We compared the clinical and analytical performance of Alzheimer’s disease (AD) plasma biomarkers measured using the single-molecule array (Simoa) and Lumipulse platforms. We quantified the plasma levels of amyloid beta 42 (Aβ42), Aβ40, phosphorylated tau (Ptau181), and total tau biomarkers in 81 patients with mild cognitive impairment (MCI), 30 with AD, and 16 with non-AD dementia. We found a strong correlation between the Simoa and Lumipulse methods. Concerning the clinical diagnosis, Simoa Ptau181/Aβ42 (AUC 0.739, 95% CI 0.592–0.887) and Lumipulse Aβ42 and Ptau181/Aβ42 (AUC 0.735, 95% CI 0.589–0.882 and AUC 0.733, 95% CI 0.567–0.900) had the highest discriminating power. However, their power was significantly lower than that of CSF Aβ42/Aβ40, as measured by Lumipulse (AUC 0.879, 95% CI 0.766–0.992). Simoa Ptau181 and Lumipulse Ptau181/Aβ42 were the markers most consistent with the CSF Aβ42/Aβ40 status (AUC 0.801, 95% CI 0.712–0.890 vs. AUC 0.870, 95% CI 0.806–0.934, respectively) at the ≥2.127 and ≥0.084 cut-offs, respectively. The performance of the Simoa and Lumipulse plasma AD assays is weaker than that of CSF AD biomarkers. At present, the analysed AD plasma biomarkers may be useful for screening to reduce the number of lumbar punctures in the clinical setting.

We have previously proposed a radical change in the current strategy to clear pathogenic proteins from the central nervous system (CNS) based on the cerebrospinal fluid (CSF)-sink therapeutic strategy, whereby pathogenic proteins can be removed directly from the CNS via CSF. To this aim, we designed and manufactured an implantable device for selective and continuous apheresis of CSF enabling, in combination with anti-amyloid-beta (Aβ) monoclonal antibodies (mAb), the clearance of Aβ from the CSF. Here, we provide the first proof of concept in the APP/PS1 mouse model of Alzheimer’s disease (AD). Devices were implanted in twenty-four mice (seventeen APP/PS1 and seven Wt) with low rates of complications. We confirmed that the apheresis module is permeable to the Aβ peptide and impermeable to mAb. Moreover, our results showed that continuous clearance of soluble Aβ from the CSF for a few weeks decreases cortical Aβ plaques. Thus, we conclude that this intervention is feasible and may provide important advantages in terms of safety and efficacy.

Lifestyle factors, including social relationships and diet, influence mood homeostasis, a mechanism often dysregulated in high-incidence mental illnesses like depression and Alzheimer’s dementia (AD). Given that insulin-like growth factor 1 (IGF-1) modulates mood and its blood levels are altered in both AD and affective disorders, we investigated whether IGF-1 activity in the brain was affected in mice subjected to social isolation or a high-fat diet (HFD). We found that both lifestyle conditions increased anxiety and depression-like behavior in C57BL/6 mice of both sexes, as determined by the elevated zero maze/open field tests and the forced swim test, respectively. These lifestyle conditions were associated with loss of neuronal responses to systemic IGF-1. Enhanced neuronal activity in the prefrontal cortex—measured via Ca⁺⁺ fiber photometry following intraperitoneal IGF-1 administration—was absent in both socially isolated and HFD-fed mice. However, only the HFD-fed group exhibited elevated serum IGF-1 levels. These findings suggest that loss of brain IGF-1 input may contribute to the observed mood disturbances, providing potential new targets to explore the heightened risk of depression and AD associated with loneliness and unhealthy diets in humans. Importantly, because reduced IGF-1 activity in the brain is not consistently reflected in serum levels, serum measurements are an unreliable indicator of brain IGF-1 activity.