Fluid and PET biomarkers for amyloid pathology in Alzheimer's disease

Abstract

Alzheimer's disease (AD) is characterized by amyloid plaques and tau pathology (neurofibrillary tangles and neuropil threads). Amyloid plaques are primarily composed of aggregated and oligomeric β-amyloid (Aβ) peptides ending at position 42 (Aβ42). The development of fluid and PET biomarkers for Alzheimer's disease (AD), has allowed for detection of A pathology in vivo and marks a major advancement in understanding the role of A in Alzheimer's disease (AD). In the recent National Institute on Aging and Alzheimer's Association (NIA-AA) Research Framework, AD is defined by the underlying pathology as measured in patients during life by biomarkers (Jack et al., 2018), while clinical symptoms are used for staging of the disease. Therefore, sensitive, specific and robust biomarkers to identify brain amyloidosis are central in AD research. Here, we discuss fluid and PET biomarkers for Aβ and their application. Alzheimer's disease (AD) is characterized by amyloid plaques and tau pathology (neurofibrillary tangles and neuropil threads), together with neuronal and synaptic degeneration, in cortical areas of the brain (Scheltens et al., 2016). Amyloid plaques are primarily composed of aggregated and oligomeric β-amyloid (Aβ) peptides ending at position 42 (Aβ42). In the recent National Institute on Aging and Alzheimer's Association (NIA-AA) Research Framework, AD is defined by the underlying pathology as measured in patients during life by biomarkers (Jack et al., 2018), while clinical symptoms (or absence thereof) is used for staging of the disease. Following these criteria, brain amyloidosis is a key factor in AD, since it is the earliest change found in the Alzheimer's continuum, and the presence of biomarker signs of amyloidosis, with normal cognition and often, normal tau and neurodegeneration biomarkers, allows for a diagnosis of preclinical Alzheimer's pathologic change (or preclinical AD). Therefore, sensitive, specific and robust methods to identify brain amyloidosis are central in AD research, drug development and clinical management. In addition to early diagnosis, amyloid biomarkers can be used to monitor treatment effects of drugs targeting Aβ, and are essential in clinical and epidemiological studies exploring AD pathophysiology and factors related to both genetic and environmental risk. AD research and development currently benefit from the availability of both fluid and positron emission tomography (PET) biomarkers to assess brain amyloidosis. Fluid and PET biomarkers provide overlapping, but partially independent, information that can be used to test hypotheses and make inferences about the neurophysiology underlying the initiation of amyloid deposition and disease progression. Fluid biomarkers for Aβ pathology The best-established fluid biomarkers for cerebral Aβ pathology are the 42 amino acid form of Aβ (Aβ42) and the Aβ42/40 ratio when measured in cerebrospinal fluid (CSF) (Ashton et al., 2018). Numerous studies have consistently shown a decrease in CSF Aβ42 in the dementia stage of AD, with meta-ana...

Biomarkers for Alzheimer’s disease—preparing for a new era of disease-modifying therapies

“…Extracellular deposition of Aβ, generated through the cleavage of amyloid precursor protein (APP) by BACE1 and γ-secretase, into plaques is the key pathological feature of AD, and has been proposed as the main pathogenic event in the disease [14]. While the amyloid cascade hypothesis was proposed three decades ago [4,15], development of tools to measure Aβ pathology in vivo and prior to autopsy, via diagnostic biomarkers in cerebrospinal fluid (CSF) and through amyloid positron emission tomography (PET) imaging [16], has improved the knowledge on the molecular processes underlying AD and facilitated the development of targeted treatments. AD CSF is characterized by reduced-by approximately 50% of normal levelsconcentration of the 42 amino acid-long and aggregation-prone form of Aβ (Aβ42) [17].…”

“…Since amyloid PET has been in use for the past 15 years, it has passed a number of hurdles. Amyloid PET has been validated against neuropathology [16], has undergone extensive standardization regarding how to quantify Aβ pathology and how to define cut-points for abnormality [22], and has appropriate use criteria [23]. Amyloid PET is the most widely used biomarker in current clinical trials, and is likely to be a first choice for clinical use, particularly in the US and Europe, when an anti-amyloid therapy is approved.…”

Blood-based molecular biomarkers for Alzheimer’s disease

“…Alzheimer's disease (AD) is characterized by the accumulation of extracellular amyloid β (Aβ) plaques, intraneuronal inclusions (neurofibrillary tangles) composed of truncated and phosphorylated forms of the microtubule-stabilizing protein tau, dystrophic neurites, loss of synapses and neurons, and a prominent gliosis that involves changes in the morphology and function of microglia and astrocytes [1]. Currently, we have validated biomarkers for amyloid pathology (Aβ positron emission tomography [PET] and the ratio of 42 over 40 amino acid long Aβ cerebrospinal fluid [CSF Aβ42/Aβ40]) [2], as well as tau dysfunction and aggregation (cerebrospinal fluid [CSF] total or phosphorylated tau and tau PET) [3]. CSF and PET examinations are, however, far from standard tests in general practice and, given the high prevalence of the disease, alternatives such as blood-based biomarkers would represent a significant development, even as screening tools to determine who should be referred to a memory clinic for specific testing.…”

Neuropathological correlates of amyloid PET imaging in Down syndrome

“…Understanding structural properties, biochemical constituents, and evolution of morphologically diverse Aβ plaques and other AD‐related pathology within and between brain regions in relation to age and development of dementia is needed to guide interpretation of amyloid PET imaging of subjects with DS (Head, Helman, Powell, & Schmitt, ; Neale, Padilla, Fonseca, Holland, & Zaman, ). Compared to the extensive number of amyloid PET studies performed in AD (Cohen et al, ), there are relatively few amyloid PET studies of DS (Annus et al, , ; Cohen et al, ; Cole et al, ; Handen et al, ; Hartley et al, ; Jennings et al, ; Landt et al, ; Lao et al, , ; Mak et al, ; Matthews et al, ; Rafii et al, ; Sabbagh et al, ), even fewer longitudinal studies (Hartley et al, ; Lao et al, ; Tudorascu et al, ), and only one imaging‐to‐autopsy analysis (Sabbagh et al, ). Building upon the understanding that AD and DS brains/pathology are not the same, the purpose of this article is to summarize amyloid PET imaging studies of people with DS in the context of neuropathology defined at autopsy, to guide interpretation of future investigations in larger numbers of subjects with DS over longer periods of time.…”