BackgroundImmunotherapy targeting the amyloid-β (Aβ) peptide is a promising strategy for the treatment of Alzheimer’s disease (AD); however, none of the active or passive vaccines tested have been demonstrated to be effective to date. We have developed the first active vaccine against the C-terminal end of Aβ40, ABvac40, and assessed its safety and tolerability in a phase I clinical trial.MethodsA randomised, double-blind, placebo-controlled, parallel-group, phase I study of ABvac40 was conducted with patients aged 50–85 years with mild to moderate AD. Participants were entered into three separate groups according to time of study entry and were randomly allocated to receive ABvac40 or placebo (overall ratio 2:1). The first group received two half-doses of ABvac40 or placebo, whereas the second and third groups received two and three full doses, respectively. All treatments were administered subcutaneously at 4-week intervals. Patients, carers and investigators were blind to treatment allocation throughout the study. The primary objective was to assess the safety and tolerability of ABvac40 by registering all adverse events (AEs). All patients who received at least one dose of treatment were included in the safety analysis. The secondary objective was to evaluate the immunogenicity of ABvac40 by titration of specific anti-Aβ40 antibodies in plasma.ResultsTwenty-four patients were randomly allocated: 16 patients to the ABvac40 group and 8 patients to the placebo group. All randomised patients completed the study, therefore the intention-to-treat and safety populations were identical. Overall, 71 AEs affecting 18 patients were recorded: 11 (69%) in the ABvac40 group and 7 (88%) in the placebo group (p = 0.6214). Neither incident vasogenic oedema nor sulcal effusion (amyloid-related imaging abnormalities corresponding to vasogenic oedema and sulcal effusions) nor microhaemorrhages (amyloid-related imaging abnormalities corresponding to microhaemorrhages and hemosiderin deposits) were detected throughout the study period in the ABvac40-treated patients. Eleven of 12 (~92%) individuals receiving three injections of ABvac40 developed specific anti-Aβ40 antibodies.ConclusionsABvac40 showed a favourable safety and tolerability profile while eliciting a consistent and specific immune response. An ongoing phase II clinical trial is needed to confirm these results and to explore the clinical efficacy of ABvac40.Trial registrationClinicalTrials.gov, NCT03113812. Retrospectively registered on 14 April 2017.Electronic supplementary materialThe online version of this article (10.1186/s13195-018-0340-8) contains supplementary material, which is available to authorized users.

Abstract. The two pathognomonic lesions in the brain of AD patients are senile plaques and intraneuronal neurofibrillary tangles (NFT). Previous studies have demonstrated that amyloid-␤ (A␤) is a component of both senile plaques and NFTs, and have showed that intracellular accumulation of A␤ is toxic for cells and precedes the appearance of extracellular amyloid deposits. Here we report that there are numerous intraneuronal NFT and extraneuronal NFT immunoreactive for A␤ x-40 in which there is no co-localization with tau staining suggesting the existence of two different neurodegenerating populations associated with the intracellular accumulation of either tau protein or A␤ x-40 in AD.Keywords: Amyloid-␤, A␤ peptides, immunohistochemistry, neurodegeneration, phosphorylated-tau, tau protein Alzheimer's disease (AD) is a neurodegenerative disease characterized by the progressive and irreversible destruction of neurons in the cerebral cortex. There are two pathognomonic lesions in the brain of AD patients: senile plaques, composed mainly of extracellular aggregates of amyloid-␤ peptides (A␤) [1], and intraneuronal neurofibrillary tangles (NFT), consisting of paired helical filaments (PHF) [2] composed primarily of hyperphosphorylated tau protein [3,4]. The relationship between these processes is uncertain and still not completely understood. The existence of intraneuronal A␤ has been known for many years. Masters and collaborators published in 1985 that A␤, initially termed amyloid A4, is deposited first intraneuronally as NFT and subsequently in the extracellular space, associated with senile plaques and blood vessels [5]. Later on, the immunolabeling of most intraneuronal NFT (iNFT) and extraneuronal NFT (eNFT) with anti-A␤ antibodies was replicated in several laboratories [6][7][8] However, other studies failed to find A␤ immunolabeling associated with iNFT [9][10][11] or with both iNFT and eNFT [12].Later on, immunostaining with specific antibodies against the C-terminal fragment of either A␤ 40 or A␤ 42 (A␤ x-40 or A␤ x-42 , respectively) enabled the visualization of A␤ 42 associated with iNFT where it was seen to collocalize with tau, whereas A␤ 40 did not associate at all or to a far lesser degree [13][14][15]. Additionally, it was reported that numerous eNFT appeared stained for A␤ x-40 , which was interpreted as a secondary deposition over remnants of iNFT exposed in brain tissue once the cells died; however, evidence of colocalization of A␤ x-40 with tau protein in these eNFT was lacking [16].Studies in cell cultures have shown that both A␤ 42 and A␤ 40 can be intracellularly produced in neurons (but apparently not in other types of cells) [17,18], mainly in the trans-Golgi network, although production of A␤ 42 is observed as well in the endoplasmic reticulum [19]. Numerous studies have shown that the intraneuronal accumulation of A␤ may be toxic and precedes its extracellular deposition both in AD brains and in transgenic mice models of the disease

This work was prompted by the finding that Aβ1-17 (Aβ17) appeared to be the second-most abundant cerebrospinal fluid (CSF) Aβ fragment, after Aβ40. We developed an ELISA to quantify levels of Aβ17 directly accessible in plasma (DA17), recovered from the proteomic plasma matrix (RP17) and associated with the cellular pellet (CP17) that remained after plasma collection. Then, we used a sample of 19 healthy control (HC), 27 mild cognitive impairment (MCI), and 17 mild Alzheimer's disease (AD) patients to explore the association of the diagnostic groups with those direct markers, their ratios or the ratios with their Aβ40 or Aβ42 counterparts. After dichotomization (d) for the median of the sample population, logistic regression analysis showed that in the AD versus HC subgroup, subjects with a dDA/CP17 higher than the median had a significantly greater risk of being AD than those with marker levels equal to or below the median (odds ratio OR; 95% confidence interval; 17.21; 1.42-208.81). Subjects with dRP17/42 below the median had an increased likelihood of being MCI (20.00; 1.17-333.33) or AD (40.00; 1.87-1000) versus being HC, than those with dRP17/42 higher than the median. Although the confidence intervals are wide, these findings suggest that assessment of Aβ17 may increase the diagnostic performance of blood-based Aβ tests which might be developed into minimally invasive first-step screening tests for people with increased risk for AD.