Biochemical studies show that phosphorylated tau, like that found in paired helical filaments (PHFs), does not promote microtubule assembly leading to the view that PHF formation leads to microtubule deficiency in Alzheimer's disease (AD). However, although this issue is one of the most important aspects to further understanding the cell biology of AD, no quantitative examination of microtubule diminution in AD and its relationship with PHFs has been performed. To examine this issue directly, we undertook a morphometric study of brain biopsy specimens from AD and control cases. Ultrastructural analysis of neurons was performed to compare the microtubule assembly state in neurons of diseased and control cases and to examine the effect of PHF accumulation. We found that both number and total length of microtubules were significantly and selectively reduced in pyramidal neurons from AD in comparison to control cases (P = 0.000004) but that this decrement in microtubule density was surprisingly unrelated to PHFs (P = 0.8). Further, we found a significant age-dependent decrease in microtubule density with aging in the control cases (P = 0.016). These findings suggest that reduction in microtubule assembly is not dependent on tau abnormalities of AD and aging.