Blood Biomarkers for Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is a multifactorial and heterogeneous disease in both its clinical and histopathological appearance. In more than 99% of cases the cause of the disease is not understood. Independent of its cause, AD is clinically characterised by a developing dementia and histopathologically characterised by neuronal degeneration. Although the presence of neurofibrillary tangles (NFTs) and neurotic (senile) plaques are the characteristic hallmarks in the AD brain, AD histopathology shows considerable qualitative and quantitative heterogeneity. A definitive diagnosis has to await a post mortem biopsy, when a histopathological examination can be performed. Therefore, the clinical diagnosis today is made primarily by excluding other causes of dementia.1 AD is becoming a major health problem in the developed world as life expectancy increases, and the disease affects about 15 million people worldwide today.2,3 The prevalence of AD is expected to rise dramatically in the next few decades and it is estimated that 20–30 million people just in the US will be living with the disease by 2030.4 Concentrated efforts are under way to identify reliable cures or preventative measures for the disease. To facilitate these investigations, biomarkers are critically needed that can reliably detect the disease at the earliest possible stage.5 In AD, the main cause of dementia is assumed to result from the progressive loss of synaptic function and neurological degeneration.6 The disease is associated with profound biochemical and pathological alterations in the brain, including aberrant amyloid precursor protein (APP), amyloid β-protein (Aβ) metabolism, tau protein phosphorylation, oxidative stress, inflammation and lipid dysregulation. NFTs and senile plaques are the neuropathological hallmarks of AD and were described by Alois Alzheimer as early as 1906. Senile plaques and NFTs, although not individually unique to AD, have a characteristic spreading and density in the diseased brain.7 The plaque is an extracellular lesion composed mainly of amyloid peptides with 40 or 42 amino acids, designated as Aβ40 or Aβ42. Aβ42 is the initial and more toxic species deposited in the brain and is also fibrillogenic in vitro.8–10 Conversely, NFTs are intracellular lesions composed mainly of paired helical fragments of highly phosphorylated and aggregated tau protein.11 The tau protein is a normal and essential component of neurons and it is the incorporation of excess phosphate groups that leads to the formation of the aggregated tau protein.11 The development of biomarkers for AD is challenging as it is complicated by several factors. In addition to the variability in clinical features and multiple molecular aetiologies, the development of AD biomarkers is burdened with a diagnostic imprecision as confirmation of the disease preferentially has to await a post mortem histopathological examination. The long asymptomatic prodromal stages, rates of progression and complex disease genetics complicate the situation further. In this article we will review the current developments in the field of biomarkers for the detection of AD in blood.