ALTERATIONS IN TAN PROTEIN-METABOLISM DURING NORMAL AGING

It is unknown whether aging and Alzheimer's disease (AD) are on the sa me continuum, or whether they are qualitatively distinct. Tan protein has been identified as a major constituent of paired helical filaments (PHFs) and AD is characterised by a major redistribution of the norma l tau protein pool into PHFs. Little is known about the changes in tau protein distribution that occur in the course of normal aging. We hav e examined PHF-bound and normal tau fractions in frontal, temporal, pa rietal and occipital neocortex, cerebellum, hippocampus and entorhinal cortex in 15 cognitively unimpaired individuals aged 19-88 years at d eath. Insoluble tau protein in the PI-IF fraction did not increase wit h aging in any brain region, despite the appearance of neurofibrillary pathology at low density in the more elderly cases. By contrast, norm al tau protein decreased with aging (r = 0.32, p < 0.001), with an ave rage loss of 14% of soluble tau per decade after the age of 20 years. This was unrelated either to neurofibrillary or beta-amyloid pathology . Frontal grey matter and hippocampus were most vulnerable to age-rela ted tau loss, decreasing by as much as 90% in the older subgroup. Thes e findings contrast with those we have previously reported in AD, wher e the redistribution of tau protein into the PHF-bound fraction was hi ghly correlated with the extent of neurofibrillary pathology, and sugg est that the mechanisms of tau loss in aging and AD are distinct. Age- related tau loss may underlie the neuropsychological impairments seen in the non-demented elderly.