Predictive value of phospho-tau/total-tau ratio in amyloid-negative Mild Cognitive Impairment

• Prognostication in MCI patients with normal amyloid biomarkers is challenging. • Patients with normal CSF amyloid-β 1-42 but low p/ t -tau ratio had higher risk of subsequent conversion to dementia . • Patients with low p/ t -tau ratio had brain atrophy involving the limbic system including medial temporal lobe, posterior cingulate and subgenual cortex. • We speculate that amyloid negative MCI who developed dementia may have had underlying TDP-43 pathology. In patients with Mild Cognitive Impairment and normal biomarkers of amyloid-β deposition, prognostication remains challenging. We aimed at identifying clinical features, patterns of brain atrophy, and risk of subsequent conversion to dementia in a clinical cohort of consecutive patients with Mild Cognitive Impairment and normal CSF amyloid-β 1-42 presenting to our Cognitive Neurology Clinic who were followed prospectively over an average of 25 months. We stratified them as Converters/Non-Converters to dementia based on clinical follow-up and compared baseline clinical features, CSF biomarkers, and pattern of atrophy on MRI data between groups. Among 111 eligible patients (mean age 65,61 years; 56,8% were male), 41 patients developed a clinical diagnosis of dementia. Subjects with low baseline p/t-tau had twofold risk of future conversion compared to high p/t-tau ratio subjects (HR = 2.0, p = 0.026). When stratifying converters according to CSF p/t-tau ratio cut off value (0,17), those with values lower than the cut-off had significantly more MRI atrophy at baseline relative to Non-Converters in limbic structures. In Mild Cognitive Impairment patients with negative CSF amyloid biomarker, CSF p/t-tau ratio may be useful to identify those at greater risk of subsequent conversion, possibly because of TDP43-related underlying pathology.