The successful development of amyloid-based biomarkers and tests for Alzheimer's disease (AD) represents an important milestone in AD diagnosis. However, two major limitations remain. Amyloid-based diagnostic biomarkers and tests provide limited information about the disease process and they are unable to identify individuals with the disease before significant amyloid-beta accumulation in the brain develops. The objective in this study is to develop a method to identify potential blood-based non-amyloid biomarkers for early AD detection. The use of blood is attractive because it is accessible and relatively inexpensive. Our method is mainly based on machine learning (ML) techniques (support vector machines in particular) because of their ability to create multivariable models by learning patterns from complex data. Using novel feature selection and evaluation modalities we identified 5 novel panels of non-amyloid proteins with the potential to serve as biomarkers of early AD. In particular, we found that the combination of A2M, ApoE, BNP, Eot3, RAGE and SGOT may be a key biomarker profile of early disease. Disease detection models based on the identified panels achieved sensitivity (SN) > 80%, specificity (SP) > 70%, and area under receiver operating curve (AUC) of at least 0.80 at prodromal stage (with higher performance at later stages) of the disease. Existing ML models performed poorly in comparison at this stage of the disease suggesting that the underlying protein panels may not be suitable for early disease detection. Our results demonstrate the feasibility of early detection of AD using nonamyloid based biomarkers.

With the increasing number of people living with Alzheimer's disease (AD), there is a need for low-cost and easy to use methods to detect AD early to facilitate access to appropriate care pathways. Neuroimaging biomarkers (such as those based on PET and MRI) and biochemical biomarkers (such as those based on CSF) are recommended by international guidelines to facilitate diagnosis. However, neuroimaging is expensive and may not be widely available and CSF testing is invasive. Bloodbased biomarkers offer the potential for the development of a low-cost and more time efficient tool to detect AD to complement CSF and neuroimaging as blood is much easier to obtain. Although no single blood biomarker is yet able to detect AD, combinations of biomarkers (also called panels) have shown good results. However, a large number of biomarkers are often needed to achieve a satisfactory detection performance. In addition, it is difficult to reproduce reported results within and across different study cohorts because of data overfitting and lack of access to the datasets used in the studies. In this study, our focus is to identify an optimum panel (in terms of the least number of blood biomarkers to meet the specified diagnostic performance of 80% sensitivity and specificity) based on a widely accessible data set, and to demonstrate a testing methodology that reinforces reproducibility of results. Realizing a panel with reduced number of markers will have significant impact on the complexity and cost of diagnosis and potential development of cost-effective point of care devices.

Biomarkers to detect Alzheimer’s disease (AD) would enable patients to gain access to appropriate services and may facilitate the development of new therapies. Given the large numbers of people affected by AD, there is a need for a low-cost, easy-to-use method to detect AD patients. Potentially, the electroencephalogram (EEG) can play a valuable role in this, but at present no single EEG biomarker is robust enough for use in practice. This study aims to provide a methodological framework for the development of robust EEG biomarkers to detect AD with clinically acceptable performance by exploiting the combined strengths of key biomarkers. A large number of existing and novel EEG biomarkers associated with slowing of EEG, reduction in EEG complexity. and decrease in EEG connectivity were investigated. Support vector machine and linear discriminate analysis methods were used to find the best combination of the EEG biomarkers to detect AD with significant performance. A total of 325,567 EEG biomarkers were investigated, and a panel of six biomarkers was identified and used to create a diagnostic model with high performance (>=85% for sensitivity and 100% for specificity).

Early detection of Alzheimer's disease (AD) is of vital importance in the development of disease-modifying therapies. This necessitates the use of early pathological indicators of the disease such as amyloid abnormality to identify individuals at early disease stages where intervention is likely to be most effective. Recent evidence suggests that cerebrospinal fluid (CSF) amyloid β1-42 (Aβ42) level may indicate AD risk earlier compared to amyloid positron emission tomography (PET). However, the method of collecting CSF is invasive. Bloodbased biomarkers indicative of CSF Aβ42 status may remedy this limitation as blood collection is minimally invasive and inexpensive. In this study, we show that APOE4 genotype and blood markers comprising EOT3, APOC1, CGA, and Aβ42 robustly predict CSF Aβ42 with high classification performance (0.84 AUC, 0.82 sensitivity, 0.62 specificity, 0.81 PPV and 0.64 NPV) using machine learning approach. Due to the method employed in the biomarker search, the identified biomarker signature maintained high performance in more than a single machine learning algorithm, indicating potential to generalize well. A minimally invasive and cost-effective solution to detecting amyloid abnormality such as proposed in this study may be used as a first step in a multi-stage diagnostic workup to facilitate enrichment of clinical trials and population-based screening.