BIOFACE: A Prospective Study of Risk Factors, Cognition, and Biomarkers in a Cohort of Individuals with Early-Onset Mild Cognitive Impairment. Study Rationale and Research Protocols

Background: Mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) diagnosis is based on cerebrospinal fluid (CSF) or neuroimaging biomarkers. Currently, non-invasive and inexpensive blood-based biomarkers are being investigated, such as neuronal-derived plasma exosomes (NPEs). Neuroinflammation and early vascular changes have been described in AD pathogenesis and can be traced in plasma and NPEs. However, they have not been studied in early onset MCI (EOMCI). Objective: To describe the rationale, design, and baseline characteristics of the participants from the BIOFACE cohort, a two-year observational study on EOMCI conducted at Fundació ACE. The study goal is to characterize the different phenotypes from a clinical, neuropsychological, and biomarker point of view and to investigate the CSF and plasma proteomics as well as the role of NPEs as early biomarkers of AD. Methods: Participants underwent extended neurological and neuropsychological batteries, multimodal biomarkers including brain MRI, blood, saliva, CSF, anthropometric, and neuro-ophthalmological examinations. Results: Ninety-seven patients with EOMCI were recruited. 59.8%were women. Mean age at symptom onset was 57 years; mean MMSE was 28. First degree and presenile family history of dementia was present in 60.8%and 15.5%, respectively. Depressive and anxiety disorders along with vascular risk factors were the most frequent comorbidities. 29%of participants were APOE ɛ4 carriers, and 67%showed a CSF normal ATN profile. Conclusion: BIOFACE is a two-year study of clinical, cognition, and biomarkers that will shed light on the physiopathology and the potential utility of plasma and NPEs as non-invasive early diagnostic and prognostic biomarkers in people younger than 65 years.

Longitudinal Speech Biomarkers for Automated Alzheimer's Detection

We introduce a novel audio processing architecture, the Open Voice Brain Model (OVBM), improving detection accuracy for Alzheimer's (AD) longitudinal discrimination from spontaneous speech. We also outline the OVBM design methodology leading us to such architecture, which in general can incorporate multimodal biomarkers and target simultaneously several diseases and other AI tasks. Key in our methodology is the use of multiple biomarkers complementing each other, and when two of them uniquely identify different subjects in a target disease we say they are orthogonal. We illustrate the OBVM design methodology by introducing sixteen biomarkers, three of which are orthogonal, demonstrating simultaneous above state-of-the-art discrimination for two apparently unrelated diseases such as AD and COVID-19. Depending on the context, throughout the paper we use OVBM indistinctly to refer to the specific architecture or to the broader design methodology. Inspired by research conducted at the MIT Center for Brain Minds and Machines (CBMM), OVBM combines biomarker implementations of the four modules of intelligence: The brain OS chunks and overlaps audio samples and aggregates biomarker features from the sensory stream and cognitive core creating a multi-modal graph neural network of symbolic compositional models for the target task. In this paper we apply the OVBM design methodology to the automated diagnostic of Alzheimer's Dementia (AD) patients, achieving above state-of-the-art accuracy of 93.8% using only raw audio, while extracting a personalized subject saliency map designed to longitudinally track relative disease progression using multiple biomarkers, 16 in the reported AD task. The ultimate aim is to help medical practice by detecting onset and treatment impact so that intervention options can be longitudinally tested. Using the OBVM design methodology, we introduce a novel lung and respiratory tract biomarker created using 200,000+ cough samples to pre-train a model discriminating cough cultural origin. Transfer Learning is subsequently used to incorporate features from this model into various other biomarker-based OVBM architectures. This biomarker yields consistent improvements in AD detection in all the starting OBVM biomarker architecture combinations we tried. This cough dataset sets a new benchmark as the largest audio health dataset with 30,000+ subjects participating in April 2020, demonstrating for the first time cough cultural bias.

A multiomics approach to heterogeneity in Alzheimer’s disease: focused review and roadmap

Aetiological and clinical heterogeneity is increasingly recognized as a common characteristic of Alzheimer’s disease and related dementias. This heterogeneity complicates diagnosis, treatment, and the design and testing of new drugs. An important line of research is discovery of multimodal biomarkers that will facilitate the targeting of subpopulations with homogeneous pathophysiological signatures. High-throughput ‘omics’ are unbiased data-driven techniques that probe the complex aetiology of Alzheimer’s disease from multiple levels (e.g. network, cellular, and molecular) and thereby account for pathophysiological heterogeneity in clinical populations. This review focuses on data reduction analyses that identify complementary disease-relevant perturbations for three omics techniques: neuroimaging-based subtypes, metabolomics-derived metabolite panels, and genomics-related polygenic risk scores. Neuroimaging can track accrued neurodegeneration and other sources of network impairments, metabolomics provides a global small-molecule snapshot that is sensitive to ongoing pathological processes, and genomics characterizes relatively invariant genetic risk factors representing key pathways associated with Alzheimer’s disease. Following this focused review, we present a roadmap for assembling these multiomics measurements into a diagnostic tool highly predictive of individual clinical trajectories, to further the goal of personalized medicine in Alzheimer’s disease.

A Multiomics Approach to Heterogeneity in Alzheimer’s Disease: Focused Review and Roadmap

Etiological and clinical heterogeneity is increasingly recognized as a common characteristic of Alzheimer’s disease and related dementias. This heterogeneity complicates diagnosis, treatment, and the design and testing of new drugs. An important line of research is discovery of multimodal biomarkers that will facilitate the targeting of subpopulations with homogeneous pathophysiological signatures. High-throughput ‘omics’ are unbiased data driven techniques that probe the complex etiology of Alzheimer’s disease from multiple levels (e.g. network, cellular, and molecular) and thereby account for pathophysiological heterogeneity in clinical populations. This review focuses on data reduction analyses that identify complementary disease-relevant perturbations for three omics techniques: neuroimaging-based subtypes, metabolomics-derived metabolite panels, and genomics-related polygenic risk scores. Neuroimaging can track accrued neurodegeneration and other sources of network impairments, metabolomics provides a global small-molecule snapshot that is sensitive to ongoing pathological processes, and genomics characterizes relatively invariant genetic risk factors representing key pathways associated with Alzheimer’s disease. Following this focused review, we present a roadmap for assembling these multiomics measurements into a diagnostic tool highly predictive of individual clinical trajectories, to further the goal of personalized medicine in Alzheimer’s disease.