Biomarkers: key elements to the early detection of Alzheimer’s disease

By Sabino Méndez Pastor

In 1906, Dr Alzheimer studied the brain tissue of a woman who had died of an unusual mental illness which symptoms included memory loss, language problems and unpredictable behaviour. In this study, he found abnormal bundles of fibres inside the patient’s neurons and clumps between them. The illness was named Alzheimer’s disease after him and these observations became the main features of it (National Institute of Aging, 2019). More than one century later, dementia, a syndrome characterised by the deterioration of memory, thinking and of the ability to perform everyday activities, affects around 50 million people worldwide and Alzheimer’s disease causes 60% to 70% of the cases. Dementia mainly affects people of age 65 or older and it is one of the major causes of disability and dependency among older people worldwide (World Health Organisation, 2019). Therefore, Alzheimer’s is a major global health issue but its causes, diagnosis, and treatment need to be examined.

Alzheimer’s disease is thought to be caused by the accumulation of Tau forming neurofibrillary tangles inside neurons and of β-amyloid plaques between neurons which correlate to the original observations of Dr Alzheimer. This process can start 20 years before the emergence of the first symptoms of dementia. Amyloid deposition or amyloidosis accelerates the formation of neurofibrillary tangles, also known as tauopathy (Randall et al., 2012). Microglial cells, a specialised population of macrophages that remove damaged neurons and other debris in the central nervous system (CNS), unsuccessfully try to clear the amyloid. Astrocytes, another type of non-neuronal cells of the CNS that contribute to its healthy function, react to the distressed microglial cells, causing chronic inflammation of the affected brain areas. This combined with the failure of the vascular system to deliver enough glucose to the brain, results in the death of many neurons. Neuronal loss leads to brain atrophy. Brain atrophy affects specially the hippocampus which volume can be reduced by up to 18% (Ridha et al., 2006) and the entorhinal cortex where the number of neurons can decrease by up to 90% in some of its layers (Gómez-Isla et al., 1996). These areas play a crucial role in forming memories and its shrinking induces the cognitive disfunction that causes memory loss, impaired decision making, language problems and other symptoms of dementia.

Alzheimer’s disease (AD) is a slowly progressing disease which begins decades before the first symptoms manifest. That is why AD cases are divided in three main stages: preclinical AD which corresponds to nondemented patients, mild cognitive impairment (MCI) which includes people who have some memory problems that do not interfere with their everyday lives and AD dementia. As AD is practically irreversible in its demented stage, it is crucial to be able to detect cases of preclinical AD and of MCI accurately in order to develop effective treatments against AD and give them to patients before amyloid plaques and neurodegeneration become too widespread. Fortunately, biological markers or ‘biomarkers’ appear many years, even decades before clinical symptoms. The Biomarkers Definitions Working Group (2001) defined a biomarker as “a characteristic that is objectively measured and evaluated as an indicator of normal biological process, pathogenic processes or pharmacologic responses to a therapeutic intervention”. AD biomarkers can be found in the cerebrospinal fluid (CSF) and/or blood plasma, but they can also be neurogenetic markers. Currently, the main CSF biomarkers for AD are total Tau protein that reflects neuronal degeneration, hyperphosphorylated Tau which indicates neurofibrillary tangle formation and the 42 amino-acid-long form of amyloid β which is inversely correlated with β-amyloid accumulation in the brain (Cavedo et al., 2015). All three are stable in symptomatic AD and can be measured in CSF samples obtained from the vertebral column by lumbar puncture (Blennow et al., 2010). Other CSF biomarkers reflect more specific pathological effects of AD such as chinase-3-like protein 1 (CHI3L1) and neurogranin which indicate microglial activation and synaptic degeneration, respectively (Cavedo et al., 2015).

Like many other chronic diseases AD results from the interactions between environmental and genetic factors. High throughput genotyping progresses have allowed the establishment of genes that are associated with higher risks of the occurrence of AD. For instance, some single nucleotide polymorphisms (SNPs) in the BIN1, PICALM and CLU genes are present in 5-10% of the AD cases and 27.3% of the patients affected by AD have the ε4 allele of the ApoE gene (Lambert et al., 2013). These genetic biomarkers are of great interest to select and classify subjects for clinical and translational studies although they are not recommended for diagnosis due to their low sensitivity and specificity.

Finally, blood biomarkers are also of great utility in clinical trials for AD as they can predict the risk of progression of the disease. For example, Hye et al. (2014) identified a 10-plasma protein algorithm that when combined with the ApoE genotype predicted the evolution from MCI to demented AD with an accuracy of 87%. 

Biomarkers are particularly important to develop an effective treatment for AD as currently there is no drug or intervention which can successfully treat it. The medications used at the moment help to reduce the symptoms by regulating neurotransmitter production, but they do not address the underlying disease process. In addition, they are not effective for all people or help for a limited time (National Institute for Aging, 2019).

Alzheimer’s disease increasingly represents a major global health crisis as the population older than 65 rapidly expands. However, the recent discoveries of many biomarkers of the neurodegenerative disease can help to diagnose Alzheimer’s cases earlier and allow researchers to test treatment candidates more effectively. In other words, there is still a long way to find a cure for Alzheimer’s disease, but we are on the right track.

References:

Bateman, RJ., Xiong, C., Berzinger, TLS., Fagan, AM., Goate, A., et al. (2012) Clinical and Biomarker Changes in Dominantly Inherited Alzheimer’s Disease. N Engl J Med. 367, 795-804.

Biomarkers Definitions Working Group (2001) Biomarkers and surrogate endpoints: preferred definitions and conceptual framework.  Clin Pharmacol Ther. 69 (3), 89-95.

Blennow, K., Hampel, H., Weiner, M. & Zetterberg, H. (2010) Cerebrospinal fluid and plasma biomarkers in Alzheimer disease.  Nature Reviews Neurology. 6, 131-144.

Braak, H. & Braak, E. (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 82, 239-259.

Cavedo, E., Lista, S., Kachaturian, Z., Aisen, P., Amouyel, P., et al. (2014) The Road Ahead to Cure Alzheimer’s Disease: Development of Biological Markers and Neuroimaging Methods for Prevention Trials Across all Stages and Target Populations. J Prev Alzheimers Dis. 1 (3), 181-202

Gómez-Isla, T., Price, JL., McKeel Jr., DW., Morris, JC. & Growdon, JH. (1996) Profound Loss of Layer II Entorhinal Cortex Neurons Occurs in Very Mild Alzheimer’s Disease. J Neurosci. 16 (14), 4491-4500.

Hye, A., Riddoch-Contreras, J., Baird, AL., Ashton, NJ., Bazenet, C., et al. (2014) Plasma proteins predict conversion to dementia from prodromal disease. Alzheimer’s Dement. 10 (6), 799-807. 

Lambert, JC., Ibrahim-Verbaas, CA., Harold, D., Naj, AC., Sims, R., et al. (2013) Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet. 45 (12), 1452-1458.

National Institute of Aging (2019). Alzheimer’s Disease Fact Sheet. Available from: https://www.nia.nih.gov/health/alzheimers-disease-fact-sheet [Accessed 19th August 2020]

Price, JL. & Morris, JC. (1999) Tangles and plaques in nondemented aging and “preclinical” Alzheimer’s disease. Ann Neurol. 45 (3), 358-368.

Ridha, BH., Barnes, J., Bartlett, JW., Godbolt, A., Pepple, T., et al. (2006) Tracking atrophy progression in familial Alzheimer’s disease: a serial MRI study.  The Lancet Neurology. 5 (10), 828-834.

Sofroniew, MV. & Vinters, HV. (2010) Astrocytes: biology and pathology. Acta Neuropathol. 119 (1), 7-35.

World Health Organisation (2019). Dementia. Available from: https://www.who.int/news-room/fact-sheets/detail/dementia#:~:text=Worldwide%2C%20around%2050%20million%20people,dependency%20among%20older%20people%20worldwide. [Accessed 20th August 2020]

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