Relative Roles of Plaques and Tangles in the Dementia of Alzheimer's Disease: Correlations Using Three Sets of Neuropathological Criteria

Abstract

We have performed a quantitative analysis of the amyloid load (plaques), neuritic plaques and neurofibrillary tangles (NFT) in the frontal, temporal and parietal association cortices of autopsied brains from 49 prospectively evaluated patients with Alzheimer''s disease (AD) diagnosed according to three sets of published pathological criteria. These patients had been assessed clinically with psychological testing of cognitive abilities within 6 months of death. Correlations were sought between severity of pathological change and cognitive status before death, duration of disease and age at death. Using Khachaturian and CERAD criteria highly positive correlations were obtained between the extent of cognitive deficit and the density of NFT in frontal and parietal lobes. The percentage area of cortex occupied by amyloid in the parietal lobe was correlated to the cognitive deficit only in the CERAD-diagnosed cases. The density of all amyloid plaques (AP) showed no correlation with the extent of cognitive deficit, but the densities of neuritic plaques did correlate with cognitive deficit. Both amyloid load and tangle densities were positively correlated with disease duration. All these correlations were reduced or absent in a sub-group of cases fulfilling the Tierney et al. A3 diagnostic criteria for AD. We found no pathological measure that correlated with the age of patients at death. Amyloid loads and NFT densities showed highly significant but selective positive correlations, the most striking being between temporal lobe NFT density and frontal and parietal lobe amyloid load and between temporal lobe NFT density and frontal and parietal lobe NFT densities. Correlations involving AP density as a measure of amyloid load were almost always less significant than those involving the percentage area of cortex occupied by amyloid, suggesting that the latter measures amyloid load more accurately. However, the highest correlations of NFT densities were with neuritic plaque densities. Overall this study highlights the relevance of neuritic changes (revealed by NFT and neuritic plaques) and the irrelevance of amyloid plaques to the dementia of AD.

Prophylactic treatment with paroxetine ameliorates behavioral deficits and retards the development of amyloid and tau pathologies in 3xTgAD mice

“…Studies of human subjects have established strong correlations between Aβ levels and neurofibrillary tangles and cognitive deficits (Nagy et al, 1995;Naslund et al, 2000). However, a cause-effect relationship between Aβ deposition, and tau pathology and synaptic dysfunction, may not apply to all cases of AD, and certainly does not apply to patients with frontotemporal lobe dementia who exhibit abundant tau pathology, but no Aβ pathology (Froelich-Fabre et al, 2004).…”

Neuronal and Axonal Loss Are Selectively Linked to Fibrillar Amyloid-β within Plaques of the Aged Primate Cerebral Cortex

“…This conclusion is consistent with the findings of a strong correlation between the density of compact neuritic plaques and severity of dementia in this disorder. 16,17 …”

“…9,15 Moreover, a strong correlation has been reported between the density of neuritic plaques and severity of dementia. 16,17 The neuritic pathology associated with fA␤ is suggestive of the toxic effects of this conformation of the peptide on neurons and their processes. In fact, in vitro and in vivo evidence indicates that fA␤ exerts powerful toxic effects on neurons.…”

Characterization of Japanese-American men with a single neocortical AD lesion type

“…When the two plaque types have been distinguished, the linkage with cognitive impairment has usually been strongest for NP. [5,31] The question of whether the presence of the subgroup NP in the neocortex is as strongly associated with cognitive decline as neocortical NFT is unresolved. Bennett reported that the association of amyloid load with AD severity is mediated by NFT.…”