DETECT2AD
Full Title
Two Alzheimer’s - Diagnosing distinct types of Alzheimer’s disease in CSF and plasmaDescription
Alzheimer’s disease is increasing worldwide due to extended life expectancy and represents by far the most common cause of dementia. The global number of persons with preclinical, prodromal and dementia AD is estimated to be as large as 20% of all persons over 50 years old and the number is expected to increase in the next years. Unfortunately, after decades of clinical trials with different experimental drugs, no treatment able to attenuate with clinical significance the irreversible course of the disease was discovered(5). Several reasons might be advanced for this failure, certainly related to the complexity of the disease. One of the possibilities is that the AD clinical picture may correspond to biologically distinct diseases.
Indeed, recent studies using CSF proteomics were able to identify different AD subtypes. In a recent study with early-stage AD patients from the Cognitive Complaints Cohort (CCC), we found that the CSF proteome could accurately separate patients with increased levels of proteins related to immune system, inflammation, blood clotting, and lipid metabolism (AD(IMMUNiTY/BBB)) from those with involvement of neuronal, synaptic and neurodevelopmental processes (AD(HIPERPLASTICITY)). These two subtypes of AD were validated, in another cohort, the European Medical Information Framework for Alzheimer’s Disease (EMIF-AD) cohort, even though using slightly different distinct diagnostic criteria, and technical approaches.
The discovery of different forms of AD has significant implications for diagnosis, treatment, and prognosis. It is particularly critical for finding new treatments. Current clinical trials with experimental drugs, involving around 184,000 participants and costing about $42.5 billion, have mostly failed. If a drug works for one subtype of AD but not for another, its benefits might be missed, leaving some patients without effective treatment. In essence, drug treatments may need to be personalized to each individual.
There is thus an urgent need to identify the different AD subtypes. However, they appear largely superimposable from a clinical, neuropsychological and neuroimaging point of view(1). We found that CSF classical AD biomarkers, phosphorylated tau, total tau and Aß42, were higher in AD(HIPERPLASTICITY) patients as compared to AD(IMMUNiTY/BBB) patients, but the differences were not large enough to allow the separation of these two AD subtypes. Identifying the different AD subtypes requires conducting complex mass spectroscopy analyses in a biologic fluid collected by an invasive procedure.
This project aims to develop a method to identify two subtypes of AD using plasma samples. First the plasma of early AD patients previously identified as either AD(BBB) or AD(HIPERPLASTICITY) based on CSF will be analysed. Then, a specific group of plasma proteins/metabolites that can better differentiate between the two AD subtypes will be identified. Finally, the effectiveness of this potential plasma protein/metabolite signature in classifying AD(BBB) and AD(HIPERPLASTICITY) patients will be tested using a separate group of early AD patients. If successful, the ability to diagnose different AD subtypes using a small set of proteins/metabolites from an easily obtained biological sample could promote further research into understanding AD’s diversity, and encourage clinical trials following a personalized approach.