Journal of Alzheimer's Disease - Volume 44, issue 4

Authors: Lane, Roger M. | Darreh-Shori, Taher

Article Type: Review Article

Abstract: Cholinesterase enzymes metabolize acetylcholine (ACh). Inhibition of acetylcholinesterase (AChE) in damaged but functional cholinergic synapses in the brains of dementia patients increases intrasynaptic ACh. This enhances cholinergic neurotransmission and improves cognition. There is a window of opportunity for this symptomatic treatment effect that opens and closes during the course of dementia depending on when significant synaptic damage occurs. Cholinesterases also metabolize extrasynaptic ACh with butyrylcholinesterase (BuChE) apparently playing the major dynamic role in extracellular ACh homeostasis. Extracellular ACh plays a key regulatory role in controlling the reactivity and functional states of non-excitable cells, such as neuroglia. Current inhibitors of cholinesterases …(ChEIs) have similar effects on intrasynaptic ACh, but differ markedly in abilities to upregulate extracellular AChE, inhibit BuChE, and influence the fibrilization of amyloid-β peptides. Importantly, ChEIs can have detrimental disease modifying effects in particular individuals characterized by age, gender, and genotype. In contrast, preliminary evidence suggests that the right dose of the right ChEI in the right patient might significantly slow the progression of neurodegenerative processes. For a particular patient, understanding the condition of cholinergic synapses and the reactivity and functional status of neuroglia could allow administration of appropriate ChEI therapy for symptomatic and disease modifying benefits. Show more

Keywords: Acetylcholinesterase, amyloid-β peptide, butyrylcholinesterase, disease modification, extrasynaptic acetylcholine, glial reactivity and functional states, intrasynaptic acetylcholine, myelin, symptomatic efficacy

DOI: 10.3233/JAD-142268

Citation: Journal of Alzheimer's Disease, vol. 44, no. 4, pp. 1039-1062, 2015

Authors: Ordóñez-Gutiérrez, Lara | Antón, Marta | Wandosell, Francisco

Article Type: Short Communication

Abstract: The accumulation of amyloid-β (Aβ) peptide is one of the major neuropathological hallmarks of Alzheimer's disease (AD). We have analyzed whether the progression of amyloidosis differentially affects males and females along aging in AβPP/PS1 transgenic mice. The levels of peripheral amyloid, Aβ40 and Aβ42 , are not modified in either sex until 9 months of age. After that, however, there is an increase in amyloid levels in plasma among females and a decrease among males. These findings could be essential to design gender-specific strategies in other in vivo experiments or even in AD treatments.

Keywords: Aging, Alzheimer's disease models, amyloid-β, AβPP/PS1, peripheral amyloid, transgenic mice

DOI: 10.3233/JAD-141158

Citation: Journal of Alzheimer's Disease, vol. 44, no. 4, pp. 1063-1068, 2015

Authors: Ryan, Natalie S. | Lashley, Tammaryn | Revesz, Tamas | Dantu, Kiran | Fox, Nick C. | Morris, Huw R.

Article Type: Short Communication

Abstract: Amyloid-related imaging abnormalities (ARIA), thought to reflect immune responses to vascular amyloid, have been detected in several amyloid-modifying therapy trials for Alzheimer's disease (AD). We report a case of ARIA developing spontaneously during the course of Presenilin 1 (PSEN1)-associated familial AD (FAD), in an APOE4 homozygous patient. Severe cerebral amyloid angiopathy with associated inflammation was subsequently found at autopsy. Recognition that ARIA may arise spontaneously during FAD and of the potential risk factors for its development are important observations given the recent launch of amyloid-modifying therapy trials for FAD.

Keywords: APOE, familial Alzheimer's disease, cerebral amyloid angiopathy-related inflammation, magnetic resonance imaging, Presenilin 1

DOI: 10.3233/JAD-142325

Citation: Journal of Alzheimer's Disease, vol. 44, no. 4, pp. 1069-1074, 2015

Authors: Kim, Yeo Jin | Cho, Hanna | Kim, Yun Joong | Ki, Chang-Seok | Chung, Sun Ju | Ye, Byoung Seok | Kim, Hee Jin | Kim, Jung-Hyun | Kim, Sung Tae | Lee, Kyung Han | Jeon, Seun | Lee, Jong-Min | Chin, Juhee | Kim, Jeong-Hun | Na, Duk L. | Seong, Joon-Kyung | Seo, Sang Won

Article Type: Research Article

Abstract: Apolipoprotein E4 (APOE4) is a genetic risk factor for developing Alzheimer's disease (AD). Once AD manifests clinically, however, the effects of APOE4 are less clear. Therefore, we investigated the longitudinal effects of APOE4 on topographical changes in AD patient brain atrophy. We prospectively recruited 35 patients with AD (19 APOE4 carriers and 16 non-carriers), and 14 normal controls, then followed them for five years. We measured hippocampal deformities and cortical thickness. Hippocampal comparison between APOE4 carriers and non-carriers with AD showed carriers had rapid changes in the head and body, while non-carriers had rapid changes in a small portion of …the body. Cortical thickness comparison between APOE4 carriers and non-carriers with AD dementia showed carriers had rapid thinning in the lateral frontal, temporal, and parietal regions, while no region showed more rapid cortical thinning in non-carriers than in carriers. These findings underlined the importance of the APOE4 allele for designing and interpreting future treatment trials in patients with AD dementia. Show more

Keywords: APOE4 allele, cortical thickness, dementia with Alzheimer's disease, hippocampal deformities, longitudinal study

DOI: 10.3233/JAD-141773

Citation: Journal of Alzheimer's Disease, vol. 44, no. 4, pp. 1075-1085, 2015

Authors: Andrews, Shea | Das, Debjani | Anstey, Kaarin J. | Easteal, Simon

Article Type: Research Article

Abstract: The apolipoprotein E (APOE) * ε4 allele and hypertension are two of the most prevalent risk factors for cognitive decline in later life. Here we investigate whether cognitive decline is affected by interaction between these two risk factors. Specifically, we examine whether APOE* ε4 moderates the association between high blood pressure and cognition in later life. Cognitive function was assessed at three time points over a period of 8 years in 1,474 cognitively normal, community-dwelling adults aged 60–64 years at baseline. Blood pressure and APOE genotype were assessed at baseline. Blood pressure was measured categorically as ‘Hypertension’ and continuously as …‘Mean Arterial Pressure’ (MAP). Multilevel models were used to investigate main and interactive effects of APOE genotype and both hypertension and MAP on the rate of change of episodic memory, working memory, verbal ability, perceptual speed, and global cognition. The APOE–hypertension interaction was associated with a small but statistically significant increase in the rate of decline of episodic memory, verbal ability, and global cognition. However, its inclusion in the model did not increase the amount of outcome variation explained beyond that already explained by the effect of time. In contrast, the APOE-MAP interaction had no effect on the rate of decline in any of these domains of cognitive performance. These results provide tentative evidence that APOE genotype moderates the association between high blood pressure and cognitive decline in later life. Show more

Keywords: Aging, apolipoprotein E, blood pressure, cognitive decline, gene-environment interaction, hypertension

DOI: 10.3233/JAD-140630

Citation: Journal of Alzheimer's Disease, vol. 44, no. 4, pp. 1087-1098, 2015

Authors: Wu, Yu-Tzu | Grant, William B. | Prina, A. Matthew | Lee, Hsin-yi | Brayne, Carol

Article Type: Research Article

Abstract: Background: Western diets are associated with obesity, vascular diseases, and metabolic syndrome and might increase dementia risk in later life. If these associations are causal, those low- and middle-income countries experiencing major changes in diet might also see an increasing prevalence of dementia. Objective: To investigate the relationship of dietary supply and the prevalence of dementia in mainland China, Hong Kong, and Taiwan over time using existing data and taking diagnostic criteria into account. Methods: Estimated total energy supply and animal fat from the United Nations was linked to the 70 prevalence studies in mainland China, …Hong Kong, and Taiwan from 1980 to 2012 according to the current, 10 years, and 20 years before starting year of investigation. Studies using newer and older diagnostic criteria were separated into two groups. Spearman's rank correlation was calculated to investigate whether trends in total energy, animal fat supply, and prevalence of dementia were monotonically related. Results: The supply of total energy and animal fat per capita per day in China increased considerably over the last 50 years. The original positive relationship of dietary supply and dementia prevalence disappeared after stratifying by newer and older diagnostic criteria and there was no clear time lag effect. Conclusion: Taking diagnostic criteria into account, there is no cross-sectional or time lag relationship between the dietary trends and changes in dementia prevalence. It may be too early to detect any such changes because current cohorts of older people did not experience these dietary changes in their early to mid-life. Show more

Keywords: China, ecological study, prevalence of dementia, nutrition

DOI: 10.3233/JAD-141926

Citation: Journal of Alzheimer's Disease, vol. 44, no. 4, pp. 1099-1106, 2015

Authors: Di Domenico, Fabio | Pupo, Gilda | Mancuso, Cesare | Barone, Eugenio | Paolini, Francesca | Arena, Andrea | Blarzino, Carla | Schmitt, Frederick A. | Head, Elizabeth | Butterfield, D. Allan | Perluigi, Marzia

Article Type: Research Article

Abstract: Bach1, among the genes encoded on chromosome 21, is a transcription repressor, which binds to antioxidant response elements of DNA thus inhibiting the transcription of specific genes involved in the cell stress response including heme oxygenase-1 (HO-1). HO-1 and its partner, biliverdin reductase-A (BVR-A), are upregulated in response to oxidative stress in order to protect cells against further damage. Since oxidative stress is an early event in Down syndrome (DS) and might contribute to the development of multiple deleterious DS phenotypes, including Alzheimer's disease (AD) pathology, we investigated the status of the Bach1/HO-1/BVR-A axis in DS and its possible implications …for the development of AD. In the present study, we showed increased total Bach1 protein levels in the brain of all DS cases coupled with reduced induction of brain HO-1. Furthermore, increased oxidative stress could, on one hand, overcome the inhibitory effects of Bach1 and, on the other hand, promote BVR-A impairment. Our data show that the development of AD in DS subjects is characterized by (i) increased Bach1 total and poly-ubiquitination; (ii) increased HO-1 protein levels; and (iii) increased nitration of BVR-A followed by reduced activity. To corroborate our findings, we analyzed Bach1, HO-1, and BVR-A status in the Ts65Dn mouse model at 3 (young) and 15 (old) months of age. The above data support the hypothesis that the dysregulation of HO-1/BVR-A system contributes to the early increase of oxidative stress in DS and provide potential mechanistic paths involved in the neurodegenerative process and AD development. Show more

Keywords: Bach1, biliverdin reductase, heme oxygenase, oxidative stress, trisomy 21

DOI: 10.3233/JAD-141254

Citation: Journal of Alzheimer's Disease, vol. 44, no. 4, pp. 1107-1120, 2015

Authors: Williams, Paul T.

Article Type: Research Article

Abstract: Background: Whether lifestyle affects Alzheimer's disease (AD) risk remains controversial. Objective: Test whether exercise, diet, or statins affect AD mortality in 153,536 participants of the National Runners' and Walkers' Health Studies. Methods: Hazard ratios (HR) and 95% confidence intervals (95% CI) were obtained from Cox proportional hazard analyses for AD mortality versus baseline metabolic equivalent (MET) hours/d of exercise energy expenditure (1 MET equals approximately 1 km run), statin use, and fruit intake when adjusted for age, race, gender, education, and exercise mode. Results: The National Death Index identified 175 subjects who died with …AD listed as an underlying (n = 116) or contributing (n = 59) cause of death during 11.6-year average mortality surveillance. Relative to exercising <1.07 MET-hours/d, AD mortality was 6.0% lower for 1.07 to 1.8 MET-hours/d (HR: 0.94, 95% CI: 0.59 to 1.46, p = 0.79), 24.8% lower for 1.8 to 3.6 MET-hours/d (HR: 0.75, 95% CI: 0.50 to 1.13, p = 0.17), and 40.1% lower for ≥3.6 MET-hours/d (HR: 0.60, 95% CI: 0.37 to 0.97, p = 0.04). Relative to non-use, statin use was associated with 61% lower AD mortality (HR: 0.39, 95% CI: 0.15 to 0.82, p = 0.01), whereas use of other cholesterol-lowering medications was not (HR: 0.78, 95% CI: 0.40 to 1.38, p = 0.42). Relative to <1 piece of fruit/day, consuming 2 to 3 pieces daily was associated with 39.7% lower AD mortality (HR: 0.60, 95% CI: 0.39 to 0.91, p = 0.02) and ≥3 pieces/day with 60.7% lower AD mortality (HR: 0.39, 95% CI: 0.22 to 0.67, p = 0.0004). Conclusion: Exercise, statin, and fruit intake were associated with lower risk for AD mortality. Show more

Keywords: Alzheimer's disease, diet, epidemiology, prevention, prospective cohort study, running, statins, walking

DOI: 10.3233/JAD-141929

Citation: Journal of Alzheimer's Disease, vol. 44, no. 4, pp. 1121-1129, 2015

Authors: Watt, Andrew D. | Perez, Keyla A. | Ang, Ching-Seng | O'Donnell, Paul | Rembach, Alan | Pertile, Kelly K. | Rumble, Rebecca L. | Trounson, Brett O. | Fowler, Christopher J. | Faux, Noel G. | Masters, Colin L. | Villemagne, Victor L. | Barnham, Kevin J.

Article Type: Research Article

Abstract: Biomarkers enabling the preclinical identification of Alzheimer's disease (AD) remain one of the major unmet challenges in the field. The blood cellular fractions offer a viable alternative to current cerebrospinal fluid and neuroimaging modalities. The current study aimed to replicate our earlier reports of altered binding within the AD-affected blood cellular fraction to copper-loaded immobilized metal affinity capture (IMAC) arrays. IMAC and anti-amyloid-β (Aβ) antibody arrays coupled with mass spectrometry were used to analyze blood samples collected from 218 participants from within the AIBL Study of Aging. Peripheral Aβ was fragile and prone to degradation in the AIBL samples, even …when stored at −80°C. IMAC analysis of the AIBL samples lead to the isolation and identification of alpha-defensins 1 and 2 at elevated levels in the AD periphery, validating earlier findings. Alpha-defensins 1 and 2 were elevated in AD patients indicating that an inflammatory phenotype is present in the AD periphery; however, peripheral Aβ levels are required to supplement their prognostic power. Show more

Keywords: α-defensins, Alzheimer's disease, amyloid-β, biomarkers, blood, inflammation, mass spectrometry

DOI: 10.3233/JAD-142286

Citation: Journal of Alzheimer's Disease, vol. 44, no. 4, pp. 1131-1143, 2015

Authors: Frederick, Christelle | Ando, Kunie | Leroy, Karelle | Héraud, Céline | Suain, Valérie | Buée, Luc | Brion, Jean-Pierre

Article Type: Research Article

Abstract: Neurofibrillary tangles are intracellular inclusions made of tau protein that accumulates in neurons in Alzheimer's disease (AD) and in other tauopathies. We have investigated the ability of the rapamycin ester CCI-779/Temsilorimus, a mTOR inhibitor with better stability and pharmacological properties compared to rapamycin, to interfere with the development of a motor phenotype and tau pathology in a mutant tau mouse model developing neurofibrillary tangles, by stimulation of mTOR dependent macroautophagy. Mutant tau mice (Tg30) were treated with CCI-779 before onset of motor signs for 7 months (from 5 to 12 months of age) or after the onset of motor signs …for 2 months (from 10 to 12 months of age). End-point motor deficits were 50% lower in the group of Tg30 mice treated for 7 months. Inhibition of mTOR signaling and stimulation of macroautophagy in the brain of CCI-779 treated Tg30 mice was suggested by decreased phosphorylation of mTOR downstream signaling molecules p70S6 kinase and Akt and increased level of the autophagy markers Rab7 and LC3-II. CCI-779 treatment decreased the brain levels of Sarkosyl-insoluble tau and phosphotau inTg30 mice both after 2 months or 7 months of treatment. The density of neurofibrillary tangles was significantly decreased when treatment was started prior onset of motor signs. These results indicate that stimulation of mTOR dependent autophagy by CCI-779 compound is efficient to counteract the accumulation of abnormal tau when administered early or late in a tauopathy model and to improve a motor deficit when started before onset of motor signs. Show more

Keywords: CCI-779, macroautophagy, mTOR, neurofibrillary tangles, tauopathy

DOI: 10.3233/JAD-142097

Citation: Journal of Alzheimer's Disease, vol. 44, no. 4, pp. 1145-1156, 2015