Journal of Alzheimer's Disease - Volume 63, issue 4

Authors: Li, Sinian | Shao, Yiming | Li, Kanglan | HuangFu, Changmei | Wang, Wenjie | Liu, Zhou | Cai, Zhiyou | Zhao, Bin

Article Type: Review Article

Abstract: Vascular cognitive impairment (VCI), the second most common cause of dementia in elderly people, is a term that refers to all forms of cognitive disorders that can be attributed to cerebrovascular disease such as manifestations of discrete infarctions, brain hemorrhages, and white matter lesions. The gut microbiota (GM) has emerged recently as an essential player in the development of VCI. The GM may affect the brain’s physiological, behavioral, and cognitive functions through the brain-gut axis via neural, immune, endocrine, and metabolic pathways. Therefore, microbiota dysbiosis may mediate or affect atherosclerosis, cerebrovascular disease, and endothelial dysfunction, which are the predominant risk …factors for VCI. Moreover, the composition of the GM includes the bacterial component lipopolysaccharides and their metabolic products including trimethylamine-N -oxide and short-chain fatty acids. These products may increase the permeability of the intestinal epithelium, leading to systemic immune responses, low-grade inflammation, and altered signaling pathways that are associated with the pathogenesis of VCI. In this review, we discuss the proposed mechanisms of the GM in the maintenance of VCI and how it is implicated in acquired metabolic diseases, particularly in VCI regulation. Show more

Keywords: Atherosclerosis, cerebrovascular disease, endothelial dysfunction, gut microbiota, lipopolysaccharides, short-chain fatty acids, trimethylamine-N-oxide, vascular cognitive impairment

DOI: 10.3233/JAD-171103

Citation: Journal of Alzheimer's Disease, vol. 63, no. 4, pp. 1209-1222, 2018

Authors: Cai, Zhiyou | Qiao, Pei-Feng | Wan, Cheng-Qun | Cai, Min | Zhou, Nan-Kai | Li, Qin

Article Type: Review Article

Abstract: The blood-brain barrier (BBB) is involved in the pathogenesis of Alzheimer’s disease (AD). BBB is a highly selective semipermeable structural and chemical barrier which ensures a stable internal environment of the brain and prevents foreign objects invading the brain tissue. BBB dysfunction induces the failure of Aβ transport from brain to the peripheral circulation across the BBB. Especially, decreased levels of LRP-1 (low density lipoprotein receptor-related protein 1) and increased levels of RAGE (receptor for advanced glycation endproducts) at the BBB can cause the failure of Aβ transport. The pathogenesis of AD is related to the BBB structural components, including …pericytes, astrocytes, vascular endothelial cells, and tight junctions. BBB dysfunction will trigger neuroinflammation and oxidative stress, then enhance the activity of β-secretase and γ-secretase, and finally promote Aβ generation. A progressive accumulation of Aβ in brain and BBB dysfunction may become a feedback loop that gives rise to cognitive impairment and the onset of dementia. The correlation between BBB dysfunction and tau pathology has been well-reported. Therefore, regulating BBB function may be a new therapeutic target for treating AD. Show more

Keywords: Alzheimer’s disease, astrocyte, blood-brain barrier, endothelial cell, pericyte

DOI: 10.3233/JAD-180098

Citation: Journal of Alzheimer's Disease, vol. 63, no. 4, pp. 1223-1234, 2018

Authors: Akingbade, Oluwatomi E.S. | Gibson, Claire | Kalaria, Raj N. | Mukaetova-Ladinska, Elizabeta B.

Article Type: Review Article

Abstract: Dementia continues to be the most burdening neurocognitive disorder, having a negative impact on the lives of millions. The search for biomarkers to improve the clinical diagnosis of dementia is ongoing, with the focus on effective use of readily accessible peripheral markers. In this review, we concentrate on platelets as biomarkers of dementia and analyze their potential as easily-accessible clinical biomarkers for various subtypes of dementia. Current platelet protein biomarkers that have been investigated for their clinical utility in the diagnosis of dementia, in particular Alzheimer’s disease, include amyloid-β protein precursor (AβPP), the AβPP secretases (BACE1 and ADAM10), α-synuclein, tau …protein, serotonin, cholesterol, phospholipases, clusterin, IgG, surface receptors, MAO-B, and coated platelets. Few of them, i.e., platelet tau, AβPP (particularly with regards to coated platelets) and secreted ADAM10 and BACE1 show the most promise to be taken forward into clinical setting to diagnose dementia. Aside from protein biomarkers, changes in factors such as mean platelet volume have the potential to play a very specific role in both the dementia diagnosis and prognosis. This review raises a number of research questions for consideration before application of the above biomarkers to routine clinical setting. It is without doubt that there is a need for more clarification on the effects of dementia on platelet morphology and protein content before these changes can be clinically applied as dementia biomarkers and explored further in differentiating distinct dementia subtypes. Show more

Keywords: Amyloid, biomarkers, blood platelets, dementia, tau protein

DOI: 10.3233/JAD-180181

Citation: Journal of Alzheimer's Disease, vol. 63, no. 4, pp. 1235-1259, 2018

Authors: Ma, Fang-Chen | Wang, Hui-Fu | Cao, Xi-Peng | Tan, Chen-Chen | Tan, Lan | Yu, Jin-Tai

Article Type: Short Communication

Abstract: The ATP-binding cassette transporter A7 (ABCA7) was identified as a known risk factor for Alzheimer’s disease (AD). However, the relation between ABCA7 and AD was still inconsistent across these studies. Here, our meta-analysis aimed at confirming the association of ABCA7 with AD. Finally, 16 case-control studies (63747 versus 85833) were retrieved from PubMed and other databases. Three common loci were confirmed to increase the risk of AD (rs3764650: OR = 1.20, 95% CI = 1.16–1.24; rs3752246: OR = 1.13,95% CI = 1.08–1.19; rs4147929: OR = 1.17, 95% CI = 1.10–1.24), but the associations varied among the different races. Furthermore, ABCA7 loss-of-function (LOF) mutations conferred a higher risk for AD than did the …above variants (LOF: OR = 1.78, 95%  = 1.43–2.22). In conclusion, ABCA7 genetic variants, especially the LOF mutations, were significantly associated with the risk of AD. Show more

Keywords: ABCA7, Alzheimer’s disease, loss-of-function, meta-analysis

DOI: 10.3233/JAD-180107

Citation: Journal of Alzheimer's Disease, vol. 63, no. 4, pp. 1261-1267, 2018

Authors: Smith, Mark A. | Bowen, Richard L. | Nguyen, Richard Q. | Perry, George | Atwood, Craig S. | Rimm, Alfred A.

Article Type: Research Article

Abstract: Background: Estrogen and hormone replacement therapies to reduce Alzheimer’s disease (AD) have yielded conflicting results. However, this study proposes that the well-characterized increase in serum gonadotropins following menopause or andropause are accountable for the increased risk of developing AD among the elderly population. Objective: To determine the role of gonadotropins in the development of AD and investigate gonadotropin-releasing hormone (GnRH) agonist therapy as a potential preventative and/or disease-modifying approach to AD management. Methods: Male Medicare beneficiaries aged 67 to 75 and hospitalized with prostate cancer (n  = 115,789) were compared to three control groups: men of the …same demographics undergoing a cholecystectomy (n  = 97,267), herniorrhaphy (n  = 68,778), or transurethral prostatectomy (n  = 267,691). A proportion of the patients hospitalized with prostate cancer were assumed to have low concentrations of serum gonadotropins and sex steroids as a result of GnRH agonist therapy, while those in the control groups were assumed to have elevated gonadotropin but lowered sex steroid levels that are associated with andropause in this age group. Results: The rates of development of select diagnoses of dementia, including AD, over a twelve-year follow-up period following surgery. When compared to control patients, men hospitalized with prostate cancer have a protection against dementia after twelve years of follow-up, with relative risks ranging from 0.48 to 0.83. Conclusion: Patients with prostate cancer are treated with the GnRH analogue leuprolide acetate, our data suggest that leuprolide acetate may be therapeutic for AD via its downregulation of serum gonadotropins. Show more

Keywords: Alzheimer’s disease, cancer, castration, epidemiology, gonadotropin receptors, hormone replacement therapy, leuprolide, Medicare Part A, testosterone

DOI: 10.3233/JAD-170847

Citation: Journal of Alzheimer's Disease, vol. 63, no. 4, pp. 1269-1277, 2018

Authors: Moustafa, Ahmed A. | El Haj, Mohamad

Article Type: Research Article

Abstract: This study investigates phenomenological reliving of future thinking in Alzheimer’s disease (AD) patients and matched controls. All participants were asked to imagine in detail a future event, and afterward, were asked to rate phenomenological characteristics of their future thinking. As compared to controls, AD participants showed poor rating for reliving, travel in time, visual imagery, auditory imagery, language, and spatiotemporal specificity. However, no significant differences were observed between both groups in emotion and importance of future thinking. Results also showed lower rating for visual imagery relative to remaining phenomenological features in AD participants compared to controls; conversely, these participants showed …higher ratings for emotion and importance of future thinking. AD seems to compromise some phenomenological characteristics of future thinking, especially, visual imagery; however, other phenomenological characteristics, such as emotion, seem to be relatively preserved in these populations. By highlighting the phenomenological experience of future thinking in AD, our paper opens a unique window into the conscious experience of the future in AD patients. Show more

Keywords: Alzheimer’s disease, emotion, future thinking, phenomenological reliving, visual imagery

DOI: 10.3233/JAD-180182

Citation: Journal of Alzheimer's Disease, vol. 63, no. 4, pp. 1279-1287, 2018

Authors: Noguchi-Shinohara, Moeko | Abe, Chiemi | Yuki-Nozaki, Sohshi | Dohmoto, Chiaki | Mori, Ayaka | Hayashi, Koji | Shibata, Syutaro | Ikeda, Yoshihisa | Sakai, Kenji | Iwasa, Kazuo | Yokogawa, Masami | Ishimiya, Mai | Nakamura, Hiroyuki | Yokoji, Hidehiro | Komai, Kiyonobu | Nakamura, Hiroyuki | Yamada, Masahito

Article Type: Research Article

Abstract: Background: Antioxidants like vitamins C and E may minimize the risk for Alzheimer’s disease. Objective: We examined whether vitamins C and E modify the apolipoprotein E (APOE) E4-related risks for developing cognitive decline. Methods: We conducted a population-based prospective study including Japanese residents aged 65 years from Nakajima, Japan. The participants received an evaluation of cognitive function and underwent blood tests including tests for vitamins C and E levels and APOE phenotypes. The APOE E4-by-gender-by-vitamin C or E interactions on developing cognitive decline were analyzed. Results: Of 606 participants with normal cognitive function determined …using a baseline survey (2007–2008), 349 completed the follow up survey between 2014 and 2016. In women with APOE E4, significantly reduced risk for cognitive decline was observed for the highest blood vitamin C concentration tertile [multivariate OR 0.10 (95% CI 0.01–0.93)] compared with the lowest tertile. In men without APOE E4, significantly reduced risk for cognitive decline was observed for the highest blood vitamin E concentration tertile [multivariate OR 0.19 (0.05–0.74)] as compared with the lowest tertile. Conclusion: Our results demonstrate significant beneficial effects of vitamins C and E in reducing the risk of cognitive decline in women with APOE E4 and men without APOE E4, respectively. Show more

Keywords: Alzheimer’s disease, apolipoprotein E, vitamin C, vitamin E

DOI: 10.3233/JAD-170971

Citation: Journal of Alzheimer's Disease, vol. 63, no. 4, pp. 1289-1297, 2018

Authors: Brown, Belinda M. | Rainey-Smith, Stephanie R. | Dore, Vincent | Peiffer, Jeremiah J. | Burnham, Samantha C. | Laws, Simon M. | Taddei, Kevin | Ames, David | Masters, Colin L. | Rowe, Christopher C. | Martins, Ralph N. | Villemagne, Victor L.

Article Type: Research Article

Abstract: Numerous animal studies have reported exercise reduces the accumulation of Alzheimer’s disease pathology, including amyloid-β (Aβ) and tau. Furthermore, we previously reported a relationship between higher levels of physical activity (PA) and lower brain Aβ burden in a human population. The recent advent of tau positron emission tomography (PET) tracers enables us to extend our investigations into the evaluation of the relationship between PA and brain tau burden. Utilizing data from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study, we have examined the cross-sectional relationship between habitual PA and PET-quantified tau burden. Forty-three cognitively healthy older adults were categorized into …low-moderate PA (LMPA; n  = 16) or high PA (HPA; n  = 27), based on self-reported PA levels. Tau PET imaging with the AV1451 tracer was conducted on all participants. The LMPA group had significantly higher neocortical tau burden (presented as a z-score; 1.22±1.98), compared to the HPA group (z-score: – 0.28±1.18). The difference between the LMPA and HPA groups was also evident when examining regional tau burden in the temporoparietal cortex and the prefrontal cortex. Our results suggest an association between self-reported PA level and brain tau burden. Future longitudinal and interventional studies utilizing larger samples sizes are vital to further investigate the nature of the relationship between tau and PA. Show more

Keywords: Alzheimer’s disease, physical activity, positron emission tomography, tau

DOI: 10.3233/JAD-170998

Citation: Journal of Alzheimer's Disease, vol. 63, no. 4, pp. 1299-1305, 2018

Authors: Kennedy, Greg | Meyer, Denny | Hardman, Roy J. | Macpherson, Helen | Scholey, Andrew B. | Pipingas, Andrew

Article Type: Research Article

Abstract: Background: Greater physical fitness is associated with reduced rates of cognitive decline in older people; however, the mechanisms by which this occurs are still unclear. One potential mechanism is aortic stiffness, with increased stiffness resulting in higher pulsatile pressures reaching the brain and possibly causing progressive micro-damage. There is limited evidence that those who regularly exercise may have lower aortic stiffness. Objective: To investigate whether greater fitness and lower aortic stiffness predict better cognitive performance in older people and, if so, whether aortic stiffness mediates the relationship between fitness and cognition. Methods: Residents of independent living …facilities, aged 60–90, participated in the study (N = 102). Primary measures included a computerized cognitive assessment battery, pulse wave velocity analysis to measure aortic stiffness, and the Six-Minute Walk test to assess fitness. Based on hierarchical regression analyses, structural equation modelling was used to test the mediation hypothesis. Results: Both fitness and aortic stiffness independently predicted Spatial Working Memory (SWM) performance, however no mediating relationship was found. Additionally, the derived structural equation model shows that, in conjunction with BMI and sex, fitness and aortic stiffness explain 33% of the overall variation in SWM, with age no longer directly predicting any variation. Conclusions: Greater fitness and lower aortic stiffness both independently predict better SWM in older people. The strong effect of age on cognitive performance is totally mediated by fitness and aortic stiffness. This suggests that addressing both physical fitness and aortic stiffness may be important to reduce the rate of age associated cognitive decline. Show more

Keywords: Aging, aortic stiffness, arterial stiffness, cognition, fitness, working memory

DOI: 10.3233/JAD-171107

Citation: Journal of Alzheimer's Disease, vol. 63, no. 4, pp. 1307-1316, 2018

Authors: Roudil, Jennifer | Deramecourt, Vincent | Dufournet, Boris | Dubois, Bruno | Ceccaldi, Mathieu | Duyckaerts, Charles | Pasquier, Florence | Lebouvier, Thibaud | and the Brainbank Neuro-CEB Neuropathology Network

Article Type: Research Article

Abstract: Background: Studies have shown the frequent coexistence of Lewy pathology (LP) in Alzheimer’s Disease (AD). Objective: The aim of this study was to determine the influence of LP on the clinical and cognitive phenotype in a cohort of patients with a neuropathological diagnosis of AD. Methods: We reviewed neuropathologically proven AD cases, reaching Braak stages V and VI in the brain banks of Lille and Paris between 1993 and 2016, and classified them according to LP extension (amygdala, brainstem, limbic, or neocortical). We then searched patient files for all available clinical and neuropsychiatric features and neuropsychological …data. Results: Thirty-three subjects were selected for this study, among which 16 were devoid of LP and 17 presented AD with concomitant LP. The latter were stratified into two subgroups according to LP distribution: 7 were AD with amygdala LP and 10 were AD with ‘classical’ (brainstem, limbic or neocortical) LP. When analyzing the incidence of each clinical feature at any point during the disease course, we found no significant difference in symptom frequency between the three groups. However, fluctuations appeared significantly earlier in patients with classical LP (2±3.5 years) than in patients without LP (7±1.7 years) or with amygdala LP (8±2.8 years; p  < 0.01). There was no significant difference in cognitive profiles. Conclusion: Our findings suggest that the influence of LP on the clinical phenotype of AD is subtle. Core features of dementia with Lewy bodies do not allow clinical diagnosis of a concomitant LP on a patient-to-patient basis. Show more

Keywords: Alzheimer’s disease, Alzheimer’s disease with amygdala Lewy bodies, braak stages, dementia with Lewy bodies, Lewy bodies, Lewy body variant of Alzheimer’s disease, neurofibrillary tangles

DOI: 10.3233/JAD-170914

Citation: Journal of Alzheimer's Disease, vol. 63, no. 4, pp. 1317-1323, 2018