Dissociation of neuropathologic findings and cognition: case report of an apolipoprotein E epsilon2/epsilon2 genotype

Abstract

Background: The apolipoprotein E (APOE) epsilon2 allele has been suggested as having a protective effect and delaying the age at onset of Alzheimer disease.

Objective: To describe a dissociation between neuropathologic findings with normal cognition in a woman with severe Alzheimer disease with the APOE epsilon2/epsilon2 genotype.

Design: Case report from a community-based prospective study of persons 90 years or older (The 90+ Study).

Participant: A 92-year-old woman without dementia with the APOE epsilon2/epsilon2 genotype who lived independently without significant cognitive or functional loss and was a participant in The 90+ Study. She died in December 2004, and postmortem examination of her brain was performed.

Intervention: Neurologic examination and a battery of neuropsychological tests were performed 6 months and 1 month before death. Neuropathologic examination included Braak and Braak staging for senile plaques and neurofibrillary tangles.

Results: Neuropathologic examination of the brain revealed advanced senile plaque and neurofibrillary tangle disease consistent with a high likelihood of Alzheimer disease. At clinical evaluation, the participant demonstrated no dementia and only mild cognitive deficits.

Conclusions: The APOE genotype may have contributed to maintenance of cognition despite advanced neuropathologic findings of Alzheimer disease. This case suggests that the APOE epsilon2 isoform may have a protective effect against cognitive decline in Alzheimer disease that may be independent from senile plaques and neurofibrillary tangles.

Figure 1

The case subject demonstrated neocortical neuropathologic features of Alzheimer disease. At histopathologic analysis, a section of inferior parietal cortex immunostained with polyclonal rabbit antihuman tau (DAKO, Carpenteria, California) showed neuritic plaque formation and neurofibrillary degeneration (arrows).

Figure 2

Neuropathologic features in the case subject compared with matched control subjects. Note pathologic features in area CA1/subiculum of the hippocampus in the case subject. β-Amyloid deposition is absent in area CA1/subiculum in a 99-year-old woman without dementia (A), primarily diffuse in the case subject (B), and associated with extracellular neurofibrillary tangles and compact neuritic plaques in a 94-year-old woman with dementia (C). Neurofibrillary tangle accumulation was sparse in the control subject without dementia (D) but was comparable in the case subject (E) and the control subject with dementia (F) AD indicates Alzheimer disease; bar, 100 μm.