Neuropathology of the Alzheimer's continuum: an update

Abstract

Alzheimer's disease (AD), the most common form of dementia worldwide, is a mixed proteinopathy (amyloid and tau). Originally defined as a clinicopathological entity, it is a heterogenous, multifactorial disorder, currently referred to as the Alzheimer's continuum. Its cardinal pathological features are extracellular β-amyloid (amyloid plaques) and intraneuronal tau aggregates forming neurofibrillary tangles, which are accompanied by vascular amyloid deposits (cerebral amyloid angiopathy), synapse and neuronal loss, as well as neuroinflammation and reactive astrogliosis. In addition to "typical" AD, various subtypes with characteristic regional patterns of tau pathology have been described that show distinct clinical features, biomarker levels, and patterns of key network destructions responsible for cognitive decline. AD is frequently associated with other age-related changes including Lewy and TDP-43 pathologies, hippocampal sclerosis, argyrophilic grain disease, cerebrovascular lesions, and others. These additional pathologies influence the clinical picture of AD, may accelerate disease progression, and can cause a number of challenges in our understanding of the disease including the threshold of each individual pathology to cause dementia and the possibility of underlying common etiologies. This article provides an up-to-date overview of AD neuropathology, its heterogeneity, and additional pathologies in order to explain the difficulties in the diagnosis and the failure of clinical trials in AD patients.

Keywords: Alzheimer subtypes; Alzheimer’s disease; Amyloid angiopathy; Co-pathologies; Oligomers; Regional vulnerabiliy; Tau pathology; β-Amyloid.

Figure 1

Comparison between formalin-fixed brain slices of the left hemispheres (level of posterior hippocampus) of an aged nondemented individual (A) and an AD patient (B). Note the marked atrophy (thinning of the gyri and deepening of the sulci) in B, in particular hippocampal atrophy (arrow in B) with widening of the inferior horn of the second ventricle (asterisk in B). Photographs by courtesy of Simon Fraser and Arthur Oakley.

Figure 2

Amyloid and neuritic plaques. A; A1. Multiple diffuse amyloid plaques in the neocortex (antibody 4G8). B, B1. Neuritic plaques that contain Aβ and tau in distended processes (i.e. dystrophic neurites). Gallyas silver stain visualizes both aggregated Aβ and tau and is therefore ideal to detect neuritic plaques (ring in B, neuritic plaque; arrow in B1, dystrophic neurite; arrowhead in B1, neurofibrillary tangle). Scale bars: 200 μm. From [71].

Figure 3

EM image of amyloid core of a neuritic plaque. Radiating bands of amyloid fibrils comprise the core (x). Note the adjacent abnormal fibrils filled with dense bodies (arrows) and surrounding damaged myelin sheaths (x 4000).

Figure 4

Multiple large hemorrhages in both frontal lobes (A) and occipital lobe (B). Diffuse white matter destruction (C). CAA in many vessels in the cerebral white matter; scale bar 70 µm (D). From [97].

Figure 5

In AD, high amounts of neurofibrillary tangles and neuropil threads are seen in the hippocampus (A). CA1, CA2, and CA4 hippocampal cornu ammonis (Ammon’s horn) sectors 1, 2, and 3, respectively; GR, granule cell layer of the dentate gyrus. Immunohistochemistry with antibody AT8. Scale bar: 50 μm. From [71].

Figure 6

Spreading pattern of neuritic AD pathology. Modified from [18].

Figure 7

Staging of Aβ, NFT, and CAA in non-demented (pre-AD) and demented AD patients. From [195].

Figure 8

Pathway of the combination of different pathological features that allows a classification of ADNC according to the NIA-AA guidelines.

Figure 9

Main factors and characteristics of the four major subtypes of AD. AD: Alzheimer’s disease; NFT: neurofibrillary tangle; WMH: white matter hyperintensity; CAA: cerebral amyloid angiopathy; EOAD: early-onset Alzheimer’s disease; LOAD: late-onset Alzheimer’s disease; LP-AD: limbic-predominant AD.