Elsevier

Neurobiology of Aging

Volume 35, Issue 2, February 2014, Pages 301-308
Neurobiology of Aging

Regular article
A 2-process model for neuropathology of Alzheimer's disease

https://doi.org/10.1016/j.neurobiolaging.2013.08.007Get rights and content

Abstract

This study examined relations among neuritic and diffuse plaques, neurofibrillary tangles, age, and apolipoprotein E (APOE) in 2 large samples of neuropathology cases, the Religious Orders Study and the Memory and Aging Project. Cognitive status ranged from normal to demented and AD neuropathology ranged from none to severe. Confirmatory factor analysis identified a best-fitting 4-factor solution to describe interrelationships among plaques and tangles: a global neuritic plaque factor; a global diffuse plaque factor; a factor defined by medial temporal neurofibrillary tangles; and a neocortical tangle factor. Results supported a hypothesis that neuritic plaques mediate the association of age and APOE with neocortical tangles, and similarly mediate the effect of APOE on medial temporal tangles. However, medial temporal tangles were related to age independent of neuritic plaques. These results support a primary amyloid-based AD process that accounts for neocortical tangles and makes the largest contribution to medial temporal tangles. A second, age-related but non-amyloid process likely contributes to medial temporal lobe tangles.

Introduction

Alzheimer's disease (AD) has been defined by neuropathological features of neuritic plaques and neurofibrillary tangles since it was first identified in 1906 and these 2 types of neuropathology continue to constitute the basis for the neuropathological diagnosis of AD (Hyman, 1997, Hyman et al., 2012, Montine et al., 2012). There is an extensive literature on the relationship of these neuropathological features to clinical status (Bennett et al., 2004, Gomez-Isla et al., 2008, Nelson et al., 2009b). A widely accepted model of neuropathological and clinical progression of AD posits that neurofibrillary tangles initially appear in the entorhinal cortex and hippocampus and later spread to the neocortex. This forms the basis for the widely used Braak and Braak staging of AD pathology (Braak and Braak, 1991, Braak et al., 1993, Thal et al., 2008) and provides an anatomical explanation for the progression of clinical symptoms. Because the hippocampus is a critical anatomical substrate of episodic memory, the early presence of neurofibrillary tangles in the hippocampus helps to explain the amnesia associated with early AD. Neurofibrillary tangle pathology in neocortical areas in later stages of AD corresponds to broader cognitive impairment, affecting non-memory domains and resulting in clinical dementia. Regional and spatial patterns of neuritic plaques do not show the same characteristic pattern as for neurofibrillary tangles (Longstreth et al., 2009, Sonnen et al., 2008, Thal et al., 2008); specifically, neuritic plaques are likely to be distributed throughout neocortical regions in the earliest stages of plaque development (Thal et al., 2008).

At the level of molecular biology, the “amyloid cascade hypothesis” has emerged as the leading theory to explain the development of AD neuropathology (Hardy and Allsop, 1991, Hardy and Higgins, 1992, Selkoe, 1991). This hypothesis posits that the formation and deposition of amyloid-β peptide (Aβ), the primary constituent of neuritic plaques, is the first step in a sequence of events that ultimately leads to impaired cell function, the formation of neurofibrillary tangles, cell death, cognitive decline, and clinical dementia (Jack et al., 2010). It is supported by the observation that all 3 genetic mutations associated with early onset AD and the apolipoprotein E polymorphism (APOE) alter the metabolism of amyloid, are associated with development of neuritic plaques composed of Aβ, and manifest tangle formation. Furthermore, preclinical data support a linkage between Aβ processing and tangle formation (Klein et al., 2004, Oddo et al., 2006).

A comprehensive explanation of the genesis of AD should incorporate neurobiology, neuropathology, and clinical characteristics. The amyloid cascade hypothesis explains many of the findings related to AD, but is problematic in some respects. Notably, this hypothesis would suggest that the presence of neurofibrillary tangles should mirror the presence of amyloid plaques (Longstreth et al., 2009). However, repeated observations indicate that this is not the case; neurofibrillary tangles are commonly observed in medial temporal lobes in the absence of amyloid plaques (Jellinger and Bancher, 1998, Murray et al., 2011, Nelson et al., 2009a).

An alternatative explanation for the observation of medial temporal neurofibrillary tangles in the absence of amyloid plaques is that medial temporal tangles could result from a second, non-AD process (Nelson et al., 2009a). We hypothesize that 2 independent processes may better explain the complex relation of amyloid and tangles to aging, AD, and cognition. Process 1 is prototypical AD, and leads to amyloid deposition throughout the neocortex and medial temporal lobes and to widespread tangle formation and impairment in multiple cognitive domains. Process 2 is a different age-related process, is associated with tangle formation in the medial temporal lobes, and presumably contributes to episodic memory deficits. It is well known that mixed pathologies commonly contribute to cognitive impairment in old age (Petrovitch et al., 2005, Schneider et al., 2007, Sonnen et al., 2007, Troncoso et al., 2008). It is also well accepted that other diseases, such as fronto-temporal lobe dementia, can manifest pathologically with tangles in the absence of amyloid (Dickson, 2009, Nelson et al., 2009a). The 1- and 2-process explanations of tangle formation generate different predictions about relations of major risk factors such as age and APOE with plaques and tangles. In the 1-process formulation, age and APOE relate to tangles via mediating effects of plaques. In the 2-process account, medial temporal tangles would have an additional relationship with age that could not be explained by plaques.

The goal of this study was to evaluate competing hypotheses from 1- and 2-process models to account for relationships among age, APOE, and regional measures of the characteristic neuropathological features of AD, neuritic plaques, diffuse plaques, and neurofibrillary tangles. One hypothesis is that these features all are manifestations of a unitary AD process. In this case, neurofibrillary pathology throughout the brain would be related to age and APOE via the mediating effects of neuritic plaques and would not be related to these risk factors after controlling for neuritic plaques. An alternative hypothesis would posit a typical AD process that would explain much of the observed neuropathology, but also an additional process that would provide incremental explanation of neurofibrillary tangles in the medial temporal lobes. This explanation would predict that the relation of age with medial temporal neurofibrillary tangles would fall outside the primary AD pathway and would not be entirely explained by neuritic plaques, whereas in contrast, APOE effects would be AD related and mediated by neuritic plaques.

This study took advantage of a relatively large neuropathology sample with well-characterized and broadly variable AD neuropathology. We used latent variable modeling to characterize the plaque and tangle neuropathology of AD and to test competing hypotheses about how neuropathology indices relate to one another and to age and APOE. Latent variables are statistical representations of conceptual constructs that are not directly measurable. They are empirically derived to explain covariance among observable but imperfect indicators of the constructs of interest, and in so doing, may help to define, measure, and clarify these constructs and how they relate to directly observed external variables.

Section snippets

Participants

The Religious Orders Study (ROS) and the Memory and Aging Project (MAP) are both community-based, prospective cohort studies of risk factors for incident AD and other chronic conditions of aging conducted by the Rush Alzheimer's Disease Center. Recruitment and inclusion criteria for these studies and subject evaluations have been previously described in detail (Wilson et al., 2003, Wilson et al., 2002a, Wilson et al., 2002b). Briefly, both studies recruit older individuals without known

Measurement model (M-1 to M-8)

The fit of the alternative models for explaining relations among the neuropathology indicators of AD using the ROS sample is summarized in Table 2. Model fit was generally good for the 3- and 4-factor models but was better for solutions with more factors. The 6-factor solution (M-8) had the best fit, but there was technical evidence suggesting that too many factors were being extracted. The 4-factor solution with single NP and DP factors and 2 NFT factors showed the best fit among the remaining

Discussion

Results of this study support the presence of 2 processes underlying amyloid plaques and neurofibrillary tangles, the characteristic neuropathological features of AD. The dominant process is a classic AD process characterized by neuritic plaques and neurofibrillary tangles throughout the brain. This process, as would be expected, was related in this study to 2 major risk factors for AD, older age and APOE ε4. Age and APOE were associated with neuritic (amyloid) plaques; neuritic plaques in turn

Disclosure statement

The authors have no conflicts of interest in relation to this study.

Acknowledgements

This work was supported by grants from the National Institute on Aging P30 AG10161 (P.I.B.), R01 AG15819 (P.I.B.), and R13 AG030995 (P.I.M.).

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