Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature

Abstract

Clinicopathologic correlation studies are critically important for the field of Alzheimer disease (AD) research. Studies on human subjects with autopsy confirmation entail numerous potential biases that affect both their general applicability and the validity of the correlations. Many sources of data variability can weaken the apparent correlation between cognitive status and AD neuropathologic changes. Indeed, most persons in advanced old age have significant non-AD brain lesions that may alter cognition independently of AD. Worldwide research efforts have evaluated thousands of human subjects to assess the causes of cognitive impairment in the elderly, and these studies have been interpreted in different ways. We review the literature focusing on the correlation of AD neuropathologic changes (i.e. β-amyloid plaques and neurofibrillary tangles) with cognitive impairment. We discuss the various patterns of brain changes that have been observed in elderly individuals to provide a perspective for understanding AD clinicopathologic correlation and conclude that evidence from many independent research centers strongly supports the existence of a specific disease, as defined by the presence of Aβ plaques and neurofibrillary tangles. Although Aβ plaques may play a key role in AD pathogenesis, the severity of cognitive impairment correlates best with the burden of neocortical neurofibrillary tangles.

Figures

FIGURE 1

Photomicrograph of a section from the cerebral neocortex of an Alzheimer disease brain stained using double-label immunohistochemistry for β-amyloid (Aβ, reddish brown) and microtubule-associated protein tau (black). Aβ plaques (AβPs; blue arrows) are roughly spherical and extracellular, whereas neurofibrillary tangles (NFTs; green arrows) develop within neurons. Note that some of the dystrophic neurites in the AβPs contain aberrant tau protein pathology (black), which is biochemically identical to that seen in intracellular NFTs. These AβPs have been described to be “neuritic plaques.” Scale bar = 50 μm.

FIGURE 2

(A, B) Correlations between antemortem cognitive status (final Mini-Mental State Examination [MMSE] scores), counted neocortical neurofibrillary tangles (NFTs; A), and neuritic β-amyloid plaques (NPs; B) for 178 patients lacking concomitant neuropathologic findings (189). Each circle represents data from a single individual. Neurofibrillary tangles and NPs were counted and summed from 4 different portions of cerebral neocortex: Brodmann areas 21/22, 18/19, 9, and 35, as described (189). Data are reprinted with permission from the Journal of Neuropathology and Experimental Neurology (2007;66:1136–46). Copyright 2007, American Association of Neuropathologists. The correlation between final MMSE scores and neocortical NFT counts is stronger than that between MMSE scores and NP counts.

FIGURE 3

Correlations between antemortem cognitive status (“dementia scores”) and counted amyloid plaques from the 1968 article by Blessed et al (254). Dementia scores were derived from “psychological tests of orientation, remote memory, recent memory, and concentration.” Amyloid plaques were visualized using the von Braunmühl silver stain. Each circle represents data from a single individual. There is reasonable correlation between the dementia scores and the number of plaques, although this work antedated the era of neocortical synucleinopathy, TDP-43, and other factors now known to both clinicians and neuropathologists. This figure was reproduced with permission from The British Journal of Psychiatry (1968;114:797–811). Copyright 1968, The Royal College of Psychiatrists.

FIGURE 4

β-Amyloid (Aβ) phase showing the relationship between cognition, as represented by the retrospectively determined clinical dementia rating scale (CDR) score, and the phase of Aβ deposition determined in the medial temporal lobe (MTL) in 202 cases (103, 262). Non–Alzheimer disease (AD) dementia cases were excluded from this analysis. (A) Almost all demented cases exhibited end phases of the expansion of Aβ deposition without major differences; cases without dementia had early-phase Aβ pathology (partial correlation controlled for age and sex for all cases: r = 0.582, p < 0.001; only for AD cases: r = 0.086, p = 0.605). (B) Relationship between Braak neurofibrillary tangle (NFT) stage and Aβ phase in 201 AD and control cases. With increasing Braak ? NFT stage, the distribution of Aβ plaque deposition expanded to end-phase Aβ deposition reached with Braak NFT stage IV (partial correlation controlled for age and sex for all cases: r = 0.621, p < 0.001; only for AD cases: r = 0.07, p = 0.671).

FIGURE 5

Development of phospho-tau (AT8)-immunoreactivity (ir) versus β-amyloid (Aβ) pathologic findings. (A) White columns indicate the relative frequency of 2,332 nonselected autopsy cases devoid of any abnormal intraneuronal tau deposits. Columns in shades of blue indicate the relative frequency of cases with all types of intraneuronal lesions (Braak NFT stages). (B) Development of extracellular Aβ deposits. Purple areas within the columns indicate subgroups of cases showing plaque-like Aβ-amyloid deposits in temporal neocortex (Phase 1, light purple), allocortex and neocortical association areas (Phases 2 and 3, middle purple and dark purple), or in virtually all cerebral cortical regions (Phase 4, black). Note the relatively late appearance of Aβ plaques in comparison to subcortical neurofibrillary tangles. This figure is reproduced with permission from the Journal of Neuropathology and Experimental Neurology (2011;70:960–99) (44). Copyright 2011, American Association of Neuropathologists.