The Preclinical Phase of the Pathological Process Underlying Sporadic Alzheimer's Disease

Heiko Braak; Kelly Del Tredici


Brain. 2015;138(10):2814-2833. 

In This Article

Abstract and Introduction


Abnormal tau lesions (non-argyrophilic pretangle material, argyrophilic neuropil threads, neurofibrillary tangles) in select types of neurons are crucial for the pathogenesis of sporadic Alzheimer's disease. Ongoing formation of these tau lesions persists into end-stage Alzheimer's disease and is not subject to remission. The early pretangle disease phase is a focus of increasing interest because only abnormal forms of the microtubule-associated protein tau are involved at that point and, in contrast to late-stage disease when amyloid-β deposition is present, this phase is temporally closer to the prevailing conditions that induce the pathological process underlying Alzheimer's disease. Extracellular and aggregated amyloid-β may only be produced under pathological conditions by nerve cells that contain abnormal tau. One potential trigger for tau protein hyperphosphorylation and conformational change in Alzheimer's disease may be the presence of a non-endogenous pathogen. Subsequently, a predictable regional distribution pattern of the tau lesions develops in phylogenetically late-appearing and ontogenetically late-maturing neurons that are connected via their axons. It is hoped that hypotheses drawn from these considerations, as well as from recent tau dissemination models, from studies of variant tau conformers, and from tau imaging will encourage the development of new preventative and disease-modifying strategies.


The present review aims to summarize and discuss key features of the early stages of a pathological process that ultimately leads to clinically overt sporadic Alzheimer's disease in a small proportion of individuals. As in many other conditions, the early stages of this process remain asymptomatic. The overall process, which may begin in young adulthood and childhood (Braak and Del Tredici, 2011a; Braak et al., 2011; Duyckaerts, 2011; Elobeid et al., 2011) is protracted; however, it is relentlessly progressive and irreversible (Montine et al., 2012; Braak and Del Tredici, 2015a). Much later, with advancing age, some individuals cross a barely detectable threshold to the symptomatic phase (Sabbagh et al., 2010; Albert et al., 2011; Yaffe et al., 2012). The prevalence of symptomatic cases rises with increasing age and, for this reason, societies with longer life expectancies are subject to a growing Alzheimer's disease burden (Brookmeyer et al., 2007; Mayeux and Stern, 2012).

The Alzheimer's disease-associated pathological process is almost entirely confined to the human CNS (Arnold et al., 2010; Dugger et al., 2013). Reliable morphological features of the Alzheimer's disease-related tau lesions make it possible to detect a typical lesional distribution pattern within the CNS, and these lesions appear to proliferate in a predictably systematic manner (Table 1, Figs 1A–D and 4B–F). Moreover, the developmental pattern and progression of the lesions also repeat phylo- and ontogenetic maturational phases of the CNS, however, this time in reverse (Braak and Braak 1996; Reisberg et al., 1999, 2002). Accordingly, late-maturing structures are frequently the ones that display the disease-associated tau lesions particularly early. Phylogenetically older and ontogenetically early-maturing components, on the other hand, prove to be resistant. Here, we focus chiefly on those structures that first emerged late phylogenetically, i.e. during the period when the human species was evolving out of higher primate precursors (Rapoport, 1988, 1990, 1999; Rapoport and Nelson, 2011).

Figure 1.

AT8-immunopositive NFT stages I-VI of the pathological process underlying sporadic Alzheimer's disease in coronal 100 μm sections cut perpendicular to the intercommissural axis. (A) NFT stages I (left) and II (right) in a cognitively unremarkable 80-year-old female, who died of myocardial infarction. The tau pathology develops first and foremost in the most superficial cellular layer (layer pre-α) of the transentorhinal (stage I) and entorhinal cortex (stage II). (B) NFT stages II (left) and IV (right) in a 75-year-old cognitively impaired male, who died of a metastatic pulmonary neoplasm. Differences between hemispheres usually do not exceed more than one NFT stage. The existence of such cases makes it very unlikely that a separate 'age-related non-Alzheimer's disease-related' tauopathy exists, in which, purportedly, the tau lesions intrinsically do not progress beyond the limits of the entorhinal cortex and hippocampus. (C) NFT stage III in a 90-year-old female (cause of death: malignant pancreas neoplasm). The section is cut through the hippocampal formation at the level of the uncus (left) and through the amygdala (right). Here, the Alzheimer's disease-related tau changes are seen not only in the transentorhinal and entorhinal cortices but also in the medially adjoining amygdala and hippocampal formation, as well as in laterally adjoining portions of the basal temporal neocortex. (D) NFT stage VI in a 72-year-old severely demented female patient with Alzheimer's disease (cause of death: aspiration pneumonia). Note that all portions of the cerebral cortex become involved in the late-phase of the Alzheimer's disease process. Scale bar in B applies to A, C and D. (E and F) Major entorhinal connectivities. (E) Neocortical afferences (black arrows) converge on the transentorhinal and entorhinal layer pre-α, whence the data are transferred via the perforant path (red arrows) to the hippocampal formation. The border between the entorhinal and transentorhinal regions is marked by a dashed grey line. (F) A dense back-projection from the subiculum in the hippocampal formation terminates in the entorhinal deep layer pri-α (blue arrows) and is transferred from there back to the neocortex (black arrows). Adapted with permission from Braak H and Del Tredici K, Alzheimers Dement 2012; 8: 227-33 and Adv Anat Embryol Cell Biol 2015a; 215: 1-162.

A shared hallmark of the structures that are vulnerable to the Alzheimer's disease-related process is that they serve 'higher' CNS functions characteristic of the human brain: either structures of the cerebral cortex itself or components of subcortical nuclei that diffusely project to and optimize complex functions of the human cerebral cortex (O'Donnell et al., 2012). On the other hand, none of them are absolutely essential for the preservation of the 'primitive' brain functions required for existence, so that their partial loss or partial impairment does not jeopardize life expectancy. The following section is intended to briefly summarize the aforementioned hallmark structures serving higher CNS functions together with their major interconnectivities.