Differences in findings may be owing to variations in methodology, small sample sizes and heterogeneity of sample populations. neurodegeneration. Circulating leukocytes are attractive candidate AD biomarkers as they can be obtained in a minimally invasive manner and are easily analyzed by widely available flow cytometry techniques. In this review, we critically analyze the potential utility of peripheral leukocytes as biological markers for AD. Keywords:autoantibody, B lymphocyte, biological marker, cytokine, dementia, dendritic cell, granulocyte, immune, inflammation, macrophage, monocyte, natural killer cell, polymorphonuclear cell, T lymphocyte Alzheimers disease (AD) is a progressive neurodegenerative disorder pathologically characterized by deposition of amyloid-b (Ab) peptides as Ab plaques, intracellular neurofibrillary tangles, low-level chronic neuroinflammation and neuronal injury, resulting in a devastating loss of cognitive function [1]. AD has emerged as a national and international epidemic. Methylphenidate It is the most common form of dementia, affecting an estimated 5.2 million Americans in 2008 alone, and that number is projected to increase to more than 13.2 million by 2050 [2,3]. While epidemiological studies have implicated genetic and environmental risk factors for AD, aging remains the most significant risk-incurring variable. Risk for developing AD is low before the age of 65 years, when prevalence for the disease is less than one person per 1000. Yet, AD prevalence Emr4 is approximately 2.53% at 65 years of age, and it approximately doubles every 5 years until age 8590 years, when it approaches 50% Methylphenidate and appears to Methylphenidate plateau [46]. However, AD prevalence is expected to increase as diagnosis of the disease improves and general medicine prolongs longevity. While a gold standard definitive diagnosis of AD can only be determined upon postmortem neuropathological examination, a battery of antemortem clinical tests may be employed to detect the disease with 8590% accuracy. Neuropsychological assessment and neuroimaging procedures for AD, including mini-mental state examination (MMSE), AD assessment scale-cognitive subscale (ADAS-cog), behavioral pathology in AD rating scale (BEHAVE-AD), Consortium to Establish a Registry for AD (CERAD) neuropsychological battery, computed tomography (CT), MRI and PET, are noninvasive and sensitive diagnostic tools that are often relied upon to arrive at a clinical diagnosis of AD. Yet, AD clinical diagnoses are typically made only after the emergence of cognitive symptoms, when significant brain pathology and neuronal injury has already transpired. In fact, there is mounting evidence that pathogenic mechanisms manifest early within the particularly long AD prodromal phase (anywhere from 5 to 20 years), which includes the mild cognitive impairment (MCI) stage that is now generally regarded to precede dementia onset [5]. Thus, development of sensitive biological markers Methylphenidate would ideally lead to an earlier clinical AD diagnosis that could be made during the extended prodromal stage of the disease, thereby allowing earlier and more effective therapeutic intervention. As first proposed by Hardy and Allsop, the amyloid cascade hypothesis purports that mismetabolism and deposition of Ab peptides as Ab plaques is the principal etiopathological event in AD, which triggers downstream events culminating in neuronal demise [7]. Ab peptides Methylphenidate are normally generated in relatively small amounts by coordinated proteolytic cleavage of the amyloid precursor protein (APP), which is executed by enzymes known as secretases. However, at some point during the AD prodromal stage, APP metabolism and/or clearance goes awry, and Ab peptides begin accumulating on the inside and outside of neurons, forming aggregates of oligomers, protofibrils and fibrils. These aggregates combine with other cellular components to form a rigid, insoluble deposit known as an Ab plaque [8,9]. Innate immune responses mediated by activated microglia and astrocytes seem to occur in tight temporal and spatial proximity to these Ab deposits [10,11]. These immune/inflammatory cells respond by synthesizing and releasing a myriad of proinflammatory cytokines, chemokines, complement proteins, proteinases, cell surface immune activation molecules and reactive oxygen species (ROS) [1219]. While this neuroinflammatory response may be beneficial for clearing infection and initiating tissue repair mechanisms, if left unresolved it exposes sensitive neurons to chronically elevated levels of potentially toxic molecules that can lead to bystander injury [20]. Although initially thought to be an epiphenomenon, multiple lines of evidence now show that.