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We developed models for individualized risk prediction of cognitive decline in mild cognitive impairment (MCI) using plasma biomarkers of β-amyloid (Aβ), tau and neurodegeneration. A total of 573 patients with MCI from the Swedish BioFINDER study and the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were included in the study. The primary outcomes were longitudinal cognition and conversion to Alzheimer’s disease (AD) dementia. A model combining tau phosphorylated at threonine 181 (P-tau181) and neurofilament light (NfL), but not Aβ42/Aβ40, had the best prognosis performance of all models (area under the curve = 0.88 for 4-year conversion to AD in BioFINDER, validated in ADNI), was stronger than a basic model of age, sex, education and baseline cognition, and performed similarly to cerebrospinal fluid biomarkers. A publicly available online tool for individualized prognosis in MCI based on our combined plasma biomarker models is introduced. Combination of plasma biomarkers may be of high value to identify individuals with MCI who will progress to AD dementia in clinical trials and in clinical practice. This study shows that combinations of blood-based biomarkers can be used to predict cognitive decline and dementia due to Alzheimer’s disease in patients with mild cognitive impairment. Biomarkers for tau and neurodegeneration provided accurate prognosis of decline and conversion over four years.

Introduction: We studied usefulness of combining blood amyloid beta (Aβ)42/Aβ40, phosphorylated tau (p-tau)217, and neurofilament light (NfL) to detect abnormal brain Aβ deposition in different stages of early Alzheimer's disease (AD). Methods: Plasma biomarkers were measured using mass spectrometry (Aβ42/Aβ40) and immunoassays (p-tau217 and NfL) in cognitively unimpaired individuals (CU, N = 591) and patients with mild cognitive impairment (MCI, N = 304) from two independent cohorts (BioFINDER-1, BioFINDER-2). Results: In CU, a combination of plasma Aβ42/Aβ40 and p-tau217 detected abnormal brain Aβ status with area under the curve (AUC) of 0.83 to 0.86. In MCI, the models including p-tau217 alone or Aβ42/Aβ40 and p-tau217 had similar AUCs (0.86–0.88); however, the latter showed improved model fit. The models were implemented in an online application providing individualized risk assessments (https://brainapps.shinyapps.io/PredictABplasma/). Discussion: A combination of plasma Aβ42/Aβ40 and p-tau217 discriminated Aβ status with relatively high accuracy, whereas p-tau217 showed strongest associations with Aβ pathology in MCI but not in CU.

APPswe/PS1dE9 and Tg2576 are very common transgenic mouse models of Alzheimer's disease (AD), used in many laboratories as tools to research the mechanistic process leading to the disease. In order to augment our knowledge about the amyloid-β (Aβ) isoforms present in both transgenic mouse models, we have developed two chromatographic methods, one acidic and the other basic, for the characterization of the Aβ species produced in the brains of the two transgenic mouse models. After immunoprecipitation and micro-liquid chromatography-electrospray ionization mass spectrometry/mass spectrometry, 10 species of Aβ, surprisingly all of human origin, were detected in the brain of Tg2576 mouse, whereas 39 species, of both murine and human origin, were detected in the brain of the APP/PS1 mouse. To the best of our knowledge, this is the first study showing the identification of such a high number of Aβ species in the brain of the APP/PS1 transgenic mouse, whereas, in contrast, a much lower number of Aβ species were identified in the Tg2576 mouse. Therefore, this study brings to light a relevant phenotypic difference between these two popular mice models of AD.

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.

It is well known that several Aβ species, including Aβ40 and Aβ42, are present in cerebrospinal fluid (CSF). Experimental results suggest that these species could play a role in Alzheimer's disease and might also have diagnostic significance. In the present work, the canine CSF β-amyloid species profile has been identified by matrix-assisted laser desorption and ionization–time-of-flight/time of flight mass spectrometry (MALDI-TOF/TOF) analysis after immunoprecipitation with different Aβ-specific antibodies. The results show that species arising from combined β- and γ-secretase activities in humans, such as Aβ1–33, Aβ1–34, Aβ1–37, Aβ1–38, Aβ1–39, Aβ1–40, and Aβ1–42, are also present in dogs. Species arising from combined α- and β-secretase activities, as well as other Aβ-degrading enzymes, are also present in both human and canine CSF, with the exception of Aβ1–13, Aβ1–14, and Aβ1–18, which are not detected in dogs. A large number of species truncated at Glu-3 and Glu-11 have also been detected. To our knowledge, this work describes a most complete Aβ species profile from canine CSF. The similarities between the canine and human CSF Aβ profile reinforce the dog as a highly appropriate animal model for research in Alzheimer's disease.