Blood Markers in Healthy-Aged Nonagenarians: A Combination of High Telomere Length and Low Amyloidß Are Strongly Associated With Healthy Aging in the Oldest Old.

Many factors may converge in healthy aging in the oldest old, but their association and predictive power on healthy or functionally impaired aging has yet to be demonstrated. By detecting healthy aging and in turn, poor aging, we could take action to prevent chronic diseases associated with age. We conducted a pilot study comparing results of a set of markers (peripheral blood mononuclear cell or PBMC telomere length, circulating Aß peptides, anti-Aß antibodies, and ApoE status) previously associated with poor aging or cognitive deterioration, and their combinations, in a cohort of "neurologically healthy" (both motor and cognitive) nonagenarians (n = 20) and functionally impaired, institutionalized nonagenarians (n = 38) recruited between 2014 and 2015. We recruited 58 nonagenarians (41 women, 70.7%; mean age: 92.37 years in the neurologically healthy group vs. 94.13 years in the functionally impaired group). Healthy nonagenarians had significantly higher mean PBMC telomere lengths (mean = 7, p = 0.001), this being inversely correlated with functional impairment, and lower circulating Aß40 (total in plasma fraction or TP and free in plasma fraction or FP), Aß42 (TP and FP) and Aß17 (FP) levels (FP40 131.35, p = 0.004; TP40 299.10, p = 0.007; FP42 6.29, p = 0.009; TP42 22.53, p = 0.019; FP17 1.32 p = 0.001; TP17 4.47, p = 0.3), after adjusting by age. Although healthy nonagenarians had higher anti-Aß40 antibody levels (net adsorbed signal or NAS ± SD: 0.211 ± 0.107), the number of participants that pass the threshold (NAS > 3) to be considered as positive did not show such a strong association. There was no association with ApoE status. Additionally, we propose a "Composite Neurologically Healthy Aging Score" combining TP40 and mean PBMC telomere length, the strongest correlation of measured biomarkers with neurologically healthy status in nonagenarians (AUC = 0.904).

Safety, tolerability and immunogenicity of an active anti-Aß40 vaccine (ABvac40) in patients with Alzheimer's disease: a randomised, double-blind, placebo-controlled, phase I trial.

BACKGROUND: Immunotherapy targeting the amyloid-ß (Aß) 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 Aß40, ABvac40, and assessed its safety and tolerability in a phase I clinical trial. METHODS: A 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-Aß40 antibodies in plasma. RESULTS: Twenty-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-Aß40 antibodies. CONCLUSIONS: ABvac40 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 REGISTRATION: ClinicalTrials.gov, NCT03113812 . Retrospectively registered on 14 April 2017.

Neurofibrillary Tangles of Aßx-40 in Alzheimer's Disease Brains.

The two pathognomonic lesions in the brain of AD patients are senile plaques and intraneuronal neurofibrillary tangles (NFT). Previous studies have demonstrated that amyloid-ß (Aß) is a component of both senile plaques and NFTs, and have showed that intracellular accumulation of Aß 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 Aßx-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 Aßx-40 in AD.

Aß1-17 is a major amyloid-ß fragment isoform in cerebrospinal fluid and blood with possible diagnostic value in Alzheimer's disease.

This work was prompted by the finding that Aß1-17 (Aß17) appeared to be the second-most abundant cerebrospinal fluid (CSF) Aß fragment, after Aß40. We developed an ELISA to quantify levels of Aß17 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 Aß40 or Aß42 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 Aß17 may increase the diagnostic performance of blood-based Aß tests which might be developed into minimally invasive first-step screening tests for people with increased risk for AD.