Ventral tegmental area disconnection contributes two years early to correctly classify patients converted to Alzheimer's Disease: implications for treatment

Background: Recent cross-sectional studies highlighted the loss of dopaminergic neurons in the ventral tegmental area (VTA) as an early pathophysiological event in Alzheimer’s disease (AD). Objective: In this study, we longitudinally investigated by resting-state fMRI (RS-fMRI) a cohort of patients with mild cognitive impairment (MCI) due to AD to evaluate the impact of VTA disconnection in predicting the conversion to AD. Methods: a cohort of 35 patients with MCI due to AD were recruited and followed-up for 24 months. They underwent cognitive evaluation and RS-fMRI to assess VTA connectivity at baseline and at follow-up. Results: At 24-month follow-up, 16 out of 35 patients converted to AD. Although converters and non-converters to AD did not differ in demographic and behavioral characteristics at baseline, the first group showed a significant reduction of VTA-driven connectivity in the posterior cingulate and precentral cortex. This pattern of additional disconnection in MCI-converters compared to non-converters remained substantially unchanged at 24-month follow-up. Discussion: This study reinforces the hypothesis of an early contribution of dopaminergic dysfunction to AD evolution by targeting the default-mode network. These results have potential implications for AD staging and prognosis and support new opportunities for therapeutic interventions to slow down disease progression