofibrillary changes have a hierarchical distribution. The progression of the neurofibrillary pathology in the various cortical areas follow a stereotyped sequence that may help to grade the severity of the disease. Progression may take decades. The relations between aging and Alzheimer disease are still poorly understood. Frequency of Alzheimer type lesions in old people could suggest that they are the inevitable burden of age, but this has been discussed.

The main lesions of Alzheimer's disease are: 1. amyloid deposits, labelled by antibodies directed against the A beta peptide (core of the senile plaques, diffuse deposits and amyloid angiopathy), 2. neurofibrillary lesions labelled by anti-tau antibodies (neurofibrillary tangles, neuropil threads, crown of the senile plaques) and 3. loss of neurons and synapses. The distribution of neurofibrillary pathology is hierarchical: they begin in the entorhinal cortex, progress along the anterograde corticocortical pathways toward the multimodal and unimodal associative cortices to reach, in the most severe cases, the primary cortices. Amyloid lesions are more diffuse, rapidly affecting all the cortical areas. The density of neurofibrillary tangles in the cerebral cortex is correlated with the severity of dementia. Neuritic plaques, synaptic and neuronal loss also contribute to the intellectual deterioration. There are various causes of Alzheimer's disease (several mutations, trisomy 21, repeated head trauma as in dementia pugilistica): it should be considered a syndrome. Its pathophysiology is complex and involves several proteins (e.g. amyloid protein precursor, tau protein, presenilins 1 and 2, and apolipoprotein E).

Transmissible non conventional agents are currently called "Prions". This is not a neutral terminology: the attractive Prion hypothesis (the infectious agent being a protein able to replicate in the absence of DNA or RNA) due to Stanley Prusiner is the prevalent one, and has shown to be heuristic, but has not been formally proven and does not easily explain all the data, unless modified and expanded. No simple account has been given for the very unusual physical, chemical, and biological properties of non conventional agents. These infectious agents are associated with degenerative diseases of the nervous system that are either the consequence of a genetic mutation or develop spontaneously in apparently normal individuals, and then can be transmitted to various susceptible hosts, including man. Thus, non conventional agents cannot be considered only as fascinating biological enigmas. They constitute a challenge for public health. The changing characteristics of prion-associated diseases has led to a renewing of their clinical and neuropathological diagnostic criteria. A brief survey of the nosology and neuropathology of prions diseases, with emphasis on new data and on difficulties, is provided. A simple classification based on the familial, sporadic or infectious variety of the disease is suggested. Familial diseases can be named according to the genetic disorder. Sporadic and infectious diseases can be classified following the main clinical symptoms and signs, and the presence or absence of amyloid plaques in the brain, until new tools (analysis of the glycosylation pattern of PrP, strain recognition) allow a more precise nomenclature. The new epidemiology of Prion disorders allowed by these new approaches relies on a full study of Prion diseases affected patients, which necessarily involves their genetic study, and the analysis of brain tissue. This, for practical and ethical reasons, is better achieved by autopsy.

The number of neuropathological markers used for the diagnosis of degenerative dementias is rapidly increasing, and this is somewhat confusing: some lesions described a long time ago, such as ballooned cells, proved to be less specific than they were supposed to be; this is also the case for Lewy bodies, that have been recognised in a larger spectrum of disorders than thought a few years ago. On the contrary, for an increasing number of neuropathologists, Pick bodies are now mandatory for the diagnosis of Pick disease, and this contrasts with the prevalent opinions of the late sixties or seventies. There are a number of reasons for the changing significance of neuropathological markers. Three of them can be easily identified: 1) the burst of immunohistochemistry into neuropathology allowed an easier recognition, a better delineation and new pathophysiological approaches to old lesions, and a dramatic increase in the description of new markers, especially in glial cells; 2) in some conditions characterized by the number and distribution of some lesions rather than by their mere presence, such as aging and Alzheimer disease, a better neuroanatomical point of view permitted new insights into the concept of disease versus age-related changes; 3) more accurate clinicopathologic correlations showed clearly the need of grouping or lumping together some entities: for example, obvious relationship aroused between progressive supranuclear palsy and corticobasal degeneration; in contrast, distinguishing different disorders in the frontal lobe dementias grouped together into "Pick disease" was felt necessary. This review summarizes the main criteria for identification, and the presumed meaning of the chief markers indicating the presence of abnormally phosphorylated tau proteins, A beta peptides, and PrP proteins. Abnormally phosphorylated tau proteins can be stored in the neurons, and participate in the constitution of many lesions (neurofibrillary tangles, neuropil threads, abnormal processes of the crown of neuritic senile plaques, Pick bodies, granulo-vacuolar degeneration, argyrophilic grains). When seen in neuroglia, they are the chief constituents of various lesions that affect mainly astrocytes (abnormal tufts of fibres, astrocytic plaques, thorn-shaped astrocytes, spiny astrocytes) and also oligodendrocytes (oligodendroglial threads and coils, glial cytoplasmic inclusions). A beta peptides, in "preamyloid" and amyloid conformations, can be seen in the extracellular space (plaques, of the neuritic or non-neuritic varieties, diffuse, focal and granular deposits) and in the vascular walls (amyloid angiopathies). Some PrP deposits are also of the amyloid variety (kuru type, multicentric or florid plaques), but immunohistochemistry, far more sensitive than conventional studies, revealed a number of other lesions (perivacuolar, neuronal, "synaptic" deposits...). Numerous markers are easily detected by ubiquitin immunohistochemistry. Lewy bodies, Pick bodies, neurofibrillary tangles had already be identified by other methods. In contrast, some ubiquitin-positive inclusions are shown, by this technique only, in amyotrophic lateral sclerosis and other conditions which were thus related to this disease. Finally, this review deals with two classic markers, ballooned cells ("Pick cells") and spongiosis seen in disorders due to non conventional agents or prions (spongiform encephalopathies).

Cerebral amyloidoses affects only the central nervous system, with rare exceptions. Most of them are related to A beta deposits. They usually occur in the absence of genetic defect in the precursor of A beta. The prevalence and density of A beta deposits increase during the aging process, and in Alzheimer's disease. This A beta amyloidosis has never been transmitted. In contrast, PrPres occurs as a sporadic or genetic event, and induces transmissible amyloidoses (Creutzfeldt-Jakob's disease and other disorders related to non conventional agents). PrPres may be the infectious agent itself (prion hypothesis). Other proteins are rarely responsible for cerebral amyloidoses. The fascinating hypothesis that a common mechanism would be acting in all cerebral amyloidoses has not yet been confirmed.