Alzheimer’s disease (AD) is a neurodegenerative disease common in the elderly. The main pathological changes were diffuse atrophy of cerebral cortex, neurofibrillary tangles and the formation of a large number of senile plaques between nerve cells. Progressive cognitive impairment and memory impairment were the main clinical symptoms. The cognitive dysfunction of AD patients from mild emotional instability, cold to the people around, gradually developed to severe amnesia, aphasia and even agnosia, and finally completely lost muscle control. This not only has a huge economic burden on the elderly and families with AD, but also has a heavy impact on their lives. With the increase of social life expectancy, the incidence of AD in the elderly population shows a significant upward trend.

In 2018, the United States is expected to have more than 5.7 million AD patients, and as the population ages faster, that number will reach 14 million by 2050. Since 2010, AD has become the sixth leading cause of death in the United States, surpassing the combined number of deaths from breast and prostate cancer, and is at a stage of rapid growth. Because the patients with AD in the middle and late stage gradually lose the ability to take care of themselves, the society needs to invest a lot of manpower and material resources to accompany them, resulting in a heavy social burden. The United States invested $277 billion in treatment and care for AD and other dementia patients in 2018. According to the Alzheimer’s Disease International, global spending on dementia treatment and care reached $1 trillion in 2018.

A long farewell: the disease process of Alzheimer’s disease

AD usually occurs in people over the age of 60. The development of the disease is relatively slow. At first, the patient has no clinical symptoms, and gradually develops into forgetfulness and changeable personality. Eventually, Alzheimer’s disease will affect the whole brain of the patient. This process can take as long as 10 or even 20 years. Alzheimer’s disease can generally be divided into five disease stages, namely, preclinical AD, mild cognitive impairment, mild dementia, moderate dementia, severe dementia. Patients with severe dementia will eventually lose control of their muscles and will not be able to complete simple movements such as swallowing, defecation, urination and so on. Most patients will die of lung infection because food enters the lungs.

Alzheimer’s disease β-amyloid hypothesis: lighthouse or trap?

The pathogenesis of AD is complex and diverse, and there is no unified conclusion. At present, β-amyloid (Aβ) hypothesis is widely accepted. The most typical pathological features of AD are extracellular β-amyloid plaque deposition and intracellular neuronal hyperphosphorylated Tau protein fibrillary tangles. Aβ is cleaved from amyloid precursor protein (APP). Aβ of different lengths was formed under different enzyme cleavage, in which β-amyloid protein 1-40 (Aβ1-40) and β-amyloid protein 1-42 (Aβ1-42) were dominant. Soluble Aβ1-42 is neurotoxic and can reduce the number of synapses. It can also induce hyperphosphorylation of Tau protein, lead to the deposition of Tau protein in neurons, form neurofibrillary tangles, further cause synaptic damage, and finally lead to the occurrence of AD.

But drug development for beta-amyloid has become a major disaster area. In 2018, Lilly, through the New England Journal of Medicine (NEJM), announced the failure of its phase III clinical trial of Solanezumab, a new drug against beta-amyloid. This not only wiped out the $9 billion invested by Lilly, but also cast a shadow over the global research and development of new AD drugs. And in this road broken halberd also includes Pfizer, Johnson, Mercado and other pharmaceutical giants.

The key to treatment: diagnosis of Alzheimer’s disease

Because the course of AD is an irreversible process, so far there is no effective treatment drugs and means. Therefore, like cancer, the key to the treatment of Alzheimer’s disease is early diagnosis, intervention and delay in the early stage of the disease. So far, however, there has not been a sufficiently accurate method to predict dementia and make an early diagnosis.

At present, the main diagnostic method is joint diagnosis. The main methods include:

  1. neuropsychological test and cognitive impairment assessment;
  2. brain magnetic resonance (MRI);
  3. β-amyloid protein PET scanning and Tau protein PET scanning;
  4. cerebrospinal fluid (CSF) markers, such as β-amyloid protein, Tau protein and so on.

The International Working Group (IWG) and the American Institute on Aging-Alzheimer’s Association (NIA-AA) revised the diagnostic criteria for AD in 2014, emphasizing the importance of molecular imaging (β-amyloid PET, Tau protein PET) and cerebrospinal fluid markers. A patient with one of the following conditions can be diagnosed as AD:

  1. the level of β-amyloid protein 1-42 in cerebrospinal fluid decreased, while the expression of total Tau and phosphorylated-Tau protein increased.
  2. β-amyloid protein PET scan showed an increase in tracer retention;
  3. autosomal dominant mutation (such as APP, PS-1, PS-2).

At present, the development of diagnostic markers of AD mainly focuses on β-amyloid protein fragment and Tau protein fragment in cerebrospinal fluid (CSF).

Roche Diagnostics

As a global leader in vitro diagnosis, Roche Diagnostics is one step ahead in the field of AD diagnosis. Roche Diagnostics reached a cooperation agreement with Lilly as early as 2016 to jointly develop a detection reagent for the detection of β-amyloid protein in cerebrospinal fluid (CSF). Lilly pays Roche in accordance with the development milestone, and Roche carries out reagent development, registration and marketing. In 2017, Roche’s β-amyloid protein 1-42, P-tau (181), total-Tau protein was certified by CE. In July 2018, β-amyloid protein 1-42, P-Tau (181) qualified for FDA breakthrough equipment in the United States, and FDA will provide support to advance the registration and approval of the two projects.

Fujirebio

Fujirebio acquired Innogenetics, based in Ghent, Belgium, in 2010. As early as 1995, Innogenetics launched the Tau protein detection kit for cerebrospinal fluid (CSF), and in 1998, it launched β-amyloid protein detection products. By 2015, following its acquisition by Fujirebio, β-amyloid protein 1-40 had also received CE certification and had successfully transferred four AD marker products to its fully automated chemiluminescence instruments of Lumipulse series.

PerkinElmer / EUROIMMUN Medical Laboratory Diagnostics

In 2017, PerkinElmer bought Euroimmun Medical Laboratory Diagnostics for $1.3 billion in cash, as well as diagnostic products in the AD field. At present, Euroimmun has four products: β-amyloid protein 1-42, β-amyloid protein 1-40, P-Tau, T-Tau. It is worth mentioning that its AD marker antibody comes from its partner ADx Neurosciences. ADx is the world’s leading developer of markers of neurodegenerative diseases, providing antibodies and technical services related to neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease, to companies around the world.

BioArctic

In September 2018, Sweden’s BioArctic signed an agreement with BBS on the development of diagnostic methods for Alzheimer’s disease. BioArctic is a listed biopharmaceutical company in Sweden, focusing on central nervous system diseases such as Alzheimer’s disease, Parkinson’s disease and so on. BBS is a company co-founded by experts in the field of Alzheimer’s disease and the University of Gothenburg in Sweden. Drawing on the extensive experience of BBS experts in Alzheimer’s disease diagnosis, with antibodies provided by BioArctic, the two companies will jointly develop the CSF marker – amyloid β protofibrils.

For now, the mainstream treatment of Alzheimer’s disease is still concentrated in β-amyloid protein and Tau protein markers of CSF. However, CSF samples need to do lumbar puncture with large damage, and mild patients often refuse to accept this method. Another problem is that the pretreatment of cerebrospinal fluid samples is not uniform, leading to different manufacturers, different laboratories of the test results are difficult to unify. Alzheimer’s disease is one of the largest unmet medical markets. According to projections by the Allied Market Research in 2018, the global market for Alzheimer’s and Parkinson’s disease markers will be about $3.95 billion in 2017 and will reach $8.57 billion by 2025. The market volume may exceed myocardial markers. But the development of new markers has always been at the same time as the risks and benefits. There is still a long way to go for the mainstream cerebrospinal fluid markers, β-amyloid and Tau protein, to be widely used in clinic. And who can lead on this road, we will wait and see.