Journal of Alzheimer's Disease - Volume 53, issue 3

Authors: Wang, Jianhui | Ye, Fuqiang | Cheng, Xiaorui | Zhang, Xiaorui | Liu, Feng | Liu, Gang | Ni, Ming | Qiao, Shanyi | Zhou, Wenxia | Zhang, Yongxiang

Article Type: Research Article

Abstract: Microbes have deserved broader attention as causal factors in Alzheimer’s disease (AD), a neurodegenerative disorder. The senescence-accelerated mouse prone 8 (SAMP8) strain, a spontaneous mice of accelerated aging, are considered a robust model for sporadic AD. LW-AFC, an herbal medicine, was prepared from LiuweiDihuang decoction, which is a classical traditional Chinese medicine prescription. Here, we showed that the treatment of LW-AFC improved cognitive impairments of SAMP8 mice, including spatial learning and memory ability, active avoidance response, and object recognition memory capability. Our data indicated that there were significantly 8 increased and 12 decreased operational taxonomic units (OTUs) in the gut …microbiota of SAMP8 mice compared with senescence accelerated mouse resistant 1 (SAMR1) strains, the control of SAMP8 mice. The treatment of LW-AFC altered 22 (16 increased and 6 decreased) OTUs in SAMP8 mice and among them, 15 OTUs could be reversed by LW-AFC treatment resulting in a microbial composition similar to that of SAMR1 mice. We further showed that there were 7 (3 negative and 4 positive correlation) OTUs significantly correlated with all the three types of cognitive abilities, at the order level, including Bacteroidales , Clostridiales , Desulfovibrionales , CW040 , and two unclassified orders. LW-AFC had influences on bacterial taxa correlated with the abilities of learning and memory in SAMP8 mice and restored them to SAMR1 mice. Our results indicate that the effects of LW-AFC on improving cognitive impairments of SAMP8 mice might be via modulating intestinal microbiome and LW-AFC could be used as a potential anti-AD agent. Show more

Keywords: Alzheimer’s disease, LW-AFC, microbiome, senescence-accelerated mouse prone 8 strain, traditional Chinese medicine

DOI: 10.3233/JAD-160138

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 907-919, 2016

Authors: Chouraki, Vincent | Reitz, Christiane | Maury, Fleur | Bis, Joshua C. | Bellenguez, Celine | Yu, Lei | Jakobsdottir, Johanna | Mukherjee, Shubhabrata | Adams, Hieab H. | Choi, Seung Hoan | Larson, Eric B. | Fitzpatrick, Annette | Uitterlinden, Andre G. | de Jager, Philip L. | Hofman, Albert | Gudnason, Vilmundur | Vardarajan, Badri | Ibrahim-Verbaas, Carla | van der Lee, Sven J. | Lopez, Oscar | Dartigues, Jean-François | Berr, Claudine | Amouyel, Philippe | Bennett, David A. | van Duijn, Cornelia | DeStefano, Anita L. | Launer, Lenore J. | Ikram, M. Arfan | Crane, Paul K. | Lambert, Jean-Charles | Mayeux, Richard | Seshadri, Sudha | for the International Genomics of Alzheimer’s Project

Article Type: Research Article

Abstract: Effective prevention of Alzheimer’s disease (AD) requires the development of risk prediction tools permitting preclinical intervention. We constructed a genetic risk score (GRS) comprising common genetic variants associated with AD, evaluated its association with incident AD and assessed its capacity to improve risk prediction over traditional models based on age, sex, education, and APOE ɛ 4. In eight prospective cohorts included in the International Genomics of Alzheimer’s Project (IGAP), we derived weighted sum of risk alleles from the 19 top SNPs reported by the IGAP GWAS in participants aged 65 and older without prevalent dementia. Hazard ratios (HR) of …incident AD were estimated in Cox models. Improvement in risk prediction was measured by the difference in C-index (Δ–C), the integrated discrimination improvement (IDI) and continuous net reclassification improvement (NRI>0). Overall, 19,687 participants at risk were included, of whom 2,782 developed AD. The GRS was associated with a 17% increase in AD risk (pooled HR = 1.17; 95% CI =   [1.13–1.21] per standard deviation increase in GRS; p -value =  2.86×10–16 ). This association was stronger among persons with at least one APOE ɛ 4 allele (HRGRS  = 1.24; 95% CI =   [1.15–1.34]) than in others (HRGRS  = 1.13; 95% CI =   [1.08–1.18]; pinteraction  = 3.45×10–2 ). Risk prediction after seven years of follow-up showed a small improvement when adding the GRS to age, sex, APOE ɛ 4, and education (Δ–Cindex =  0.0043 [0.0019–0.0067]). Similar patterns were observed for IDI and NRI>0. In conclusion, a risk score incorporating common genetic variation outside the APOE ɛ 4 locus improved AD risk prediction and may facilitate risk stratification for prevention trials. Show more

Keywords: Alzheimer’s disease, clinical utility, cohort studies, genetic risk score, IGAP, meta-analysis, risk prediction

DOI: 10.3233/JAD-150749

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 921-932, 2016

Authors: Mohseni, Hedieh K. | Cowan, David | Chettle, David R. | Milić, Ana Pejović | Priest, Nicholas | Matysiak, Witold | Atanackovic, Jovica | Byun, Soo Hyun | Prestwich, William V.

Article Type: Research Article

Abstract: Aluminum, being the most abundant metal in the earth’s crust, is widely distributed in the environment, and is routinely taken up by the human body through ingestion and inhalation. Aluminum is not considered an essential element and it can be toxic in high concentrations. Most of the body burden of aluminum is stored in the bones. Aluminum has been postulated to be involved in the causality of Alzheimer’s disease. A system for non-invasive measurement of bone aluminum using the in vivo neutron activation analysis technique has been developed and previously reported in the literature by our group. The results …are reported as ratio of Al to Ca in order to eliminate the variations in beam parameters and geometry as well as the physical variations among the subjects such as size of the hand and bone structure. This pilot study included 30 subjects, 15 diagnosed with Alzheimer’s disease in mild and moderate stages and 15 control subjects, all of whom were 60 years of age or older. The mean value of aluminum for the control group was 2.7±8.2μg Al/g Ca (inverse-variance weighted mean 3.5±0.9μg Al/g Ca) and for the Alzheimer’s disease subjects was 12.5±13.1μg Al/g Ca (inverse-variance weighted mean 7.6±0.6μg Al/g Ca). The difference between the mean of the Alzheimer’s disease group and the mean of the control group was 9.8±15.9μg Al/g Ca, with a p-value of 0.02. An age-dependent linear increase in bone aluminum concentration was observed for all subjects. The difference in serum aluminum levels between the two groups did not reach significance. Show more

Keywords: Aluminum, Alzheimer’s disease, bone, gamma spectroscopy, in vivo, neutron activation analysis

DOI: 10.3233/JAD-160194

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 933-942, 2016

Authors: Cavuoto, Marina G. | Ong, Ben | Pike, Kerryn E. | Nicholas, Christian L. | Bei, Bei | Kinsella, Glynda J.

Article Type: Research Article

Abstract: Background: Sleep disturbance is implicated in memory function across normal aging and neurodegenerative disease. Furthermore, there is mounting evidence to suggest that high levels of subjective memory decline (SMD) may signal very early neurodegenerative changes associated with Alzheimer’s disease (AD). This view prompts research examining the relationship between SMD and other risk factors for cognitive decline, including sleep disturbance. Objective: To determine whether objective and subjective indices of sleep predict SMD in older adults. Methods: 181 community-based older adults were divided into groups of high and low SMD based on their responses to the Memory …Assessment Complaint Questionnaire (MAC-Q). They undertook two weeks of objective sleep monitoring (actigraphy), and completed a subjective sleep quality assessment using the Pittsburgh Sleep Quality Index. Results: Hierarchical logistic regression indicated that after controlling for demographics and mood, objective sleep quality predicted high SMD group status (Δ Nagelkerke R2  = 0.07, χ 2  = 9.80 (3), p  = 0.020), while subjective sleep quality did not. Contrary to expectation, however, less sleep disruption predicted high SMD. Conclusion: These unexpected results may suggest a non-linear trajectory between sleep and memory decline in aging. The findings are discussed in relation to previous research, which taken together, may indicate compensatory sleep patterns of reduced sleep disruption in people with high levels of SMD. These preliminary findings suggest the utility of including analysis of sleep behavior in further longitudinal research of this at-risk group of older people. Show more

Keywords: Actigraphy, cognition, early diagnosis, memory, memory disorders, sleep

DOI: 10.3233/JAD-160187

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 943-953, 2016

Authors: González, Hector M. | Tarraf, Wassim | Gouskova, Natalia | Rodríguez, Carlos J. | Rundek, Tatjana | Grober, Ellen | Pirzada, Amber | González, Patricia | Lutsey, Pamela L. | Camacho, Alvaro | Daviglus, Martha L. | Wright, Clinton | Mosley, Thomas H.

Article Type: Research Article

Abstract: Background: Hispanics/Latinos are purportedly at increased risk for neurocognitive decline and dementias. Without dementia cures, low-cost, well-tolerated public health means for mitigating neurocognitive decline are needed. Objective: We examined associations between neurocognition and cardiovascular health (CVH) metrics (Life’s Simple 7; LS7) among diverse Hispanics/Latinos. We hypothesized that higher LS7 would be associated with healthier brain function (neurocognitive performance). Methods: We used baseline (2008–2011) Hispanic Community Health Study/Study of Latinos (HCHS/SOL; N = 9,623; ages 45–74 years) to examine neurocognition in relation to CVH LS7 scores. Results: In age and sex adjusted models, a one unit …LS7 score increase (range = 0–14) was associated with higher neurocognitive function on the B-SEVLT sum (0.23 [p  < 0.01]; range = 3–42), B-SEVLT recall (0.12 [p  < 0.01]; range = 0–15), Word Fluency (phonemic; 0.46 (p  < 0.01); range = 0–49), and Digit Symbol Substitution (0.49 (p  < 0.01); range = 0–83) tests, respectively. Stated differently, a change from the minimum LS7 (0) to maximum LS7 (14) score corresponded to higher scores on verbal learning (4.62) and memory (2.24), verbal fluency (7.0), and psychomotor processing speed (12). In fully adjusted models the associations were attenuated, but remained statistically significant. Incremental adjustments indicated that Latino background and, to a lesser extent, education were primary contributors to the evinced attenuations. Conclusions: We found that higher neurocognitive function was associated with better LS7 CVH metrics among middle-aged and older Hispanics/Latinos. Associations between neurocognitive function and LS7 were strongest among two at-risk groups for neurocognitive decline and dementia, women and Hispanics/Latinos with lower education. Public health efforts to reduce cardiovascular disease morbidity and mortality may have additional neurocognitive benefits among at-risk Hispanics/Latinos. Show more

Keywords: Cardiovascular system, cognition, epidemiology, Hispanic Americans

DOI: 10.3233/JAD-151125

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 955-965, 2016

Authors: Hofrichter, Jacqueline | Krohn, Markus | Schumacher, Toni | Lange, Cathleen | Feistel, Bjöorn | Walbroel, Bernd | Pahnke, Jens

Article Type: Research Article

Abstract: Nowadays, Alzheimer’s disease is the most prevalent epiphenomenon of the aging population. Although soluble amyloid-β (Aβ) species (monomers, oligomers) are recognized triggers of the disease, no therapeutic approach is able to stop it. Herbal medicines are used to treat different diseases in many regions of the world. On the Balkan Peninsula, at the eastern Mediterranean Sea, and adjacent regions, Sideritis species are used as traditional medicine to prevent age-related problems in elderly. To evaluate this traditional knowledge in controlled experiments, we tested extracts of two commonly used Sideritis species, Sideritis euboea and Sideritis scardica, with regard …to their effects on cognition in APP-transgenic and aged, non-transgenic C57Bl/6 mice. Additionally, histomorphological and biochemical changes associated with Aβ deposition and treatment were assessed. We found that daily oral treatment with Sideritis spp. extracts highly enhanced cognition in aged, non-transgenic as well as in APP-transgenic mice, an effect that was even more pronounced when extracts of both species were applied in combination. The treatment strongly reduced Aβ42 load in APP-transgenic mice, accompanied by increased phagocytic activity of microglia, and increased expression of the α -secretase ADAM10. Moreover, the treatment was able to fully rescue neuronal loss of APP-transgenic mice to normal levels as seen in non-transgenic controls. Having the traditional knowledge in mind, our results imply that treatment with Sideritis spp. extracts might be a potent, well-tolerated option for treating symptoms of cognitive impairment in elderly and with regard to Alzheimer’s disease by affecting its most prominent hallmarks: Aβ pathology and cognitive decline. Show more

Keywords: Aging, Alzheimer’s disease, amyloid-β , microglia, neuroprotection, Sideritis spp

DOI: 10.3233/JAD-160301

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 967-980, 2016

Authors: Skrobot, Olivia Anna | McKnight, Amy Jayne | Passmore, Peter Anthony | Seripa, Davide | Mecocci, Patrizia | Panza, Francesco | Kalaria, Rajesh | Wilcock, Gordon | Munafò, Marcus | Erkinjuntti, Timo | Karhunen, Pekka | Pessi, Tanja | Martiskainen, Mika | Love, Seth | the Genetic and Environmental Risk for Alzheimer’s disease Consortium (GERAD1) | Kehoe, Patrick Gavin

Article Type: Research Article

Abstract: Vascular cognitive impairment (VCI), including its severe form, vascular dementia (VaD), is the second most common form of dementia. The genetic etiology of sporadic VCI remains largely unknown. We previously conducted a systematic review and meta-analysis of all published genetic association studies of sporadic VCI prior to 6 July 2012, which demonstrated that APOE (ɛ 4, ɛ 2) and MTHFR (rs1801133) variants were associated with susceptibility for VCI. De novo genotyping was conducted in a new independent relatively large collaborative European cohort of VaD (nmax  = 549) and elderly non-demented samples (nmax  = 552). Where available, genotype data derived …from Illumina’s 610-quad array for 1210 GERAD1 control samples were also included in analyses of genes examined. Associations were tested using the Cochran-Armitage trend test: MTHFR rs1801133 (OR = 1.36, 95% CI 1.16–1.58, p  = <0.0001), APOE rs7412 (OR = 0.62, 95% CI 0.42–0.90, p  = 0.01), and APOE rs429358 (OR = 1.59, 95% CI 1.17–2.16, p  = 0.003). Association was also observed with APOE epsilon alleles; ɛ 4 (OR = 1.85, 95% CI 1.35–2.52, p  = <0.0001) and ɛ 2 (OR = 0.67, 95% CI 0.46–0.98, p  = 0.03). Logistic regression and Bonferroni correction in a subgroup of the cohort adjusted for gender, age, and population maintained the association of APOE rs429358 and ɛ 4 allele. Show more

Keywords: Association, cognitive impairment, dementia, gene, meta-analysis, vascular

DOI: 10.3233/JAD-150862

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 981-989, 2016

Authors: Peter, Jessica | Lahr, Jacob | Minkova, Lora | Lauer, Eliza | Grothe, Michel J. | Teipel, Stefan | Köstering, Lena | Kaller, Christoph P. | Heimbach, Bernhard | Hüll, Michael | Normann, Claus | Nissen, Christoph | Reis, Janine | Klöppel, Stefan

Article Type: Research Article

Abstract: Acetylcholine is critically involved in modulating learning and memory function, which both decline in neurodegeneration. It remains unclear to what extent structural and functional changes in the cholinergic system contribute to episodic memory dysfunction in mild cognitive impairment (MCI), in addition to hippocampal degeneration. A better understanding is critical, given that the cholinergic system is the main target of current symptomatic treatment in mild to moderate Alzheimer’s disease. We simultaneously assessed the structural and functional integrity of the cholinergic system in 20 patients with MCI and 20 matched healthy controls and examined their effect on verbal episodic memory via multivariate …regression analyses. Mediating effects of either cholinergic function or hippocampal volume on the relationship between cholinergic structure and episodic memory were computed. In MCI, a less intact structure and function of the cholinergic system was found. A smaller cholinergic structure was significantly correlated with a functionally more active cholinergic system in patients, but not in controls. This association was not modulated by age or disease severity, arguing against compensational processes. Further analyses indicated that neither functional nor structural changes in the cholinergic system influence verbal episodic memory at the MCI stage. In fact, those associations were fully mediated by hippocampal volume. Although the cholinergic system is structurally and functionally altered in MCI, episodic memory dysfunction results primarily from hippocampal neurodegeneration, which may explain the inefficiency of cholinergic treatment at this disease stage. Show more

Keywords: Basal forebrain cholinergic system, mediation, mild cognitive impairment, short afferent inhibition

DOI: 10.3233/JAD-160273

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 991-1001, 2016

Authors: Armstrong, Joshua J. | Godin, Judith | Launer, Lenore J. | White, Lon R. | Mitnitski, Arnold | Rockwood, Kenneth | Andrew, Melissa K.

Article Type: Research Article

Abstract: Background: As cognitive decline mostly occurs in late life, where typically it co-exists with many other ailments, it is important to consider frailty in understanding cognitive change. Objective: Here, we examined the association of change in frailty status with cognitive trajectories in a well-studied cohort of older Japanese-American men. Methods: Using the prospective Honolulu-Asia Aging Study (HAAS), 2,817 men of Japanese descent were followed (aged 71–93 at baseline). Starting in 1991 with follow-up health assessments every two to three years, cognition was measured using the Cognitive Abilities Screening Instrument (CASI). For this study, health data …was used to construct an accumulation of deficits frailty index (FI). Using six waves of data, multilevel growth curve analyses were constructed to examine simultaneous changes in cognition in relation to changes in FI, controlling for baseline frailty, age, education, and APOE-ɛ 4 status. Results: On average, CASI scores declined by 2.0 points per year (95% confidence interval 1.9–2.1). Across six waves, each 10% within-person increase in frailty from baseline was associated with a 5.0 point reduction in CASI scores (95% confidence interval 4.7–5.2). Baseline frailty and age were associated both with lower initial CASI scores and with greater decline across the five follow-up assessments (p  < 0.01). Discussion: Cognition is adversely affected by impaired health status in old age. Using a multidimensional measure of frailty, both baseline status and within-person changes in frailty were predictive of cognitive trajectories. Show more

Keywords: Aging, cognition, cohort studies, frail elderly, risk factors

DOI: 10.3233/JAD-151172

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 1003-1013, 2016

Authors: Woody, Sarah K. | Zhou, Helen | Ibrahimi, Shaher | Dong, Yafeng | Zhao, Liqin

Article Type: Research Article

Abstract: Humans possess three major isoforms of the apolipoprotein E (ApoE) gene encoded by three alleles: ApoE ɛ 2 (ApoE2), ApoE ɛ 3 (ApoE3), and ApoE ɛ 4 (ApoE4). It is established that the three ApoE isoforms confer differential susceptibility to Alzheimer’s disease (AD); however, an in-depth molecular understanding of the underlying mechanisms is currently unavailable. In this study, we examined the cortical proteome differences among the three ApoE isoforms using 6-month-old female, human ApoE2, ApoE3, and ApoE4 gene-targeted replacement mice and two-dimensional proteomic analyses. The results reveal that the three ApoE brains differ primarily in two areas: cellular bioenergetics and …synaptic transmission. Of particular significance, we show for the first time that the three ApoE brains differentially express a key component of the catalytic domain of the V-type H + -ATPase (Atp6v), a proton pump that mediates the concentration of neurotransmitters into synaptic vesicles and thus is crucial in synaptic transmission. Specifically, our data demonstrate that ApoE2 brain exhibits significantly higher levels of the B subunit of Atp6v (Atp6v1B2) when compared to both ApoE3 and ApoE4 brains, with ApoE4 brain exhibiting the lowest expression. Our additional analyses show that Atp6v1B2 is significantly impacted by aging and AD pathology and the data suggest that Atp6v1B2 deficiency could be involved in the progressive loss of synaptic integrity during early development of AD. Collectively, our findings indicate that human ApoE isoforms differentially modulate regulatory mechanisms of bioenergetic and synaptic function in female brain. A more efficient and robust status in both areas—in which Atp6v may play a role—could serve as a potential mechanism contributing to the neuroprotective and cognition-favoring properties associated with the ApoE2 genotype. Show more

Keywords: Alzheimer’s disease, ApoE2, ApoE3, ApoE4, cellular bioenergetics, synaptic transmission, V-type H+-ATPase

DOI: 10.3233/JAD-160307

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 1015-1031, 2016