O4-08-04: Cerebrospinal fluid tau levels increase with age and are associated with neurodegeneration even in the absence of cerebral amyloid

We have known for more than 20 years that isolated medial temporal lobe (MTL) neurofibrillary pathology (in the absence of amyloid plaques) is increasingly common with age. In contrast, the amyloid hypothesis of Alzheimer's disease (AD) posits that amyloid plaques are an early feature followed by tau-related neurodegeneration. JL Price and others have proposed that mild MTL and nearby temporal cortical neurofibrillary pathology may be nearly universal with aging and is not necessarily accompanied by amyloid pathology, but that in the presence of amyloid pathology, neurofibrillary pathology is accelerated. To date, this proposal has received little direct investigation. We included data from the ADNI-1 database from individuals who were cognitively normal or diagnosed with mild cognitive impairment (MCI) and who had baseline MRI and cerebrospinal fluid (CSF) data. Using CSF beta-amyloid levels, we classified individuals as likely to have cerebral amyloid consistent with AD pathology (<192) or not (>192). We compared cortical thickness between these groups and also examined cortical thickness correlates of CSF tau levels. We tested the hypothesis that individuals without evidence of cerebral amyloid would demonstrate cortical atrophy in the MTL and nearby regions in association with CSF tau levels, and that this relationship would be stronger in the presence of cerebral amyloid. CSF tau but not beta-amyloid levels increase with age. In the entire sample, CSF tau levels were strongly related to cortical atrophy, particularly in MTL but also including ventral and lateral temporal as well as lateral parietal and precuneus cortex. When amyloid negative individuals were examined, a similar though more restricted pattern was observed. In amyloid-negative MCI subjects, elevated CSF tau levels are associated with MTL atrophy which is correlated with memory impairment. Increasing CSF tau levels are associated with age and, even in the absence of brain amyloid, relate to regional cortical atrophy with a topographic pattern similar to that reported in post-mortem studies. In MCI, age-related neurofibrillary pathology in the absence of cerebral amyloid may be one underlying cause of memory system neurodegeneration and memory impairment.