One of the most exciting findings in neuroscience has been the discovery of peripheral blood factors with rejuvenating or ageing effects on the mouse brain. These factors were discovered by parabiosis experiments in which the blood circulation of young and old animals is fused. The findings imply that the properties of young blood can rejuvenate the older brain. Ageing is the most important risk factor for Alzheimer’s Disease (AD), but there have been only limited attempts to develop therapies targeting the ageing process. Also, it is not known whether humans have similar blood factors that could be therapeutic targets in AD. The overall aim of the HeBe project is to discover blood factors with a rejuvenating or ageing effect on the human brain that can thus become therapeutic targets for AD and other age-related brain diseases. For ethical reasons, parabiosis experiments are not possible in humans. HeBe will circumvent this problem using a highly original approach in which I will define extreme biological age phenotypes in women and men based on the difference between biological and chronological age. I will use advanced proteomics and metabolomics to identify blood factors that differ between these extreme phenotypes, and then develop a targeted assay toolkit to measure these factors in large longitudinal cohorts of cognitively unimpaired and preclinical AD individuals. The main hypothesis of HeBe is that higher levels of rejuvenating blood factors decrease the rate of neurodegeneration, while higher levels of ageing blood factors increase the rate of neurodegeneration. If this hypothesis is confirmed, I will provide a new therapeutic target for AD. By the end of HeBe, I will also design a proof-of-concept clinical trial to assess whether life-style or pharmacological interventions modify blood levels of rejuvenating or ageing factors. Thus, the HeBe project is the first and a key step in the translational continuum towards interventions in clinical practice.

Neurodegenerative diseases are one of the most important contributors to morbidity and mortality in the elderly. In Europe, over 14 million people are currently living with dementia, at a cost of over 400 billion EUR annually. Comorbidities with these conditions are frequent and a major obstacle to optimal diagnosis and management. Recent advances in diagnostic technologies and the advent of disease-modifying therapies (DMT) for Alzheimer’s disease (AD), the most common aetiology of dementia, heralds the beginning of precision medicine in this disease area. PROMINENT will develop a digital platform for precision medicine that will remove barriers that currently exists for leveraging these technological advancements in the routine care of patients with neurodegenerative disorders and co-morbidities. The platform gives clinicians access to prediction models leveraging multimodal diagnostic data automatically derived from multiple sources (imaging repositories, medical records, mobile devices), helping them choose optimal care pathways and improving diagnostic precision. It will provide personalized, relevant and meaningful information on diagnosis and prognosis in a format understandable by patients and care partners. Further, it will support the introduction of new health technologies such as DMT for AD, by ensuring adherence to appropriate use guidelines and facilitating the prospective collection of data on real-world usage, safety and effectiveness. The expected impact of the project is to increase diagnostic accuracy and optimized use of existing and new treatment options. It will empower patients and caregivers by engaging them in more person-centric health care decisions, leading to improved adherence and patient experience. Ultimately this is expected to lead to cost-effective care, improved health outcomes and quality of life.

The overall aim of the planned research is to test whether pro-aging and pro-youthful blood factors are associated with cognitive performance and neuroimaging outcomes in normal ageing and in individuals at risk of Alzheimer’s disease (AD), and whether this association is modified by lifestyle habits (e.g. exercise or diet) or genetic factors. Ageing is the most important risk factor for AD. However, the exact mechanism that link ageing and AD is still unknown and, up to now, potential therapies for AD by targeting ageing have been poorly explored. Thus, in the present project we aim to provide a better understanding of the link between ageing and AD by measuring in human blood those factors that have been found to be ‘pro-youthful’ (GDF-11) or ‘pro-aging’ (CCL2, CCL11 and CCL19) in experimental animal models, but have not been comprehensively studied in humans. For these purposes, we will first develop novel and highly specific and sensitive assays based on the state-of-the-art Simoa platform. Next, we will measure these factors in the participants of the ALFA (Alzheimer and Families) study, which is currently taking place in the Barcelonaβeta Brain Research Centre (BBRC), the host institution of this project. The ALFA cohort is composed of 2743 cognitively healthy individuals (45 to 75 years old) from which comprehensive clinical, neuropsychological, neuroimaging, genetic and environmental and lifestyle factors data are already available. Measurements will be performed in two steps: a training cohort and a validation cohort. Finally, we will investigate the association of the levels of the pro-aging/pro-youthful blood factors with features known to be related to AD such as clinical and life-style variables, neuroimaging outcomes and signatures and genetic variables. Altogether, the results of this project will clarify whether those blood pro-aging or pro-youthful factors may become potential therapeutic targets in AD.