Mechanisms of Risk Reduction in the Clinical Practice of Alzheimer’s Disease Prevention

Schelke, Matthew W.; Attia, Peter; Palenchar, Daniel J.; Kaplan, Bob; Mureb, Monica; Ganzer, Christine A.; Scheyer, Olivia; Rahman, Aneela; Kachko, Robert; Krikorian, Robert; Mosconi, Lisa; Isaacson, Richard S.

doi:10.3389/fnagi.2018.00096

Cited by 38 publications

(30 citation statements)

References 164 publications

(169 reference statements)

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“…Participants were lowcognitive functioning but non-demented older people (Ngandu et al, 2015). Similar results from multidomain interventions have been reported in older people showing cognitive decline (Schelke et al, 2018) and in patients with "mild cognitive impairment" (MCI), a precursor state to Alzheimer's disease (Rovner et al, 2018). This evidence is consistent with Stillman et al in showing the interrelatedness of diet and physical fitness on neurocognitive health.…”

Section: Discussionsupporting

confidence: 82%

Editorial: Cognitive and Brain Aging: Interventions to Promote Well-Being in Old Age

Baldwin

Greenwood

2020

Front. Aging Neurosci.

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Editorial on the Research Topic Cognitive and Brain Aging: Interventions to Promote Well-Being in Old Age This Research Topic is dedicated to the memory of Raja Parasuraman who passed away prematurely on March 22, 2015, ending a remarkable career spanning both diverse and intersecting research areas. Over the course of his career Raja used a variety of techniques ranging from behavioral studies, signal detection theory, electrophysiology, fMRI, and genetic analysis to contribute to different disciplines including human factors, cognitive neuroscience, and the intersection of the two in his founding of the field of neuroergonomics. He maintained an interest in cognitive aging throughout most of his career, studying the effects of not only disease states, such as Alzheimer's, but also interindividual differences in cognitive performance through cognitive genetics and cognitive training. This Research Topic celebrates the aspects of Raja's contributions that are related to cognitive aging and brain aging. Some of Raja's contributions in this area include work examining age-related changes in visuospatial processing and working memory, the role of the genetics of apolipoprotein E (APOE) in cognitive aging, in particular in Alzheimer's disease, and methods for supporting healthy cognitive aging. This work culminated in a book co-authored with Pam Greenwood entitled, "Nurturing the Older Brain and Mind" published by MIT Press (Greenwood and Parasuraman, 2012). Considered together, the contributions to this special issue build on Raja's work and, importantly, show a way for the field to move forward in the future. Interventions are needed to ameliorate age-related cognitive decline which is a risk factor for the devastation of dementia, robbing older people of their well-being and shortening their lives. Interventions aimed at cognitive decline are the focus of this Research Topic dedicated to Raja Parasuraman. In recent years, cognitive aging research has pivoted from simply cataloging age-related cognitive decline to seeking interventions aimed at slowing or delaying that decline and improving quality of life in old age. Efforts to develop interventions to ameliorate cognitive aging rely on assumptions that interventions can heighten brain integrity and/or induce compensation for age-related decline in brain integrity. These assumptions are supported by evidence that aerobic exercise increases (a) adult-onset birth and integration of new neurons (neurogenesis) (Anacker and Hen, 2017; Kempermann, 2019) and (b) hippocampal blood flow in a manner related to improved recall (Pereira et al., 2007; Maass et al., 2015). These assumptions are also supported by evidence of cortical reorganization in older people following cognitive training (Maguire et al., 2000; Taub et al., 2002; Greenwood, 2007). This evidence of cortical reorganization related to training raises questions about the ability of the brain respond adaptively to age-related declines.

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Section: Discussionsupporting

confidence: 82%

Editorial: Cognitive and Brain Aging: Interventions to Promote Well-Being in Old Age

Baldwin

Greenwood

2020

Front. Aging Neurosci.

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“… 63 Based on positron emission tomography (PET) imaging, the observed benefits were associated with a combination of decreased tau accumulation and amyloid burden. 63 , 64 Additionally, beyond its ability to protect against Aβ toxicity, curcumin has also been shown to protect against lead neurotoxicity 65 and oxidative damage. 66 All in all, curcumin appears to be a promising diagnostic, preventive, and potentially therapeutic AD molecule.…”

Section: Introductionmentioning

confidence: 99%

Interactions between Curcumin Derivatives and Amyloid-β Fibrils: Insights from Molecular Dynamics Simulations

Jakubowski

Orr

2019

J. Chem. Inf. Model.

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The aggregation of amyloid-β (Aβ) peptides into senile plaques is a hallmark of Alzheimer’s disease (AD) and is hypothesized to be the primary cause of AD related neurodegeneration. Previous studies have shown the ability of curcumin to both inhibit the aggregation of Aβ peptides into oligomers or fibrils and reduce amyloids in vivo . Despite the promise of curcumin and its derivatives to serve as diagnostic, preventative, and potentially therapeutic AD molecules, the mechanism by which curcumin and its derivatives bind to and inhibit Aβ fibrils’ formation remains elusive. Here, we investigated curcumin and a set of curcumin derivatives in complex with a hexamer peptide model of the Aβ 1–42 fibril using nearly exhaustive docking, followed by multi-ns molecular dynamics simulations, to provide atomistic-detail insights into the molecules’ binding and inhibitory properties. In the vast majority of the simulations, curcumin and its derivatives remain firmly bound in complex with the fibril through primarily three different principle binding modes, in which the molecules interact with residue domain 17 LVFFA 21 , in line with previous experiments. In a small subset of these simulations, the molecules partly dissociate the outermost peptide of the Aβ 1–42 fibril by disrupting β-sheets within the residue domain 12 VHHQKLVFF 20 . A comparison between binding modes leading or not leading to partial dissociation of the outermost peptide suggests that the latter is attributed to a few subtle key structural and energetic interaction-based differences. Interestingly, partial dissociation appears to be either an outcome of high affinity interactions or a cause leading to high affinity interactions between the molecules and the fibril, which could partly serve as a compensation for the energy loss in the fibril due to partial dissociation. In conjunction with this, we suggest a potential inhibition mechanism of Αβ 1–42 aggregation by the molecules, where the partially dissociated 16 KLVFF 20 domain of the outermost peptide could either remain unstructured or wrap around to form intramolecular interactions with the same peptide’s 29 GAIIG 33 domain, while the molecules could additionally act as a patch against the external edge of the second outermost peptide’s 16 KLVFF 20 domain. Thereby, individually or concurrently, these could prohibit fibril elongation.

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“…Such models already exist [e.g. among many others see 35]. In particular, understanding how the brain protects itself from getting infected, and once infected has methods to cope with the infection is an important aspect of neuropathological development.…”

Section: The Causes Of Alzheimer's Diseasementioning

confidence: 99%

The pitfalls of crowdfunding Alzheimer's disease research

Garrett¹

2019

Int Med

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With pharmaceutical companies' repeated failures at finding effective interventions for Alzheimer's disease, together with an increasing reliance on the growing federal funding for research, there is an emergent opportunity for financing alternate research through crowdfunding. Crowdfunding-where funding is obtained from small donations from a large group of people-has become a new source of funding for medical research. By understanding how the research community has evolved to study Alzheimer's disease the pitfalls of this strategy can be highlighted. Alzheimer's disease research is complex. From its inception in the early 1900s, Alzheimer's disease has been at the center of movement within psychiatry to define the disease on the basis of its biology. Recent emphasisthrough the DSM (Diagnostic and Statistical Manual of Mental Disorders), RDC (Research Diagnostic Criteria), RDoC (Research Domain Criteria) as well as the more recent Framework from the U.S. National Institute on Aging-have supported an exclusive emphasis on biology. But by excluding other aspects of the disease, such as its clinical expression, this research approach will be shown to be faulty and contradictory. So far, this approach has resulted in 100% failures. By examining the historical and financial circumstances of the industry centered on Alzheimer's disease a strong warning is given to the public to mistrust crowdfunding Alzheimer's disease research. A broader and more inclusive approach is likely to generate a better understanding of the disease and therefore hold better promise for understanding the disease in the long term. Such a nuanced approach competes badly with the more binary search for a cure and is less receptive to public support through crowdfunding.

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Mechanisms of Risk Reduction in the Clinical Practice of Alzheimer’s Disease Prevention

Cited by 38 publications

References 164 publications

Editorial: Cognitive and Brain Aging: Interventions to Promote Well-Being in Old Age

Editorial: Cognitive and Brain Aging: Interventions to Promote Well-Being in Old Age

Interactions between Curcumin Derivatives and Amyloid-β Fibrils: Insights from Molecular Dynamics Simulations

The pitfalls of crowdfunding Alzheimer's disease research

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