Thinking outside the box: Alzheimer-type neuropathology that does not map directly onto current consensus recommendations

The brains of many cognitively impaired patients fall into neuropathologic diagnostic categories that cannot be defined explicitly by guidelines of the National Institute on Aging and Reagan Institute. Here, 2 specific case categories are considered: i) "tangle-intensive" patients with the highest density of neurofibrillary tangles (as graded by the Braak staging system) but only moderate density of neuritic amyloid plaques (as graded by the Consortium to Establish a Registry for Alzheimer's Disease); and ii) "plaque-intensive" patients with intermediate severity neurofibrillary tangles and high density of neuritic amyloid plaques. To understand these technically unclassifiable cases better, we analyzed 1,677 cases with antemortem diagnoses of dementia from the National Alzheimer's Coordinating Center Registry; this registry includes both clinical and pathologic data from the National Institute on Aging-funded Alzheimer Disease Center. To evaluate the diagnostic tendencies of Alzheimer Disease Center neuropathologists, we assessed how the plaque-intensive and tangle-intensive cases were diagnosed. Tangle-intensive cases were more likely to be designated "high likelihood" that the dementia was due to Alzheimer disease, whereas plaque-intensive cases were typically designated as "intermediate likelihood." Only the Braak Stage VI tangle-intensive cases had lower final Mini-Mental State Examination scores than the plaque-intensive cases (p < 0.02). We conclude that more explicit diagnostic categories and a better understanding of the pathology in earlier phases of the disease may be helpful for guiding neuropathologists in the diagnosis of Alzheimer disease.