back to Fifth International Conference
Evolution of Alzheimer's Disease Related Intraneuronal
H.Braak* and E.Braak
Department of Anatomy, J.W.Goethe University, Theodor Stern Kai 7,
D-60590 Frankfurt/Main, Fed. Rep. Germany.
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
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.