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Alzheimer's disease is the leading cause of dementia in the world. It affects 6 million people in the United States and 50 million people worldwide. Alzheimer's disease is characterized by the accumulation of amyloid-β plaques (Aβ), an increase in tau protein neurofibrillary tangles, and a loss of synapses. Since the 1990s, removing and reducing Aβ has been the focus of Alzheimer's treatment and prevention research. The accumulation of Aβ can lead to oxidative stress, inflammation, neurotoxicity, and eventually apoptosis. These insults impair signaling systems in the brain, potentially leading to memory loss and cognitive decline. Aniracetam is a safe, effective, cognitive-enhancing drug that improves memory in both human and animal studies. Aniracetam may prevent the production and accumulation of Aβ by increasing α-secretase activity through two distinct pathways: 1) increasing brain derived neurotrophic factor expression and 2) positively modulating metabotropic glutamate receptors. This is the first paper to propose an evidence-based model for aniracetam reducing the accumulation and production of Aβ. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a debilitating neurodegenerative disorder affecting 50 million people globally. It is characterized by the presence of extracellular senile plaques and intracellular neurofibrillary tangles, consisting of amyloid-β and hyperphosphorylated tau proteins, respectively. Despite global research efforts, there is currently no cure available, due in part to an incomplete understanding of the disease pathogenesis. Numerous possible mechanisms, or hypotheses, explaining the origins of sporadic or late-onset AD have been proposed, including the amyloid-β, inflammatory, vascular, and infectious hypotheses. However, despite ample evidence, the failure of multiple trial drugs at the clinical stage illuminates the possible pitfalls of these hypotheses. Systems biology is a strategy which aims to elucidate the interactions between parts of a whole. Using this approach, the current paper shows how the four previously mentioned hypotheses of AD pathogenesis can be intricately connected. This approach allows for seemingly contradictory evidence to be unified in a system-focused explanation of sporadic AD development. Within this view, it is seen that infectious agents, such as P. gingivalis, may play a central role. The data presented here shows that when present, P. gingivalis or its virulence factors, such as gingipains, may induce or exacerbate pathologies underlying sporadic AD. This evidence supports the view that infectious agents, and specifically P. gingivalis, may be suitable treatment targets in AD. [ABSTRACT FROM AUTHOR]

Background: Early identification of Alzheimer's disease (AD) may be extremely beneficial for delaying disease progression. Subjective cognitive decline (SCD) may be an early indicator of AD pathology. Not all individuals with SCD will eventually develop AD, making it critical to identify biomarkers during the SCD stage which indicate likely clinical progression.Objective: The present review aims to summarize available data on structural MRI and cerebrospinal fluid (CSF) biomarkers and their association with clinical progression to mild cognitive impairment (MCI) or AD in people with SCD.Methods: Database searches were conducted using Embase and PubMed until June 2020. Longitudinal studies assessing biomarkers in individuals with SCD and assessing clinical progression to MCI/AD were included. Two assessors performed data extraction and assessed the risk of bias in the included studies. Data were synthesized narratively.Results: An initial search identified 1,065 papers; after screening and review 14 studies were included. Sample size of the included studies ranged from 28-674, mean age was 60.0-68.6 years, and 10.2%-52%of participants converted to MCI/AD. Lower levels of CSF Aβ42 were consistently associated with clinical progression. Combination measures identifying an AD-like profile of Aβ42 and tau levels were strongly associated with clinical progression. Biomarkers identified with structural MRI were less conclusive, as some studies found significant associations while others did not.Conclusion: Biomarkers may be able to predict clinical progression in those with cognitive complaints. Aβ42, or combinations of Aβ42 and tau may be useful biomarkers in identifying individuals with SCD who will progress to MCI/AD. [ABSTRACT FROM AUTHOR]

Subjective cognitive impairment (SCI) refers to concerns regarding one's cognitive functioning in the absence of objective evidence of impairment, and may represent an early stage of Alzheimer's disease. However, as not all individuals with SCI cognitively decline, there is growing interest in the early identification of those individuals with SCI who are most at risk of developing Alzheimer's disease. One promising method of early identification involves the use of biomarkers that are known to be associated with the pathophysiology of the disease; in particular, markers of amyloid and tau accumulation. While there has been substantial research on amyloid and tau biomarkers in the context of mild cognitive impairment (MCI), only recently has attention shifted to SCI, which may represent an even earlier stage in the disease course. The purpose of this paper is to qualitatively review the literature on amyloid and tau biomarkers in SCI. A brief discussion of non-amyloid/tau biomarkers is also included. Not surprisingly, we found that amyloid and tau biomarker profiles become increasingly abnormal from SCI, to MCI, to Alzheimer's disease. Additionally, although amyloid and tau biomarkers appear to be unable to differentiate between SCI and healthy controls, there is some evidence to suggest that they may be able to differentiate between those individuals with SCI who cognitively decline over time and those who do not. While this finding has potential clinical implications, achieving optimal predictive value will likely require further research into the use of numerous biomarkers in combination. [ABSTRACT FROM AUTHOR]

Subjective cognitive impairment (SCI) refers to concerns regarding one's cognitive functioning in the absence of objective evidence of impairment, and may represent an early stage of Alzheimer's disease. However, as not all individuals with SCI cognitively decline, there is growing interest in the early identification of those individuals with SCI who are most at risk of developing Alzheimer's disease. One promising method of early identification involves the use of biomarkers that are known to be associated with the pathophysiology of the disease; in particular, markers of amyloid and tau accumulation. While there has been substantial research on amyloid and tau biomarkers in the context of mild cognitive impairment (MCI), only recently has attention shifted to SCI, which may represent an even earlier stage in the disease course. The purpose of this paper is to qualitatively review the literature on amyloid and tau biomarkers in SCI. A brief discussion of non-amyloid/tau biomarkers is also included. Not surprisingly, we found that amyloid and tau biomarker profiles become increasingly abnormal from SCI, to MCI, to Alzheimer's disease. Additionally, although amyloid and tau biomarkers appear to be unable to differentiate between SCI and healthy controls, there is some evidence to suggest that they may be able to differentiate between those individuals with SCI who cognitively decline over time and those who do not. While this finding has potential clinical implications, achieving optimal predictive value will likely require further research into the use of numerous biomarkers in combination. [ABSTRACT FROM AUTHOR]

The papers selected by the Journal of Alzheimer's Disease for commentary cover three interlinked areas of research: the search for genetic susceptibility of trait markers, the search for biomarkers or state markers, and the search for novel therapeutic targets through an understanding of the mechanisms of disease. This work is reviewed and some directions of travel for the next phase of research suggested. Specifically both state and trait marker research will benefit from advances in technology but will require, on the one hand, larger sample sets and, on the other, the use of study designs other than case-control. Routine collection of data through the electronic medical record coupled with samples collected in clinical care represents a major opportunity to scale these studies. Success in identifying trait markers for stratification and state markers for experimental medicine may be necessary to exploit the increased understanding of mechanisms and the new therapeutic opportunities this is allowing. [ABSTRACT FROM AUTHOR]

Several studies have linked stress with Alzheimer's disease (AD) vulnerability; however, the mechanism remains to be fully elucidated. In the current paper, we investigated the role of glucocortitcoids on the AD-like phenotype. We administered the glucocorticoid dexamethasone to Tg2576 mice for 4 weeks and then investigated its effect on memory, amyloid-β and tau levels, and metabolism. At the end of the treatment period, we observed that mice receiving dexamethasone had a significant impairment in the fear conditioning paradigm compared with controls. Dexamethasone-treated animals showed a significant increase in the amount of brain soluble Aβ40 levels, but no alteration in the steady state levels of its precursor protein, AβPP, or in the major protease enzymes involved in its metabolism (i.e., ADAM-10, BACE-1, or γ-secretase complex). While total tau protein levels were unaltered between the two groups, we found that dexamethasone significantly reduced tau phosphorylation at specific sites that were mediated by decreases in glycogen synthase kinase-3β protein level activity. Finally, we observed a direct correlation between memory impairments and tau phosphorylation levels. Our study highlights the significant role that glucocorticoids play in exacerbating AD-like cognitive impairments via alteration of tau protein phosphorylation state. [ABSTRACT FROM AUTHOR]