Apolipoprotein E immunoreactivity in neurons and neurofibrillary degeneration of aged non-demented and Alzheimer's disease patients.

Apolipoprotein E (ApoE) genotype is a risk factor for Alzheimer's disease (AD) but its relationship with neurofibrillary degeneration remains obscure. To further analyze this relationship, hippocampal, entorhinal, temporopolar, and insular cortices of 10 non-demented and 7 Alzheimer disease brains were studied with both light and electron microscopy. Focus was directed on pretangles and neurons starting to accumulate tangles. ApoE immunolabeling in neurons and tangles was independent of ApoE individual genotype. The majority of the neurons in all of the brains were ApoE-negative, but virtually every brain also contained groups of ApoE-immunoreactive neurons, with diffuse cytoplasmic labeling. Most of the ApoE-positive tangles were extracellular, but a few tangles were shown to be intraneuronal when studied ultrastructurally. No ApoE immunoreactivity was found in neuropil threads, as well as in neurites associated with senile plaques. Double protocols with both AT-8 and anti-ApoE antibodies, performed to determine whether ApoE-positive neurons were pretangle neurons, did not detect cytoplasmic AT-8 in ApoE-positive neurons. Though careful electron microscopy studies found ApoE reaction product in an occasional ApoE-positive pretangle-like neuron and a few intracellular tangles, these findings do not support that ApoE is necessary for the accumulation of hyperphosphorylated tau protein. The more consistent colocalization of anti-ApoE and AT-8 in extracellular tangles reveals that ApoE mainly binds to tangles once they are in the extracellular space, in a manner similar to that described for amyloid fibrils.