Relative to the gray matter, there is a paucity of information regarding white matter biochemicalalterations and their contribution to Alzheimer's disease (AD). Biochemical analyses of AD white mattercombining size-exclusion, normal phase, and gas chromatography, immunoassays, and Western blottingrevealed increased quantities of A
40 and A
42 in AD white matter accompanied by significant decreasesin the amounts of myelin basic protein, myelin proteolipid protein, and 2',3'-cyclic nucleotide3'-phosphodiesterase. In addition, the AD white matter cholesterol levels were significantly decreasedwhile total fatty acid content was increased. In some instances, these white matter biochemical alterationswere correlated with patient apolipoprotein E genotype, Braak stage, and gender. Our observations suggestthat extensive white matter axonal demyelination underlies Alzheimer's pathology, resulting in loss ofcapacitance and serious disturbances in nerve conduction, severely damaging brain function. These whitematter alterations undoubtedly contribute to AD pathogenesis and may represent the combined effects ofneuronal degeneration, microgliosis, oligodendrocyte injury, microcirculatory disease, and interstitial fluidstasis. To accurately assess the success of future therapeutic interventions, it is necessary to have a completeappreciation of the full scope and extent of AD pathology.