Journal of Alzheimer's Disease - Volume 81, issue 1

Authors: Miranda, Alvaro | Montiel, Enrique | Ulrich, Henning | Paz, Cristian

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is associated with marked atrophy of the cerebral cortex and accumulation of amyloid plaques and neurofibrillary tangles. Amyloid plaques are formed by oligomers of amyloid-β (Aβ) in the brain, with a length of 42 and 40 amino acids. α-secretase cleaves amyloid-β protein precursor (AβPP) producing the membrane-bound fragment CTFα and the soluble fragment sAβPPα with neuroprotective activity; β-secretase produces membrane-bound fragment CTFβ and a soluble fragment sAβPPβ. After α-secretase cleavage of AβPP, γ -secretase cleaves CTFα to produce the cytoplasmic fragment AICD and P3 in the non-amyloidogenic pathway. CTFβ is cleaved by γ -secretase producing AICD as …well as Aβ in amyloidogenic pathways. In the last years, the study of natural products and synthetic compounds, such as α-secretase activity enhancers, β-secretase inhibitors (BACE-1), and γ -secretase activity modulators, have been the focus of pharmaceuticals and researchers. Drugs were improved regarding solubility, blood-brain barrier penetration, selectivity, and potency decreasing Aβ42 . In this regard, BACE-1 inhibitors, such as Atabecestat, NB-360, Umibecestat, PF-06751979 Verubecestat, LY2886721, Lanabecestat, LY2811376 and Elenbecestat, were submitted to phase I-III clinical trials. However, inhibition of Aβ production did not recover cognitive functions or reverse disease progress. Novel strategies are being developed, aiming at a partial reduction of Aβ production, such as the development of γ -secretase modulators or α-secretase activity enhancers. Such therapeutic tools shall focus on slowing down or minimizing the progression of neuronal damage. Here, we summarize structures and activities of the latest compounds designed for AD treatment, with remarkable in vitro , in vivo , and clinical phase activities. Show more

Keywords: Alzheimer disease, α-secretase enhancers, β-secretase inhibitors, clinical trials, γ-secretase modulators

DOI: 10.3233/JAD-201027

Citation: Journal of Alzheimer's Disease, vol. 81, no. 1, pp. 1-17, 2021

Authors: Yang, Jianwei | Jia, Longfei | Li, Yan | Qiu, Qiongqiong | Quan, Meina | Jia, Jianping

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) research is entering a unique moment in which enormous information about the molecular basis of this disease is being translated into therapeutics. However, almost all drug candidates have failed in clinical trials over the past 30 years. These many trial failures have highlighted a need for the incorporation of biomarkers in clinical trials to help improve the trial design. Fluid biomarkers measured in cerebrospinal fluid and circulating blood, which can reflect the pathophysiological process in the brain, are becoming increasingly important in AD clinical trials. In this review, we first succinctly outline a panel of fluid biomarkers …for neuropathological changes in AD. Then, we provide a comprehensive overview of current and future application of fluid biomarkers in clinical trials for AD. We also summarize the many challenges that have been encountered in efforts to integrate fluid biomarkers in clinical trials, and the barriers that have begun to be overcome. Ongoing research efforts in the field of fluid biomarkers will be critical to make significant progress in ultimately unveiling disease-modifying therapies in AD. Show more

Keywords: Alzheimer’s disease, biomarkers, blood biomarkers, cerebrospinal fluid, clinical trials

DOI: 10.3233/JAD-201068

Citation: Journal of Alzheimer's Disease, vol. 81, no. 1, pp. 19-32, 2021

Authors: Gaudreault, Roger | Hervé, Vincent | van de Ven, Theo G.M. | Mousseau, Normand | Ramassamy, Charles

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder, responsible for nearly two-thirds of all dementia cases. In this review, we report the potential AD treatment strategies focusing on natural polyphenol molecules (green chemistry) and more specifically on the inhibition of polyphenol-induced amyloid aggregation/disaggregation pathways: in bulk and on biosurfaces. We discuss how these pathways can potentially alter the structure at the early stages of AD, hence delaying the aggregation of amyloid-β (Aβ) and tau. We also discuss multidisciplinary approaches, combining experimental and modelling methods, that can better characterize the biochemical and biophysical interactions between proteins and phenolic ligands. …In addition to the surface-induced aggregation, which can occur on surfaces where protein can interact with other proteins and polyphenols, we suggest a new concept referred as “confinement stability”. Here, on the contrary, the adsorption of Aβ and tau on biosurfaces other than Aβ- and tau-fibrils, e.g., red blood cells, can lead to confinement stability that minimizes the aggregation of Aβ and tau. Overall, these mechanisms may participate directly or indirectly in mitigating neurodegenerative diseases, by preventing protein self-association, slowing down the aggregation processes, and delaying the progression of AD. Show more

Keywords: Alzheimer’s disease, amyloid, blood cells, computer simulation, polyphenols, tau

DOI: 10.3233/JAD-201549

Citation: Journal of Alzheimer's Disease, vol. 81, no. 1, pp. 33-55, 2021

Authors: Tjahyo, Alvin Surya | Gandy, Joan | Porter, Judi | Henry, Christiani Jeyakumar

Article Type: Review Article

Abstract: Weight loss, a hallmark feature of dementia, is associated with higher mortality in older people. However, there is a lack of consensus in the literature as to whether the weight loss commonly observed in older people with dementia results from reduced energy intake and/or increased energy expenditure. Understanding the cause of energy imbalance in older people with dementia would allow more targeted interventions to avoid detrimental health effects in this vulnerable group. In this paper, we review studies that have considered weight change, energy intake, and energy expenditure in older people with and without dementia. We critically assess the studies’ …methodology and outline the various factors which may decrease and increase energy intake and expenditure respectively in older people with and without dementia. Current available literature does not support the view that there is a lower energy intake and/or a higher energy expenditure in older people with dementia when compared to those without dementia. The need for more high-quality studies is also highlighted in order to shed more light towards this issue which continues to elude researchers and clinicians alike. Show more

Keywords: Aged, dementia, energy intake, energy metabolism, weight loss

DOI: 10.3233/JAD-201496

Citation: Journal of Alzheimer's Disease, vol. 81, no. 1, pp. 57-73, 2021

Authors: Toniolo, Sofia | Di Lorenzo, Francesco | Scarioni, Marta | Frederiksen, Kristian Steen | Nobili, Flavio

Article Type: Research Article

Abstract: Acute delirium and other neuropsychiatric symptoms have frequently been reported in COVID-19 patients and are variably referred to as acute encephalopathy, COVID-19 encephalopathy, SARS-CoV-2 encephalitis, or steroid-responsive encephalitis. COVID-19 specific biomarkers of cognitive impairment are currently lacking, but there is some evidence that SARS-CoV-2 could preferentially and directly target the frontal lobes, as suggested by behavioral and dysexecutive symptoms, fronto-temporal hypoperfusion on MRI, EEG slowing in frontal regions, and frontal hypometabolism on 18 F-FDG-PET imaging. We suggest that an inflammatory parainfectious process targeting preferentially the frontal lobes (and/or frontal networks) could be the underlying cause of these shared clinical, neurophysiological, …and imaging findings in COVID-19 patients. We explore the biological mechanisms and the clinical biomarkers that might underlie such disruption of frontal circuits and highlight the need of standardized diagnostic procedures to be applied when investigating patients with these clinical findings. We also suggest the use of a unique label, to increase comparability across studies. Show more

Keywords: Biomarkers, COVID-19, delirium, frontal lobe, SARS-CoV-2

DOI: 10.3233/JAD-210008

Citation: Journal of Alzheimer's Disease, vol. 81, no. 1, pp. 75-81, 2021

Authors: Åström, Daniel Oudin | Adolfsson, Rolf | Segersson, David | Forsberg, Bertil | Oudin, Anna

Article Type: Article Commentary

Abstract: Exposure to fine particulate air pollution (PM2.5 ) is emerging as a risk factor for Alzheimer’s disease (AD), but existing studies are still limited and heterogeneous. We have previously studied the association between dementia (AD and vascular dementia) and PM2.5 stemming from vehicle exhaust and wood-smoke in the Betula cohort in Northern Sweden. The aim of this commentary is to estimate the association between total PM2.5 and dementia in the Betula cohort, which is more relevant to include in future meta-estimates than the source-specific estimates. The hazard ratio for incident dementia associated with a 1μ g/m3 increase in …local PM2.5 was 1.38 (95% confidence interval: 0.99 –1.92). The interpretation of our results is that they indicate an association between local contrasts in concentration of PM2.5 at the residential address and incidence of dementia in a low-level setting. Show more

Keywords: Air pollution, Alzheimer’s disease, dementia, particulate air pollution, PM2.5

DOI: 10.3233/JAD-201538

Citation: Journal of Alzheimer's Disease, vol. 81, no. 1, pp. 83-85, 2021

Authors: Dias, Irundika H.K. | Griffiths, Helen R.

Article Type: Article Commentary

Abstract: Neuroinflammation has been implicated in Alzheimer’s disease onset and progression. Chronic neuroinflammation is initiated by amyloid-β-activated microglial cells that secrete immuno-modulatory molecules within the brain and into the vasculature. Inflammation is normally self-limiting and actively resolves by “switching off” the generation of pro-inflammatory mediators and by non-phlogistic clearance of spent cells and their debris to restore tissue homeostasis. Deficits in these anti-inflammatory/pro-resolution pathways may predispose to the development of chronic inflammation. The synthesis of endogenous lipid mediators from arachidonic acid, lipoxins via cyclooxygenase 2 and lipoxygenases, and conversion of exogenous polyunsaturated fatty acids, namely docosahexaenoic acid and eicosapentaenoic acid, to …resolvins contributes to effective, timely resolution of acute inflammation. Work by Xiuzhe et al., 2020 in the Journal of Alzheimer ’s Disease reported that plasma level of LXA4 is related to cognitive status in ischemic stroke patients suggesting that decreased LXA4 may be a potential risk factor for post post-stroke cognitive impairment. As evident by recent clinical trials and development of drug analogues, there is recent drive to search for lipoxin analogues as therapeutics for inflammatory diseases. Understanding how bioactive lipid signaling is involved in resolution will increase our understanding of controlling inflammation and may facilitate the discovery of new classes of therapeutic pro-resolution agents for evaluation in AD prevention studies. Show more

Keywords: Alzheimer’s disease, Lipoxin A4, lipoxygenase, LXA4 drug analogues, neuroinflammation, pro-resolution, stroke, therapy

DOI: 10.3233/JAD-210121

Citation: Journal of Alzheimer's Disease, vol. 81, no. 1, pp. 87-90, 2021

Authors: Yogev-Seligmann, Galit | Eisenstein, Tamir | Ash, Elissa | Giladi, Nir | Sharon, Haggai | Nachman, Shikma | Bregman, Noa | Kodesh, Einat | Hendler, Talma | Lerner, Yulia

Article Type: Research Article

Abstract: Background: Aerobic training has been shown to promote structural and functional neurocognitive plasticity in cognitively intact older adults. However, little is known about the neuroplastic potential of aerobic exercise in individuals at risk of Alzheimer’s disease (AD) and dementia. Objective: We aimed to explore the effect of aerobic exercise intervention and cardiorespiratory fitness improvement on brain and cognitive functions in older adults with amnestic mild cognitive impairment (aMCI). Methods: 27 participants with aMCI were randomized to either aerobic training (n  = 13) or balance and toning (BAT) control group (n  = 14) for a 16-week intervention. Pre- and …post-assessments included functional MRI experiments of brain activation during associative memory encoding and neural synchronization during complex information processing, cognitive evaluation using neuropsychological tests, and cardiorespiratory fitness assessment. Results: The aerobic group demonstrated increased frontal activity during memory encoding and increased neural synchronization in higher-order cognitive regions such as the frontal cortex and temporo-parietal junction (TPJ) following the intervention. In contrast, the BAT control group demonstrated decreased brain activity during memory encoding, primarily in occipital, temporal, and parietal areas. Increases in cardiorespiratory fitness were associated with increases in brain activation in both the left inferior frontal and precentral gyri. Furthermore, changes in cardiorespiratory fitness were also correlated with changes in performance on several neuropsychological tests. Conclusion: Aerobic exercise training may result in functional plasticity of high-order cognitive areas, especially, frontal regions, among older adults at risk of AD and dementia. Furthermore, cardiorespiratory fitness may be an important mediating factor of the observed changes in neurocognitive functions. Show more

Keywords: Brain plasticity, cardiorespiratory fitness, cognition, functional MRI, mild cognitive impairment, physical exercise

DOI: 10.3233/JAD-201429

Citation: Journal of Alzheimer's Disease, vol. 81, no. 1, pp. 91-112, 2021

Authors: Graff-Radford, Jonathan | Lesnick, Timothy G. | Mielke, Michelle M. | Constantopoulos, Eleni | Rabinstein, Alejandro A. | Przybelski, Scott A. | Vemuri, Prashanthi | Botha, Hugo | Jones, David T. | Ramanan, Vijay K. | Petersen, Ronald C. | Knopman, David S. | Boeve, Bradley F. | Murray, Melissa E. | Dickson, Dennis W. | Jack, Clifford R. | Kantarci, Kejal | Reichard, R. Ross

Article Type: Research Article

Abstract: Background: The relationship between cerebral microbleeds (CMBs) on hemosiderin-sensitive MRI sequences and cerebral amyloid angiopathy (CAA) remains unclear in population-based participants or in individuals with dementia. Objective: To determine whether CMBs on antemortem MRI correlate with CAA. Methods: We reviewed 54 consecutive participants with antemortem T2* GRE-MRI sequences and subsequent autopsy. CMBs were quantified on MRIs closest to death. Autopsy CAA burden was quantified in each region including leptomeningeal/cortical and capillary CAA. By a clustering approach, we examined the relationship among CAA variables and performed principal component analysis (PCA) for dimension reduction to produce two scores …from these 15 interrelated predictors. Hurdle models assessed relationships between principal components and lobar CMBs. Results: MRI-based CMBs appeared in 20/54 (37%). 10 participants had ≥2 lobar-only CMBs. The first two components of the PCA analysis of the CAA variables explained 74% variability. The first rotated component (RPC1) consisted of leptomeningeal and cortical CAA and the second rotated component of capillary CAA (RPC2). Both the leptomeningeal and cortical component and the capillary component correlated with lobar-only CMBs. The capillary CAA component outperformed the leptomeningeal and cortical CAA component in predicting lobar CMBs. Both capillary and the leptomeningeal/cortical components correlated with number of lobar CMBs. Conclusion: Capillary and leptomeningeal/cortical scores correlated with lobar CMBs on MRI but lobar CMBs were more closely associated with the capillary component. The capillary component correlated with APOE ɛ 4, highlighting lobar CMBs as one aspect of CAA phenotypic diversity. More CMBs also increase the probability of underlying CAA. Show more

Keywords: Alzheimer’s disease, capillaries, cerebral amyloid angiopathy, neuropathology

DOI: 10.3233/JAD-201536

Citation: Journal of Alzheimer's Disease, vol. 81, no. 1, pp. 113-122, 2021

Authors: Hayat, Shabina A. | Luben, Robert | Khaw, Kay-Tee | Brayne, Carol

Article Type: Research Article

Abstract: Background: Exploring the domains of cognitive function which are most strongly associated with future dementia may help with understanding risk factors for, and the natural history of dementia. Objective: To examine the association of performance on a range of cognitive tests (both global and domain specific) with subsequent diagnosis of dementia through health services in a population of relatively healthy men and women and risk of future dementia. Methods: We examined the association between performance on different cognitive tests as well as a global score and future dementia risk ascertained through health record linkage in a …cohort of 8,581 individuals (aged 48–92 years) between 2004–2019 with almost 15 years follow-up (average of 10 years) before and after adjustment for socio-demographic, lifestyle, and health characteristics. Results: Those with poor performance for global cognition (bottom 10%) were almost four times as likely to receive a dementia diagnosis from health services over the next 15 years than those who performed well HR = 3.51 (95% CI 2.61, 4.71 p  < 0.001) after adjustment for socioeconomic, lifestyle, and biological factors and also prevalent disease. Poor cognition performance in multiple tests was associated with 10-fold increased risk compared to those not performing poorly in any test HR = 10.82 (95% CI 6.85, 17.10 p  < 0.001). Conclusion: Deficits across multiple cognitive domains substantially increase risk of future dementia over and above neuropsychological test scores ten years prior to a clinical diagnosis. These findings may help further understanding of the natural history of dementia and how such measures could contribute to strengthening future models of dementia. Show more

Keywords: Cognition, dementia, epidemiology, risk

DOI: 10.3233/JAD-210030

Citation: Journal of Alzheimer's Disease, vol. 81, no. 1, pp. 123-135, 2021