Biomarkers will Revolutionize the way we Diagnose and Treat Alzheimer's Disease

“It has been estimated that the number of people with AD will be over 100 million by 2050, unless we are able to treat or prevent the disease ”

There are more than 60 causes of dementia but the most common form of dementia is Alzheimer's disease (AD), which affects more than 30 million people worldwide [101]. The incidence of AD increases with age: 5% of those over 65 years have the disease but this increases dramatically so that over 30% of individuals aged 85 years and older develop AD. The rate of AD is also higher in women than men in all age groups [102]. It has been estimated that the number of people with AD will be over 100 million by 2050, unless we are able to treat or prevent the disease.

Clinical and pathological studies have demonstrated that AD is a chronic disease with a long preclinical phase, in which AD pathological markers accumulate in the absence of dementia. The aggregation of amyloid-β (Aβ) into senile plaques and tau into neurofibrillary tangles is associated with synapse loss and neurodegeneration ultimately leading to the onset of clinical symptoms. The symptomatic phase of the disease is characterized by global deterioration in cognition and executive function. Both the age at onset of symptoms and the rate of progression of cognitive decline are highly variable.

It is widely acknowledged that effective treatments for AD are unlikely to reverse neurodegeneration but will need to be administered during the preclinical phase of the disease in order to delay or prevent the onset of symptoms. Given this scenario, it will be essential to identify biomarkers. A range of biomarkers is needed in order to measure different aspects of the disease including: the risk of developing disease; diagnosing disease; monitoring disease progression; and evaluating response to treatment. This issue of Biomarkers in Medicine attempts to summarize the progress we have made toward these goals and the variety of ways in which biomarkers will impact diagnosis and treatment of AD [1].

The most commonly studied genetic marker is APOE, however, despite the strength of association, APOE genotype does not have high specificity or sensitivity for AD. Advances in genomics are likely to lead to many other polymorphisms that not only influence disease risk but also disease progression and response to treatment. In combination, these are likely to have higher predictive power than any single marker.

Two areas that have received the most attention are the identification of imaging and fluid biomarkers. Most studies have focused on the utility of a single biomarker, usually identified as a player in the AD pathological process (e.g., Aβ and tau as well as markers of oxidative stress or inflammation) [2]. The development of imaging agents that specifically bind to fibrillar Aβ, as well as sensitive immunoassays that enable accurate measurement of Aβ and tau in cerebrospinal fluid (CSF), have had a profound effect on our understanding of the chronic nature of AD pathology [3]. Although these biomarkers have been very useful for research, there is clearly a need for less-invasive, less-expensive modalities before their use becomes widespread in clinical practice. The development of new Aβ and tau ligands that enable imaging of plaques and tangles is an active area of research, and has produced some promising leads. The ratio of CSF tau to Aβ₄₂ levels is already being used as part of the diagnostic work-up in some countries and is more sensitive than any single marker alone in detecting changes indicative of the presence of disease, as well as those at high risk of imminent cognitive decline but who are still cognitively normal. However, the development of a simple blood, urine or saliva test remains the goal of much biomarker-oriented research [4,5]. It is very likely that unbiased screens, both proteomic and genomic, in either blood or CSF will lead to the identification of clusters of markers that provide high specificity and sensitivity in a variety of settings including presymptomatic diagnosis, predictors of the rate of cognitive/global decline among symptomatic patients, and predictors and indicators of response to drug treatment.

“...the development of a simple blood, urine or saliva test remains the goal of much biomarker-oriented research.”

In the absence of a treatment for AD that addresses the underlying pathogenic process, biomarkers also have an important role to play in clinical trials where they may be used in a number of important ways [6]. For example, they can be used to demonstrate proof-of-concept regarding the mechanism of a drug: do β-secretase and γ-secretase inhibitors lead to decreased levels of CSF or interstitial fluid Aβ? Biomarkers can also be used as the initial outcome measure in clinical trials and/or to identify homogeneous subject groups, for example, asymptomatic individuals with high tau/Aβ₄₂ ratios [7]. Both of these approaches will lead to more efficient clinical trials that require smaller patient numbers and shorter duration for the trial, substantially reducing costs without losing power [8].

Financial & competing interests disclosure

DM Holtzman and AM Goate have received grant support from NIH (P01AG03991, P50AG05681 and P01AG026276). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

DM Holtzman and AM Goate have received grant support from NIH (P01AG03991, P50AG05681 and P01AG026276). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.