Neurofibrillary tangles and senile plaques, together with cells immunoreactive for the Alz-50 antibody (A50-ir cells) or for an antibody against paired helical filaments (PHF-ir cells), and amyloid deposits stained with antibodies against beta-(or A4)-amyloid, have been mapped throughout the ventral forebrains of 25 old people. The cognitive status of each individual was assessed and a "Clinical Dementia Rating" (CDR) assigned, either before death in the Memory and Aging Project of Washington University, or by a postmortem interview, with an appropriate collateral source. The cases studied included 13 nondemented cases (CDR = 0), six very mildly to mildly demented cases (CDR = 0/0.5 to 1) and six more severely demented cases (CDR = 2 to 3). Because even the very mildly demented brains showed substantial pathological change, emphasis was placed on examining the nondemented cases for the earliest changes that could be associated with Alzheimer's disease. Different distributions were found for tangles and plaques. Tangles (and A50-ir and PHF-ir cells) were present in all of the brains examined. In the younger nondemented cases (aged 54 to 63) there were a few affected cells in the anterior olfactory nucleus and the parahippocampal gyrus. In older nondemented cases (aged 73-89) more tangles were found in the same areas, and also in hippocampal field CA1. The very mildly demented cases had many more tangles, but their distribution was similar. Only in the severely demented cases were large numbers of tangles present in the neocortex. In contrast, no plaques (or beta-amyloid immunoreactivity) were found in any of the younger nondemented cases or in four of the eight older nondemented cases. In three older nondemented cases there were a few primitive plaques, which were restricted to localized regions of the neocortex (e.g., a portion of the inferior temporal cortex). In one nondemented case and all of the very mildly to mildly demented cases there were very large numbers of mostly primitive plaques, particularly in the neocortex. With greater severity of dementia there is a shift from primitive to mature plaques. These results were interpreted to imply that the first development of tangles and plaques occurs in different parts of the brain. Tangles appear during aging in the anterior olfactory nucleus, the parahippocampal gyrus and the hippocampus, but are rare in the neocortex except in demented brains. Conversely plaques may develop first in the neocortex. Unlike tangles, plaques are not a consistent feature of aging, at least up to age 80.

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The relationship between tangle and plaque formation during healthy aging and mild dementia.

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Formation of diffuse and fibrillar tangles in aging and early Alzheimer's disease.

The changes in tau that are associated with the early formation of tangles in aging and in preclinical and very mild Alzheimer's Disease (AD) were studied with two antibodies against AD-specific tau: PHF-1, which recognizes a phosphorylated epitope at Ser396 through 404, and MC-1, which recognizes a folded, conformational epitope that includes amino acids at both 7 through 9 and 312 through 342. Both antibodies demonstrated cells with diffuse or granular staining (diffuse tangles) and cells with fibrillar staining (fibrillar tangles). The fibrillar tangles corresponded to classical tangles and increase exponentially with age and severity of AD. The diffuse tangles seemed to represent an earlier form of tangles; their density peaked around preclinical AD, and then decreased in more severe stages of AD. MC-1 consistently stained more diffuse tangles than PHF-1, suggesting that the conformational change in tau precedes phosphorylation at the PHF-1 epitope during paired helical filament formation.

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Synaptic loss and pathological change in older adults--aging versus disease?

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Diagnostic criteria for Alzheimer's disease.

This paper summarizes changes that distinguish early Alzheimer's disease (AD) from nondemented aging based on 49 well characterized cases (30 nondemented, 10 very mildly demented, and 9 severely demented). Tangles were found in all nondemented cases (aged 54 to 88) concentrated in limbic structures. The probability of high tangle density increases with age, even in the absence of plaques or dementia. Based on plaques, nondemented cases can be divided into three groups: 1) cases younger than 73 years of age with one-third of older cases had no plaques; 2) about one-half of cases over 74 years of age had a few diffuse plaques in restricted patches in the neocortex; 3) about one-quarter of cases over 74 years of age had many neuritic and diffuse plaques throughout the neocortex; these may represent "preclinical" AD. Very mildly demented cases had high concentrations of neuritic and diffuse plaques in the neocortex and tangles in limbic structures. The observations indicate that the minimal diagnostic criterion for AD is plaques throughout the neocortex together with neurofibrillary changes (tangles in limbic structures and neuritic plaques in cortex). Tangles are a necessary but not sufficient criterion.

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