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

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.

Keywords: APOE; Age; Alzheimer's disease; Latent variable modeling; Neuropathology.

Figure 1

Analytic model and structural relationships among age, APOE, and latent neuropathology factors. Heavy solid lines show effects of age and APOE on neuropathology factors. Heavy dashed lines show effects on neuritic and diffuse plaques on neurofibrillary tangles. This represents the primary structural model (S-1) in which all of the indicated parameters were simultaneously estimated. Factor loadings were estimated in this model but are not presented. Paths from neuritic and diffuse plaques to neurofibrillary tangle (heavy dashed lines) were dropped in a secondary analysis to evaluate simple effects of age and APOE on neurofibrillary tangles. ENT – entorhinal cortex, HC = hippocampus, MT = mid-temporal cortex, MF = mid-frontal cortex, IP = inferior parietal cortex.

Figure 2

Conceptual model to explain how risk factors (age and APOE) relate to neuritic plaque and neurofibrillary tangle neuropathology. Solid boxes are observed variables in this study, and solid ovals are latent variables in this study measured by the observed neuropathology ratings. Curved dotted lines represent paths tested in this study, and values are the estimated standardized regression coefficients for these paths. Dashed ovals in the center are hypothesized processes to explain study results. Primary AD is a postulated, amyloid based, causative agent for neuritic plaques and neurofibrillary tangles. The mechanisms of Primary AD require future clarification, but correlations of plaques with tangles are hypothesized to result from their common relations with Primary AD. A non-amyloid process, or processes, is required to explain the association of age with medial temporal neurofibrillary tangles that cannot be explained by the amyloid path.