## 2 Alzheimer's Disease--Epidemiology, Progression, ATN Biomarkers  
Alzheimer's disease (AD) is an age-related chronic illness characterized by progressive global deterioration in learning, memory, communication, and general cognitive functioning. AD is the most common cause of dementia spectrum disorder (DSD) and accounts for nearly two-thirds of all dementia diagnoses worldwide [12]. Currently, there are approximately 26 million people worldwide living with AD-derived dementia, and this number is expected to increase dramatically to over 100 million by the mid-century, or an estimated prevalence of 324 per 10,000 persons, and an annual cost of care in the hundreds of billions of dollars worldwide [12, 13]. AD patients are likely to require extensive personal care for the remainder of their lives due to their cognitive impairment [14]. There is no effective treatment or cure for AD, and the continued neurodegeneration is ultimately fatal to the patient. The available treatment options focus on slowing down the progression and the severity of the symptoms of AD. Some preventative measures have also been identified, such as the maintenance of a cognitive reserve or the elimination of behavioral risk factors [14]. Other non-preventable risk factors, such as genetics, have also been identified. Pharmaceutical support does exist in the form of acetylcholinesterase inhibitors [15]. The recent development and accelerated FDA approval of amyloid beta-targeting drugs such as aducanumab have raised hopes; however, their uses are limited, and their efficacy remains controversial [16,17]. AD is histopathologically characterized by abnormal accumulations of protein on the brain or altered protein content in cerebrospinal fluid (CSF). Well-known examples include an increase in extracellular amyloid plaques (also known as senile plaques) on the brain and decreased amyloid protein levels found in CSF; the appearance of intracellular neurofibrillary tangles composed of hyperphosphorylated tau proteins; and decreased total tau protein levels in CSF. The accumulation of these is followed by generalized neurodegeneration and cognitive decline [6,18]. Single-cell transcriptome analysis reveals that there are multiple genes that are involved in the development of AD, most notably those that affect the ability of microglia to clear amyloid proteins from the brain or that affect the regulation of astrocytes [19]. It must be noted that the exact etiology of AD is currently unknown, and that many different factors (synaptic, mitochondrial, inflammatory, neuronal, cytoskeletal, vascular, age, lifestyle, demographic, and genetic) are likely to play mutually overlapping roles in the progression of AD. [PERSON] et al., have proposed the now commonly known amyloid-tau-neurodegenerative (ATN) biomarker-based staging framework, which incorporates the most widely recognized clinical biomarkers of AD [18]. The ATN framework is a descriptive system for communicating multimodal biomarkers for a patient suspected of having AD. Status is reported in a binary fashion (positive or negative) to support the ease of use, clarity, and portability between medical domains. Amyloid positivity is supported by either significant ligand retention in amyloid-PET or low amyloid levels in CSF. Tau positivity is similarly supported by high ligand retention in tau-PET or else elevated levels of phosphorylated tau proteins in CSF. Neurodegeneration (or neuronal injury) is supported by elevated total tau protein levels in CSF, hypometabolism in fluorodeoxypositron emission tomography (FDG-PET), or atrophy in specific brain regions revealed by structural magnetic resonance (MR) images [18]. It is important to note that while extracellular amyloid plaques and intracellular neurofibrillary tangles of hyperphosphorylated tau proteins are not causal factors in AD pathogenesis, AD is characterized along a biologically progressive spectrum by the abnormal accumulation of these specific proteins. In combination with neurodegeneration, they form the primary diagnostic markers [18].