Journal of Alzheimer's Disease - Volume 71, issue 3

Authors: Elmaleh, David R. | Farlow, Martin R. | Conti, Peter S. | Tompkins, Ronald G. | Kundakovic, Ljiljana | Tanzi, Rudolph E.

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) clinical trials, focused on disease modifying drugs and conducted in patients with mild to moderate AD, as well as prodromal (early) AD, have failed to reach efficacy endpoints in improving cognitive function in most cases to date or have been terminated due to adverse events. Drugs that have reached clinical stage were reviewed using web resources (such as clinicaltrials.gov, alzforum.org, company press releases, and peer reviewed literature) to identify late stage (Phase II and Phase III) efficacy clinical trials and summarize reasons for their failure. For each drug, only the latest clinical trials and ongoing trials that …aimed at improving cognitive function were included in the analysis. Here we highlight the potential reasons that have hindered clinical success, including clinical trial design and choice of outcome measures, heterogeneity of patient populations, difficulties in diagnosing and staging the disease, drug design, mechanism of action, and toxicity related to the long-term use. We review and suggest approaches for AD clinical trial design aimed at improving our ability to identify novel therapies for this devastating disease. Show more

Keywords: Alzheimer’s disease, amyloid-β, biomarkers, clinical trial design, combined modality therapy, inflammation, selection of subjects, tau protein, treatment outcomes

DOI: 10.3233/JAD-190507

Citation: Journal of Alzheimer's Disease, vol. 71, no. 3, pp. 715-732, 2019

Authors: Oudin, Anna | Andersson, John | Sundström, Anna | Nordin Adolfsson, Annelie | Oudin Åström, Daniel | Adolfsson, Rolf | Forsberg, Bertil | Nordin, Maria

Article Type: Research Article

Abstract: It is widely known that the apolipoprotein E (APOE ) ɛ 4 allele imposes a higher risk for Alzheimer’s disease (AD). Recent evidence suggests that exposure to air pollution is also a risk factor for AD, and results from a few studies indicate that the effect of air pollution on cognitive function and dementia is stronger in APOE ɛ 4 carriers than in non-carriers. Air pollution and interaction with APOE ɛ 4 on AD risk thus merits further attention. We studied dementia incidence over a 15-year period from the longitudinal Betula study in Northern Sweden. As a marker …for long-term exposure to traffic-related air pollution, we used modelled annual mean nitrogen oxide levels at the residential address of the participants at start of follow-up. Nitrogen oxide correlate well with fine particulate air pollution levels in the study area. We had full data on air pollution, incidence of AD and vascular dementia (VaD), APOE ɛ 4 carrier status, and relevant confounding factors for 1,567 participants. As expected, air pollution was rather clearly associated with dementia incidence. However, there was no evidence for a modifying effect by APOE ɛ 4 on the association (p -value for interaction > 0.30 for both total dementia (AD+VaD) and AD). The results from this study do not imply that adverse effects of air pollution on dementia incidence is limited to, or stronger in, APOE ɛ 4 carriers than in the total population. Show more

Keywords: Air pollution, Alzheimer’s disease, apolipoprotein E, dementia

DOI: 10.3233/JAD-181037

Citation: Journal of Alzheimer's Disease, vol. 71, no. 3, pp. 733-740, 2019

Authors: Folley, Stephanie | Zhou, Ang | Llewellyn, David J. | Hyppönen, Elina

Article Type: Research Article

Abstract: Background: Apolipoprotein E (APOE) genotype affects the risk of Alzheimer’s disease (AD) with inconclusive evidence on the opportunity to mitigate related adverse effects by lifestyle changes. Objective: To examine the individual and interactive associations of APOE and objectively-measured physical activity (PA) and sedentary activity with cognitive decline. Methods: We used data from middle-aged and older UK Biobank participants with repeat tests on visuospatial memory (n  = 52,767) and fluid intelligence (n  = 19,713), and who also took part in the accelerometer sub-study. PA and sedentary activity were assessed by a wrist-worn accelerometer over a seven-day period. …Cognitive decline was defined as >1 standard deviation (SD) reduction in memory or fluid intelligence score, and the mean follow up from baseline was 5.8 years. Results: There was an age dependent association between APOE ɛ 4 genotype and memory decline (page-interaction  = 0.01), with the association only seen in participants who were >65 years (OR 1.33, 95% CI 1.11 to 1.24; for <65 years OR 1.06, 95% CI 0.99 to 1.14). The OR for the APOE ɛ 4 association with fluid intelligence decline was 1.11 (95% CI 0.99 to 1.24), and there was no evidence for age interaction (page -interaction  = 0.99). High PA and low sedentary activity were associated with reduced mean memory decline (p  < 0.02 for both). There was no interaction between PA or sedentary activity with APOE ɛ 4 regarding either of the cognitive decline measures (p  > 0.63 for all). Conclusion: This large-scale study using objectively measured PA did not find differential effects of PA on cognitive decline based on APOE genotype. Show more

Keywords: Accelerometry, Apolipoprotein E, APOE, cognitive decline, dementia, gene-environment interaction, physical activity, sedentary, UK Biobank

DOI: 10.3233/JAD-181132

Citation: Journal of Alzheimer's Disease, vol. 71, no. 3, pp. 741-750, 2019

Authors: André, Perrine | Samieri, Cécilia | Buisson, Charline | Dartigues, Jean-François | Helmer, Catherine | Laugerette, Fabienne | Féart, Catherine

Article Type: Research Article

Abstract: Background: Identifying the mechanisms involved in the pathogenesis of Alzheimer’s disease (AD) remains crucially important. Chronic age-related low-grade inflammation is considered to be one such mechanism, although its causes are unclear. Lipopolysaccharide (LPS)-type endotoxins, a major component of the outer membrane of Gram-negative bacteria, are known as potent pro-inflammatory molecules. Therefore, we hypothesized that greater exposure to circulating LPS, potentially mediated by the inflammatory pathway, would be a key step of the onset of AD. Objective: The aim of this study was to investigate the link between plasma endotoxin-exposure, inflammation, and AD. Methods: Applying a nested …case-control design, we evaluated the associations among baseline plasma endotoxin-exposure (assessed by measuring LPS-binding protein (LBP) and soluble cluster of differentiation-14 (sCD14) levels), inflammation (assessed by measuring interleukin-6 (IL6) levels), and the odds of developing AD over 12 years. Selected from a population-based cohort, 212 incident cases of AD were matched with 424 controls without dementia with regard to age, gender, and education level. Results: After adjusting for a large set of confounders, including the use of anti-inflammatory drugs, only higher LBP levels were significantly associated with a 30% higher odds of developing AD over 12 years (OR 1.30, 95% CIs [1.07–1.59]), regardless of IL6 levels. Conclusion: This large case-control study provides preliminary results concerning plasma endotoxin-exposure among the elderly and suggests that higher LBP levels, an acute-phase reactant involved in the pro-inflammatory response to LPS, are associated with higher odds of developing AD. Show more

Keywords: Alzheimer’s disease, dementia, endotoxins, inflammation, interleukin-6, lipopolysaccharide, lipopolysaccharide-binding protein, soluble cluster of differentiation-14

DOI: 10.3233/JAD-190295

Citation: Journal of Alzheimer's Disease, vol. 71, no. 3, pp. 751-761, 2019

Authors: Karayiannis, Christopher | Moran, Chris | Sharman, James E. | Beare, Richard | Quinn, Stephen J. | Phan, Thanh G. | Wood, Amanda G. | Thrift, Amanda G. | Wang, Wei C. | Srikanth, Velandai

Article Type: Research Article

Abstract: Background: Type 2 diabetes (T2D) is associated with an increased risk of cognitive impairment and dementia with poorly understood underlying mechanisms. Objective: We examined the role of blood pressure (BP), aortic stiffness, and hemodynamics in this association. Methods: Cross-sectional sample of late middle-aged twins discordant for T2D from the Australian Twin Registry. Measurements included neuropsychological battery and brain MRI including arterial spin labelling (ASL) to measure cerebral perfusion. Mobil-o-Graph devices were used to non-invasively obtain 24-hour BP, aortic stiffness, and hemodynamic measures. Using mixed modelling, we studied associations of T2D with cognition, MRI measures, BP, aortic …stiffness, and hemodynamics. Results: There were 23 twin pairs with mean age 63.7 (SD = 6.1) years. T2D (β=–0.45, p  < 0.001) and age (β=–0.05, p  = 0.022) were independently associated with poorer attention but not with memory or perceptual speed. T2D was associated with reduced nocturnal central systolic BP dipping (β=–3.79, p  = 0.027), but not with BP, aortic stiffness, cerebral perfusion, or other hemodynamic measures. There was a statistically significant interaction between T2D and central systolic BP dipping in predicting attention scores (both p  < 0.05 for the interaction term) whereby there was a positive association between BP dipping and attention scores in those with T2D, but not in those without T2D. Conclusion: We found an association between T2D and reduced nocturnal central systolic dipping, but not with any other measures of BP, stiffness or hemodynamic measures. Further study of the role of nocturnal central BP dipping in the association between T2D and cognitive impairment may help identify potential mechanisms. Show more

Keywords: Blood pressure, cerebrovascular circulation, cognitive dysfunction, dementia, hemodynamics, type 2 diabetes mellitus, vascular stiffness

DOI: 10.3233/JAD-190319

Citation: Journal of Alzheimer's Disease, vol. 71, no. 3, pp. 763-773, 2019

Authors: Chatterjee, Pratishtha | Elmi, Mitra | Goozee, Kathryn | Shah, Tejal | Sohrabi, Hamid R. | Dias, Cintia B. | Pedrini, Steve | Shen, Kaikai | Asih, Prita R. | Dave, Preeti | Taddei, Kevin | Vanderstichele, Hugo | Zetterberg, Henrik | Blennow, Kaj | Martins, Ralph N.

Article Type: Research Article

Abstract: Background: Aberrant amyloid-β (Aβ) deposition in the brain occurs two decades prior to the manifestation of Alzheimer’s disease (AD) clinical symptoms and therefore brain Aβ load measured using PET serves as a gold standard biomarker for the early diagnosis of AD. However, the uneconomical nature of PET makes blood markers, that reflect brain Aβ deposition, attractive candidates for investigation as surrogate markers. Objective: Investigation of plasma Aβ as a surrogate marker for brain Aβ deposition in cognitively normal elderly individuals. Methods: Plasma Aβ40 and Aβ42 concentrations were measured using the ultrasensitive Single Molecule Array …(Simoa) assay in 95 cognitively normal elderly individuals, who have all undergone PET to assess brain Aβ deposition. Based on the standard uptake value ratios (SUVR) obtained from PET imaging, using the tracer 18 F-Florbetaben, plasma Aβ was compared between 32 participants assessed to have low brain Aβ load (Aβ–, SUVR <1.35) and 63 assessed to have high brain Aβ load (Aβ+, SUVR ≥1.35). Results: Plasma Aβ42 /Aβ40 ratios were lower in the Aβ+ group compared to the Aβ–group. Plasma Aβ40 and Aβ42 levels were not significantly different between Aβ–and Aβ+ groups, although a trend of higher plasma Aβ40 was observed in the Aβ+ group. Additionally, plasma Aβ42 /Aβ40 ratios along with the known AD risk factors, age and APOE ɛ 4 status, resulted in Aβ+ participants being distinguished from Aβ–participants based on an area under the receiver operating characteristic curve shown to be 78%. Conclusion: Plasma Aβ ratios in this study are a potential biomarker for brain Aβ deposition and therefore, for preclinical AD. However, this method to measure plasma Aβ needs further development to increase the accuracy of this promising AD blood biomarker. Show more

Keywords: Alzheimer’s disease, blood biomarkers, plasma amyloid-β, plasma amyloid-β ratios, preclinical Alzheimer’s disease, single molecule array

DOI: 10.3233/JAD-190533

Citation: Journal of Alzheimer's Disease, vol. 71, no. 3, pp. 775-783, 2019

Authors: Vaskivuo, Laura | Hokkanen, Laura | Hänninen, Tuomo | Antikainen, Riitta | Bäckman, Lars | Laatikainen, Tiina | Paajanen, Teemu | Stigsdotter-Neely, Anna | Strandberg, Timo | Tuomilehto, Jaakko | Soininen, Hilkka | Kivipelto, Miia | Ngandu, Tiia

Article Type: Research Article

Abstract: Background: Subjective memory complaints (SMCs) may be the first sign of cognitive decline in aging. Objective: To examine whether SMCs reported by oneself and informant predict cognitive change over 2 years among at-risk elderly people, and to determine the relationship of different types of SMCs (prospective and retrospective memory complaints) and change in cognitive function. Methods: This investigation is part of the FINGER project, which is a multicenter randomized controlled trial aiming at preventing cognitive decline in cognitively healthy older adults with increased risk of dementia. A subsample of 303 control-group participants (aged 60–80 years) and …their informants (n  = 261) rated the frequency of SMCs, using the Prospective and Retrospective Memory Questionnaire (PRMQ). Cognitive performance was measured at baseline and at 1- and 2-year follow-up visits using a neuropsychological test battery. Results: Participants who reported more SMCs improved less in global cognition, executive function, and memory during the subsequent 2 years in the fully-adjusted analyses. Self-reported retrospective memory problems predicted less improvement in all cognitive domains, whereas prospective memory problems did not. Informant-reported memory problems were not linked to subsequent change in cognition. Conclusion: Our results indicate that self-reported SMCs, measured with PRMQ, predict future cognitive change in several cognitive domains. By contrast, reports by informants were not linked to changes in cognition. Among cognitively healthy at-risk elderly individuals, the persons themselves observe more easily problems relevant for their future cognitive trajectories than their informants. Show more

Keywords: Aging, cognition, dementia, memory

DOI: 10.3233/JAD-190133

Citation: Journal of Alzheimer's Disease, vol. 71, no. 3, pp. 785-795, 2019

Authors: Supasitthumrong, Thitiporn | Tunvirachaisakul, Chavit | Aniwattanapong, Daruj | Tangwongchai, Sookjaroen | Chuchuen, Phenphichcha | Tawankanjanachot, Itthipol | Snabboon, Thiti | Hemrungrojn, Solaphat | Carvalho, Andre F. | Maes, Michael

Article Type: Research Article

Abstract: Background: The Apolipoprotein E4 (ApoE4) genotype is strongly associated with Alzheimer’s disease (AD), although the presence of the ApoE4 allele alone is not sufficient to explain AD. The pathophysiology of amnestic mild cognitive impairment (aMCI) remains unclear. Objective: This study aims to examine associations between peripheral blood biomarkers coupled with ApoE4 and episodic and semantic memory. Methods: The CERAD battery was completed and various biomarkers were assayed in 60 subjects with aMCI, 60 with AD, and 62 healthy controls. Results: Deficits in semantic and episodic memory were significantly predicted by anion gap and bicarbonate, …albumin, and glucose coupled with ApoE4. Furthermore, these peripheral biomarkers interacted with ApoE to predict greater memory impairments. Conclusions: Peripheral blood biomarkers may interact with pathways related to ApoE4 to predict greater semantic and episodic memory impairments, thus contributing to the pathophysiology of aMCI and AD. Our data suggest that the transition from aMCI to AD could at least in some cases be associated with significant interactions between ApoE4 and those peripheral blood biomarkers. Show more

Keywords: Anion gap, apolipoprotein, biomarkers, dementia, episodic memory, inflammation

DOI: 10.3233/JAD-190114

Citation: Journal of Alzheimer's Disease, vol. 71, no. 3, pp. 797-811, 2019

Authors: Pedrinolla, Anna | Tamburin, Stefano | Brasioli, Anna | Sollima, Alessio | Fonte, Cristina | Muti, Ettore | Smania, Nicola | Schena, Federico | Venturelli, Massimo

Article Type: Research Article

Abstract: Background: Behavioral and psychological symptoms of dementia (BPSD) affect 60–90% of patients with Alzheimer’s disease (AD). Objective: To determine if environmental therapy is an effective strategy to reduce BPSD, we tested 163 patients with AD with Neuropsychiatric Inventory (NPI) before and after 6 months of an indoor therapeutic garden (TG) or standard environment. Methods: A single-blind randomized controlled trial on AD patients with BPSD. Participants were randomized to an indoor TG (N = 82), or standard environment (control, N = 81) for 6 months. Primary outcome: change in the NPI score from baseline (T0) to end of treatment (T1). Secondary …outcomes: change in use of quetiapine, cognition, activities of daily living, salivary cortisol, blood pressure from T0 to T1. Results: NPI score significantly ameliorated (TG versus control: –31.8 points), quetiapine dosage (–150 mg), blood pressure (–2.6 mm Hg), and salivary cortisol (–6.4 to –2.1 Nmol/l) were significantly reduced, the Mini-Mental State Examination significantly improved (1.8 points) in the TG versus control arm at T1 (p  < 0.001). No adverse events were reported. Conclusion: The indoor TG seems safe and may reduce BPSD, medication intake, and cortisol levels in AD. Show more

Keywords: Alzheimer’s disease, behavioral symptoms, cortisol, gardens, non-pharmacological treatment, 0000-0002-1561-2187

DOI: 10.3233/JAD-190394

Citation: Journal of Alzheimer's Disease, vol. 71, no. 3, pp. 813-823, 2019

Authors: Tian, Yuan | Song, Mingrui

Article Type: Research Article

Abstract: Administration of sevoflurane (SEVO) may induce learning and memory deficits, which increases the chances of developing Alzheimer’s disease. Here, we studied the effects of SEVO exposure on rats with a focus on the role of insulin-like growth factor (IGF) signaling. SEVO exposure significantly increased neuron cell apoptosis, and caused poor performance of the rats in behavior tests, by suppressing IGF-1 receptor (IGF1R). Bioinformatic analysis predicted microRNA(miR)-223-3p as an IGF1R-binding miRNA, the level of which increased in neurons after exposure to SEVO. In vitro , miR-223-3p suppressed the translation of IGF1R in neural cells. Moreover, transfection with antisense of miR-223-3p significantly …attenuated SEVO exposure-induced neuron cell apoptosis. Taken together, these data suggest that SEVO-induced miR-223-3p upregulation suppresses IGF1R to impair IGF signaling, which subsequently leads to learning and memory impairments. Show more

Keywords: Alzheimer’s disease, IGF1R, miR-223-3p, sevoflurane

DOI: 10.3233/JAD-190596

Citation: Journal of Alzheimer's Disease, vol. 71, no. 3, pp. 825-832, 2019