The disease


In 1906 Alois Alzheimer defined the disease that was later to carry his name as a condition that involves progressive memory loss and behavioural changes (Alzheimer, 1906). Alzheimer’s disease is now the most common cause of dementia affecting over 35.6 million people worldwide and representing one of the greatest medical challenges of this century (Prince et al., 2013). Alzheimer’s disease is now considered a slowly progressive brain disease that begins well before clinical symptoms emerge (Giannakopoulos et al., 2003). The diagnosis of Alzheimer's disease remains essentially based on clinical symptoms, which manifest after extensive brain damage has already occurred (McKhann et al., 2011).


The causes


The hallmarks of the disease are the progressive accumulation of the protein fragment beta-amyloid (plaques) outside neurons in the brain (Masters et al., 1985) and twisted strands of protein tau (tangles) inside neurons (Grundke-Iqbal, et al., 1986). These changes are eventually accompanied by the damage and death of neurons (Giannakopoulos et al., 2003). Brain changes in Alzheimer’s disease begin many years before symptoms emerge and, therefore, the disease process spans a continuum from asymptomatic to prodromal stages, and finally to the dementia stage. People at the asymptomatic stage can only be identified by biomarkers of Alzheimer’s disease, but whether biomarkers in the asymptomatic stage can predict clinical symptoms in the future remains unclear.


Current and Future treatments


Current available medications such as oral cholinesterase inhibitors are only partially effective (Raina et al., 2008). Treatments that slow or prevent disease progression of Alzheimer’s are still challenging and an unmet need. Several novel clinical trials assessing the efficacy of amyloid (Ivanoiu et al., 2016; Sevigny et al., 2016) and tau-lowering (Moebius et al., 2016) compounds are ongoing. However, these disease-modifying treatments are more likely to be effective at the early stage of the disease before extensive neuronal damage has occurred. Hence, the development of a biomarker that provides an objective measure of the underlying disease state, which could be used to ensure accurate diagnosis and as an outcome measure to provide an objective determinant of disease progression, would be a great advance in defining a neuroprotective treatment.




"The diagnosis of Alzheimer's disease remains essentially based on clinical symptoms, which manifest after extensive brain damage has already occurred."

In the last decades, substantial technological advances in neuroimaging, blood and cerebrospinal fluid analysis allowed the development of biomarkers related to Alzheimer's disease. Positron emission tomography (PET) is a special type of brain scan that can be used to measure chemical changes within the brain and consequently study the functions of the brain. Recent advances in PET imaging have enabled to assess beta-amyloid (Villemagne, 2016) and tau aggregates (Johnson et al., 2016) in the brain of living people.  Abnormal accumulation of these proteins can already be seen in the prodromal stage of the disease, when functional disability is absent and before the development of full-blown dementia. Different genes are also associated with an increased risk of Alzheimer’s disease (Giri et al., 2016). However, having one of these versions may only have a small effect on risk of developing dementia, and there is still a lot to be understood about these genes and their importance. Beside the most well-known risk gene called APOE, other genes were found to be associated to an increased risk of Alzheimer’s disease (Singhrao et al., 2016). TREM2 variants could also confer risk for Alzheimer’s disease. This gene plays an important role in regulating the immune system and inflammatory response in the brain (Ulrich et al., 2017). Abnormal amyloid and tau levels can be measured also in the cerebrospinal fluid (Mattsson et al., 2017). However, analysis of cerebrospinal fluid biomarker needs to be validated and cut-off values for normal ranges will need to be defined. Magnetic Resonance Imaging (MRI) can detect volume loss in specific areas of the brain, which are relevant to cognitive function (Scheltens et al., 1992). However, volume loss occurs at the latest stage of the disease and this assessment has limited specificity when used alone.


Conclusions and future directions


The combination of tau and amyloid imaging with fluid biomarkers will enable to diagnose Alzheimer’s disease at the prodromal stage with great accuracy and monitor response to treatment and progression of the disease. The development of new disease-modifying treatments have increased the relevance and urgency for accurate diagnostic tools to select the appropriate patients (ie, with presence of amyloid or tau aggregates), properly stage the disease, and monitor response to treatment. The use of such biomarkers can substantially contribute to the detection of Alzheimer’s disease at the prodromal stage when future curative treatments might be more efficacious.


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