Neuropathological alterations in Alzheimer disease

Abstract

The neuropathological hallmarks of Alzheimer disease (AD) include "positive" lesions such as amyloid plaques and cerebral amyloid angiopathy, neurofibrillary tangles, and glial responses, and "negative" lesions such as neuronal and synaptic loss. Despite their inherently cross-sectional nature, postmortem studies have enabled the staging of the progression of both amyloid and tangle pathologies, and, consequently, the development of diagnostic criteria that are now used worldwide. In addition, clinicopathological correlation studies have been crucial to generate hypotheses about the pathophysiology of the disease, by establishing that there is a continuum between "normal" aging and AD dementia, and that the amyloid plaque build-up occurs primarily before the onset of cognitive deficits, while neurofibrillary tangles, neuron loss, and particularly synaptic loss, parallel the progression of cognitive decline. Importantly, these cross-sectional neuropathological data have been largely validated by longitudinal in vivo studies using modern imaging biomarkers such as amyloid PET and volumetric MRI.

Figure 1.

Photomicrographs of the core pathological lesions observed in Alzheimer and Lewy body diseases. (A) Plaque evident on routine H&E stained section of frontal cortex; (B) tangle in a hippocampal pyramidal neuron on routine H&E stained section; (C) silver stain highlights both a plaque and a tangle; (D) immunohistochemistry against Aβ highlights plaques; (E) immunohistochemistry against tau highlights tangles; (F) a cortical Lewy body can be seen in a layer V neuron on a routine H&E stained section of frontal cortex.

Figure 2.

Spatiotemporal pattern of neurofibrillary degeneration. Shading indicates the distribution of NFTs with darker colors representing increasing densities. Amyg = Amygdala; EC = Entorhinal cortex; CA1 = Cornus ammonis 1 hippocampal subfield; Cg = Cingulate cortex; Prec = Precuneus; 4 = Primary motor cortex; 3-1-2 = Primary sensory cortex; 17 = Primary visual cortex; 18 = Associative visual cortex (data based on Arnold et al. 1991; Braak and Braak 1991; Arrigada et al 1992a,b; Braak et al. 1994).

Figure 3.

Spatiotemporal pattern of amyloid plaque deposition according to Thal et al. (2002). Coronal (A), axial (B), and sagittal (C) views of the brain. The five Thal stages of amyloid deposition are here summarized in three stages. Amyloid deposits accumulate first in isocortical areas (stage 1 or isocortical, in red), followed by limbic and allocortical structures (stage 2 or limbic, in orange), and in a later stage, by subcortical structures including basal ganglia, selected nuclei in diencephalon and brainstem, and the cerebellar cortex (stage 3 or subcortical, in yellow). Amyg = Amygdala; EC = Entorhinal cortex; Hipp = Hippocampus; Cg = Cingulate cortex; Cd = Caudate nucleus; Put = Putamen; Gpe = Globus pallidus externus; Gpi = Globus pallidus internus; Cl = Claustrum; Ins = Insular cortex; Die = Diencephalon; Mid = Midbrain; Med = Medulla oblongata; Cblm = Cerebellum.