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Evolution of Alzheimer's Disease Related Intraneuronal Changes

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The neuropathologic hallmark of Alzheimer's disease (AD) is the deposition of abnormal proteins, both within and between the nerve cells. The extracellular deposits consist chiefly of specific a4-amyloid proteins, while abnormally phosphorylated tau proteins dominate among the intraneuronal changes (neurofibrillary tangles, neuropil threads, and components of neuritic plaques). Both, the a4-amyloid deposits and the neurofibrillary changes develop selectively in specific cortical predilection sites. The changes then spread in a predictable, non-random manner across other areas. This sequence is subject to little variation, and provides a basis for distinguishing stages in the evolution of the changes. Initial deposits of a4-amyloid appear in basal neocortical areas (stage A). They spread superolaterally (stage B), and eventually extend into primary neocortical areas (stage C). Six stages of disease propagation can be distinguished with respect to the location and the severity of the intraneuronal changes (transentorhinal stages I-II: clinically silent cases; limbic stages III-IV: incipient AD; neocortical stages V-VI: fully developed AD).

These stages bear a striking resemblance to the inverse sequence of cortical myelination. Such reciprocal similarities can hardly be attributed to chance. It is very likely that the two hierarchical processes are related.

Examination of more than 2000 brains of non-selected cases obtained at autopsy demonstrates that neither type of lesion - even when only minimally present - is a normal concomitant of brain aging. The two lesions develop independently of each other. Initial neurofibrillary changes generally appear in brain tissue still devoid of a4-amyloid deposits. The first appearance of transentorhinal tangle-bearing pyramidal cells indicates the beginning of AD. A small proportion of cases display particularly early development of the changes. Advanced age is thus no prerequisite to the evolution of the intraneuronal lesions: AD is an age-related, but not an age-dependent brain disorder. Cases exclusively showing extraneuronal "ghost" tangles were not found. All cases with neurofibrillary pathology revealed the presence of intraneuronal changes, indicating that the pathologic process was active up to the time of death. Spontaneous remissions do not occur in AD.

Supported by the Deutsche Forschunsgemeinschaft and the Bundesministerium fr Forschung und Technologie.