To illustrate, various studies have demonstrated that elevated levels of CSF chemokine (C-C motif) ligand 2 (CCL2) envision expedited clinical deterioration in AD, particularly during pre-dementia stages [94,95]. aggregated amyloid beta and phosphorylated tau. The accumulation of excess A aggregated into toxic fibrillar deposits in the brain has been implicated in dementia and neuronal degeneration via the disruption of synaptic and neuronal function [3]. Furthermore, AD can be grouped into different subtypes based upon the pathological factors, with subjects differing in terms of gender distribution, age of onset, cognitive deterioration, and APOE genotype [4]. Due to this, AD manifests itself as a multi-domain amnestic disorder, with different patients revealing variant syndromes [4,5]. Furthermore, aging appears to be the most critical factor for AD due to its considerable repercussions on the immune system [6]. Despite our advancing knowledge of AD pathogenesis, there have been more than 200 unsuccessful clinical trials in the last decade [7]. In general, this could be attributed to recruiting subjects with a high degree of heterogeneity, which might lead to inappropriate single protein targeting in such a multifactorial disease [5,7,8]. In the present review, the effects of aging on the peripheral immune system are discussed, as well as recent advances in active and passive immunotherapies in an effort to rebalance the immune system of AD patients. Suggestions are also offered in the form of personalized medicine in an effort to find effective immunotherapies for AD treatment. 2. Pathological Theories of AD Alzheimers disease is characterized by the accumulation of amyloid-beta (A) formed by neuritic plaques and neurofibrillary tangles (NFTs) [9]. The two components of neuropathological changes associated with AD include positive lesions due to the accumulation of deposits in the brain and negative Vilazodone Hydrochloride Rabbit Polyclonal to C-RAF lesions due to losses by atrophy resulting from neural and synaptic loss [9]. The hallmark proteinopathies for AD include A and pathologic tau which serve as potential biomarkers for onset of AD [10]. Studies have shown abnormal amyloid deposition can lead to rapid decline of cognition, progressive atrophy, and hypometabolism [10]. Vilazodone Hydrochloride Amyloid precursor protein (APP) is a type 1 membrane protein which plays a significant role in the development of AD with the proteolytic activity of – and -secretase complex [11]. The two byproducts of APP metabolism that are generated in neurotoxic amyloid plaques consists of abnormally folded A40 and A42 [11]. An imbalance between the production and clearance of these alternate forms can initiate AD pathogenesis. A42 experiences conformational changes, making it more prone to aggregation into oligomers due to the increased hydrophobic nature in the C-terminus, furthering the formation of fibrils, plaques, and phosphorylated tau. This results in neuritic dystrophy and Vilazodone Hydrochloride furthers the spread of neurodegeneration [12]. The oligomeric A42 is found in abundance around plaques, making oligomers the causative agent for neurodegeneration while also inducing tau hyperphosphorylation [13]. It has been found in animal models that A oligomers impair memory, inhibit long-term potentiation, and decrease synapse density [13]. As such, an approach to AD treatment has been to slow A peptide formation in the brain via the manipulation of – and -secretases (Figure 1) [14]. In general, immunotherapy targeting A has been prominently used in AD because the accumulation of A within the brain has been noted to be an early trigger [15]. Open in a separate window Figure 1 APP amyloidogenic and non-amyloidogenic processing pathways. In the nonamyloidogenic pathway, APP is cleaved by -secretase to produce a soluble amino-terminal of the amyloid precursor protein, as well as a C-terminal fragment (C83) that can subsequently be cleaved by -secretase to produce the p3 extracellular fragment and amyloid precursor protein intracellular domain (AICD). In the amyloidogenic pathway, -secretase cleaves APP to generate the soluble amyloid precursor protein – and a C-terminal fragment (C99). Then, the cleavage of C99 by -secretase leads to the release of amyloid- and AICD. Tau pathology is another contributing factor in AD pathogenesis. The essential functions of tau proteins are to promote the interaction and stability of microtubules and tubulin in the neural network [16]. In AD, Vilazodone Hydrochloride however, tau mutations can occur inhibiting these.