Diagnosis

Alzheimer's disease

The current estimate is that there are more than 50 million people living with dementia worldwide, a figure that is expected to rise to 152 million by 2050. Every 3 seconds a new person develops dementia. The global cost of dementia is estimated at more than half a trillion euros per year (~690 billion), a figure that could double by 2030 (Alzheimer’s Disease International. Final Report. World Alzheimer Report 2019. Attitudes to dementia. September 2019. Recover from https://www.alzint.org/what-we-do/research/world-alzheimer-report).

Alzheimer’s disease (AD) is the leading cause of dementia in people over 65 years of age (more than 70% of cases).

AD is a neurodegenerative disease with an insidious and irreversible course that ends with the death of the patient, on average about 10 years after diagnosis. The risk of developing the disease doubles approximately every five years after the age of 65, affecting more than 30% of people over the age of 90.

Currently available treatments temporarily alleviate some of the symptoms but fail to modify the course of the disease, which makes the patient completely dependent for activities of daily living, causing a heavy emotional burden for caregivers and an enormous social and economic cost for families and social-health care systems.

It is now known that the pathological processes leading to AD, in particular the accumulation of amyloid peptides in the cerebral cortex, can start up to 20 years or more before the onset of the first symptoms of dementia. For this reason, most research into new treatments for AD aims to eliminate or prevent the formation of these clusters before the most disabling symptoms of the disease appear.

However, detecting those people (approximately 30% of those over 65) in whom the disease has already started but who do not yet show symptoms in the general population is not a simple task.

Robust biomarkers based on neuroimaging or cerebrospinal fluid (CSF) analysis capable of detecting the accumulation of Aβ peptides in the brain already exist. However, the high cost and/or complexity of using these procedures greatly limits their widespread use.

These limitations have exerted a strong stimulus for the development of more accessible biomarkers, based on blood tests of different molecules, in particular β-amyloid peptides, which could help in the early diagnosis of the disease.

Since its foundation in 2004, Araclon Biotech has contributed to this effort by developing ABtest-IA assays , fully validated analytically whose main feature is that they allow accurate and robust determination of free (FP40 and FP42) and total (TP40 and TP42) levels of Aβ40 and Aβ42 in plasma.

We have recently developed a state-of-the-art assay that allows the simultaneous determination of total Aβ40 and Aβ42 levels in plasma by liquid chromatography coupled to mass spectrometry (ABtest-MS).

In studies carried out in different cohorts such as AIBL (https://pubmed.ncbi.nlm.nih.gov/32179698), AB255 (https://pubmed.ncbi.nlm.nih.gov/31787105) and FACEHBI (https://pubmed.ncbi.nlm.nih.gov/30497535), the TP42/40 ratio has made it possible to discriminate patients with cortical beta-amyloid (Aβ) pathology confirmed by positron emission tomography (Aβ-PET positive) from those who are Aβ-PET negative with sensitivities between 77-89% and negative predictive value (NPV) between 64-97% which are highly relevant values for a screening test.

Plasma TP42/40 ratio levels correlated significantly with Aβ-PET levels measured in in Standardized Uptake Value Ratio (SUVR) and Aβ42 in cerebrospinal fluid (CSF) (https://pubmed.ncbi.nlm.nih.gov/32179698 and https://pubmed.ncbi.nlm.nih.gov/31787105).

Additionally, the lower the TP42/40 ratio the faster the Aβ-PET-SUVR increases (https://pubmed.ncbi.nlm.nih.gov/28948206) and the higher the risk of developing dementia in patients with mild cognitive impairment (MCI) (https://pubmed.ncbi.nlm.nih.gov/31787105).

Additionally, a lower TP42/40 ratio was found to be associated with increased cortical tau protein in AD-related regions on both regional and voxel-wise analyzes of [18F] flortaucipir PET scan (https://pubmed.ncbi.nlm.nih.gov/31384662).

We have recently found a correlation between the natural pattern of the TP42/40 ratio in plasma and cortical Aβ-PET-SUVR (https://pubmed.ncbi.nlm.nih.gov/32954297). These findings show a close association between plasma changes and brain amyloid-β and would support the future use of the plasma TP42/40 ratio as a surrogate marker of cortical Aβ burden.