Journal of Alzheimer's Disease - Volume 47, issue 1

Authors: Rudnitskaya, Ekaterina A. | Muraleva, Natalia A. | Maksimova, Kseniya Yi. | Kiseleva, Elena | Kolosova, Nataliya G. | Stefanova, Natalia A.

Article Type: Research Article

Abstract: Melatonin is a multifunctional molecule and plays a crucial role in the regulation of circadian rhythms. The role of melatonin in the protection of the central nervous system is well documented. Therefore, melatonin was proposed as a possible therapeutic agent for reducing the severity of Alzheimer’s disease (AD), a progressive neurodegenerative disease characterized by cognitive decline and memory dysfunction. Recently, we showed beneficial neuroprotective effects of prophylactic supplementation with melatonin in a suitable model of sporadic AD: OXYS rats, which exhibit disturbances in melatonin secretion. In the present study, we demonstrated that melatonin administration, when started at the age of …active progression of AD-like pathology, decreased the amyloid-β 1 - 42 and amyloid-β 1 - 40 levels in the hippocampus and amyloid-β 1 - 42 levels in the frontal cortex of OXYS rats. Furthermore, oral administration of melatonin slowed down degenerative alterations in hippocampal neurons of OXYS rats. The most noticeable improvement was observed in the CA1 region of the hippocampus. Melatonin administration prevented the decrease in the mitochondria-occupied portion of the neuronal volume and improved the ultrastructure of mitochondria in the neurons of the CA1 region. Additionally, melatonin treatment of OXYS rats slowed down an increase in anxiety and deterioration of reference memory. Thus, melatonin administration could alleviate the burden of AD and may be considered a promising pharmaceutical treatment of the disease. Show more

Keywords: Alzheimer’s disease, melatonin, neurodegeneration, senescence-accelerated OXYS rats

DOI: 10.3233/JAD-150161

Citation: Journal of Alzheimer's Disease, vol. 47, no. 1, pp. 103-116, 2015

Authors: Wolf, Dominik | Fischer, Florian U. | Scheurich, Armin | Fellgiebel, Andreas | Andreas Fellgiebel and for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Cerebral amyloid-β accumulation and changes in white matter (WM) microstructure are imaging characteristics in clinical Alzheimer’s disease and have also been reported in cognitively healthy older adults. However, the relationship between amyloid deposition and WM microstructure is not well understood. Here, we investigated the impact of quantitative cerebral amyloid load on WM microstructure in a group of cognitively healthy older adults. AV45-positron emission tomography and diffusion tensor imaging (DTI) scans of forty-four participants (age-range: 60 to 89 years) from the Alzheimer’s Disease Neuroimaging Initiative were analyzed. Fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (DR), and axial diffusivity (DA) were …calculated to characterize WM microstructure. Regression analyses demonstrated non-linear (quadratic) relationships between amyloid deposition and FA, MD, as well as RD in widespread WM regions. At low amyloid burden, higher deposition was associated with increased FA as well as decreased MD and DR. At higher amyloid burden, higher deposition was associated with decreased FA as well as increased MD and DR. Additional regression analyses demonstrated an interaction effect between amyloid load and global WM FA, MD, DR, and DA on cognition, suggesting that cognition is only affected when amyloid is increasing and WM integrity is decreasing. Thus, increases in FA and decreases in MD and RD with increasing amyloid load at low levels of amyloid burden may indicate compensatory processes that preserve cognitive functioning. Potential mechanisms underlying the observed non-linear association between amyloid deposition and DTI metrics of WM microstructure are discussed. Show more

Keywords: ADNI, cerebral amyloid deposition, cognitively healthy older adults, quadratic polynomial regression analyses, tract-based spatial statistics, white matter microstructure

DOI: 10.3233/JAD-150049

Citation: Journal of Alzheimer's Disease, vol. 47, no. 1, pp. 117-127, 2015

Authors: Johnson, Leigh A. | Gamboa, Adriana | Vintimilla, Raul | Cheatwood, Austin J. | Grant, Alyann | Trivedi, Ashesh | Edwards, Melissa | Hall, James R. | O’Bryant, Sid E.

Article Type: Research Article

Abstract: Background: The links between diabetes, depression, and Alzheimer’s disease (AD) has been established, but they are still poorly understood. However, little research has examined the effect that comorbidity of depression and diabetes has on cognitive impairment in an ethnically diverse sample. Objective: The purpose of this study was to investigate the relationship between comorbid diabetes and depression on cognitive dysfunction; and examine the relationship in an ethnically diverse population. Methods and Results: Analyses of data from 2,436 participants (914 men and 1,522 women) of three separate cohorts: HABLE, FRONTIER, and TARCC. In …the HABLE cohort, comorbidity (odds ratio [OR] = 3.008; 95% CI = 1.358–6.667), age (OR = 1.138; 95% CI = 1.093–1.185), and education (OR = 0.915; 95% CI = 0.852–0.982) increased the risk of mild cognitive impairment (MCI) diagnosis among elderly Mexican American. In the TARCC cohort, results showed an increase risk of MCI in both non-Hispanic whites (OR = 18.795; 95% CI = 2.229–158.485) and Mexican Americans (OR = 8.417; 95% CI = 2.967–23.878). Finally, results in the FRONTIER cohort showed that in elderly Mexican Americans, comorbidity (OR = 2.754; 95% CI = 1.084–6.995) and age (OR = 1.069; 95% CI = 1.023–1.118) significantly increased risk of MCI. In non-Hispanic whites, comorbidity did not significantly increase risk of MCI. Conclusions: Among elderly Mexican Americans, comorbid depression and diabetes significantly increased risk for MCI and AD across cohorts. Effects of comorbid diabetes and depression on MCI were inconclusive. Our results support the link between comorbid diabetes and depression and risk for cognitive decline among Mexican Americans. This finding is of critical importance as the Hispanic population is at higher risk of developing AD. Show more

Keywords: Alzheimer’s disease, cognitive decline, comorbidity, depression, diabetes, elderly, Mexican American, mild cognitive impairment

DOI: 10.3233/JAD-142907

Citation: Journal of Alzheimer's Disease, vol. 47, no. 1, pp. 129-136, 2015

Authors: Waring, Jeffrey F. | Tang, Qi | Robieson, Weining Z. | King, David P. | Das, Ujjwal | Dubow, Jordan | Dutta, Sandeep | Marek, Gerard J. | Gault, Laura M.

Article Type: Research Article

Abstract: Background: Previous studies have investigated associations between apolipoprotein E (APOE )-ɛ 4 allele status and acetylcholinesterase inhibitor treatment response in patients with Alzheimer’s disease. The ability to draw definitive conclusions regarding the effect of APOE -ɛ 4 genotype on treatment response has been hindered by inconsistent results among studies and methodological limitations that restrict interpretation of study findings. Objective: To determine whether APOE -ɛ 4 carrier status influences the magnitude of change in 13-item Alzheimer’s Disease Assessment Scale−Cognitive Subscale (ADAS-cog) score associated with acetylcholinesterase inhibitor treatment (i.e., donepezil). Methods: Analyses were performed …using pooled data from the donepezil and placebo treatment arms of three consecutive, similarly designed, 12-week, multi-national, randomized clinical studies that enrolled patients with mild-to-moderate Alzheimer’s disease. Correlations between APOE -ɛ 4 carrier status and ADAS-cog scores were evaluated using analysis of covariance. Results: No appreciable interaction between donepezil response and APOE -ɛ 4 carrier status or copy number was detected. Both carriers and non-carriers of APOE -ɛ 4 who received donepezil experienced significant improvements from baseline in ADAS-cog score versus placebo (p  <  0.05). Change from baseline to final observation in the donepezil treatment group was – 2.95 for APOE -ɛ 4 carriers and – 4.09 for non-carriers (p  = 0.23). In contrast, non-carriers of APOE -ɛ 4 in the placebo treatment group exhibited a greater improvement from baseline versus carriers (–2.38 versus – 0.60, p  = 0.05). Conclusion: Within this population, APOE genotype had no statistically significant effect on cognitive response to donepezil treatment; however, APOE -ɛ 4 allele status was associated with a difference in the magnitude of the change in ADAS-cog of placebo-treated patients. Show more

Keywords: Acetylcholinesterase inhibitors, apolipoprotein E, genotype, placebo effect, treatment efficacy

DOI: 10.3233/JAD-142589

Citation: Journal of Alzheimer's Disease, vol. 47, no. 1, pp. 137-148, 2015

Authors: Ashford, J. Wesson

Article Type: Research Article

Abstract: In this issue, an article by Waring et al. provides a meta-analysis of the effects of apo-lipo-protein E (APOE) genotype on the beneficial effect of acetyl-cholinesterase inhibitors (AChEIs) in patients with Alzheimer’s disease (AD). There was no significant effect found. As of 2015, AChEI medications are the mainstay of AD treatment, and APOE genotype is the most significant factor associated with AD causation. This lack of a significant effect of APOE is analyzed with respect to the “Cholinergic Hypothesis” of AD, dating from 1976, through the recognition that cholinergic neurons are not the sole target of AD, but rather that …AD attacks all levels of neuroplasticity in the brain, an idea originated by Ashford and Jarvik in 1985 and which still provides the clearest explanation for AD dementia. The “Amyloid Hypothesis” is dissected back to the alpha/beta pathway switching mechanism affecting the nexin-amyloid pre-protein (NAPP switch). The NAPP switch may be the critical neuroplasticity component of all learning involving synapse remodeling and subserve all learning mechanisms. The gamma-secretase cleavage is discussed, and its normal complementary products, beta-amyloid and the NAPP intracellular domain (NAICD), appear to be involved in natural synapse removal, but the link to AD dementia may involve the NAICD rather than beta-amyloid. Understanding neuroplasticity and the critical pathways to AD dementia are needed to determine therapies and preventive strategies for AD. In particular, the effect of APOE on AD predisposition needs to be established and a means found to adjust its effect to prevent AD. Show more

Keywords: Alzheimer disease, cholinesterase inhibitors, ApoE, acetylcholine, neuronal plasticity, MAPT protein, human amyloid beta-protein, leptin

DOI: 10.3233/JAD-150381

Citation: Journal of Alzheimer's Disease, vol. 47, no. 1, pp. 149-156, 2015

Authors: Wang, Qianqian | Jia, Jianping | Qin, Wei | Wu, Liyong | Li, Dan | Wang, Qi | Li, Hanzhi

Article Type: Research Article

Abstract: Background: Mutations within exons 16 and 17 of the amyloid-β protein precursor (AβPP) gene were the first known causes of early-onset familial Alzheimer’s disease (EOFAD). Since the first AβPP mutation was reported, 39 different AβPP variations have been discovered in EOFAD. Objective: We described a novel AβPP M722K mutation found in a Chinese familial Alzheimer’s disease pedigree and confirmed its effects on amyloid-β (Aβ) secretion and tau phosphorylation. Methods: We performed direct sequencing of exons 16 and 17 of the AβPP gene and coding exons 3–12 of the PSEN1 and PSEN2 genes for …genetic analysis. N2a cells were transfected with wild-type AβPP, AβPP constructs harboring the M722K mutation, or AβPP constructs harboring the Swedish mutation to demonstrate the effects of the AβPP M722K mutation on Aβ secretion and tau phosphorylation. Results: Different phenotypes of patients carrying the AβPP M722K mutation maybe were related to different apolipoprotein E genotypes. The expression of AβPP M722K in mouse neuroblastoma N2a cells induced a 1.7-fold increased ratio of Aβ 42 to Aβ 40 without changes in sAβPPα and sAβPPβ. Tau phosphorylation at the AT8 sites was also increased. Conclusion: Maybe the AβPP M722K mutation contributed to the cause of EOFAD in this Chinese pedigree mediated by increased Aβ 42 /Aβ 40 . Further studies should be conducted to validate the pathogenicity of AβPP M722K and the interactions among γ -secretase, APOE, and AβPP. Show more

Keywords: Aβ42/Aβ40, AβPP M722K mutation, amyloid-β protein precursor, familial Alzheimer’s disease, tau phosphorylation

DOI: 10.3233/JAD-143231

Citation: Journal of Alzheimer's Disease, vol. 47, no. 1, pp. 157-165, 2015

Authors: Zhao, Qianhua | Roberts, Rosebud O. | Ding, Ding | Cha, Ruth | Guo, Qihao | Meng, Haijiao | Luo, Jianfeng | Machulda, Mary M. | Shane Pankratz, V. | Wang, Bei | Christianson, Teresa J.H. | Aakre, Jeremiah A. | Knopman, David S. | Boeve, Bradley F. | Hong, Zhen | Petersen, Ronald C. | and the Shanghai Aging Study (SAS), the Mayo Clinic Study of Aging (MCSA)

Article Type: Research Article

Abstract: Background and Objectives: It remains unknown whether the association between diabetes mellitus (DM) and cognitive function differs in Eastern and Western populations. This study aimed to elucidate whether DM is associated with worse cognitive performance in both populations. Methods: The Shanghai Aging Study (SAS) and the Mayo Clinic Study of Aging (MCSA) are two population-based studies with similar design and methodology in Shanghai, China and Rochester, MN, USA. Non-demented participants underwent cognitive testing, and DM was assessed from the medical record. Separate analyses were performed in SAS and MCSA regarding the association between DM and cognitive performance. …Results: A total of 3,348 Chinese participants in the SAS and 3,734 American subjects in the MCSA were included. Compared with MCSA subjects, SAS participants were younger, less educated, and had lower frequency of vascular disease, APOE ɛ 4 carriers and obesity. Participants with DM (compared to non-DM participants) performed significantly worse on all the cognitive domains in both the SAS and MCSA. After adjustment for age, gender, education, and vascular covariates, DM was associated with worse performance in executive function (β =−0.15, p  = 0.001 for SAS, and β =−0.10, p  = 0.008 for MCSA) in the total sample and in the cognitively normal sub-sample. Furthermore, DM was associated with poor performance in visuospatial skills, language, and memory in the SAS, but not in the MCSA. Conclusions: Diabetes is associated with cognitive dysfunction and, in particular, exerts a negative impact on executive function regardless of race, age, and prevalence of vascular risk factors. Show more

Keywords: Cognition, cross-sectional studies, diabetes mellitus, executive function

DOI: 10.3233/JAD-150073

Citation: Journal of Alzheimer's Disease, vol. 47, no. 1, pp. 167-176, 2015

Authors: Busse, Stefan | Steiner, Johann | Alter, Juliane | Dobrowolny, Henrik | Mawrin, Christian | Bogerts, Bernhard | Hartig, Roland | Busse, Mandy

Article Type: Research Article

Abstract: Although monocytes and macrophages could serve as new therapeutic targets for treatment of Alzheimer’s disease (AD) and aging of the human innate immune system, its role in the pathogenesis of neurodegenerative disorders such as AD are only poorly understood. We have addressed this here by determining the number of CD14+ monocytes and the frequency of HLA-DR-, CD80-, and CD86-expression in peripheral blood from healthy volunteers aged 20–79 years, and in AD patients at diagnosis and after 12, 30, and 52 weeks of rivastigmine treatment. While the number of CD14+ monocytes remained constant, the expression of HLA-DR, CD80, and CD86 by …monocytes increased with age. However, no differences were identified by comparing AD patients with age-matched healthy controls or following treatment of AD patients with rivastigmine. These results indicate that changes in the expression of HLA-DR, CD80, and CD86 are caused by immunosenescence rather than by AD pathology or treatment of AD patients with rivastigmine. Show more

Keywords: Alzheimer’s disease, monocytes, CD80, CD86, HLA-DR

DOI: 10.3233/JAD-150217

Citation: Journal of Alzheimer's Disease, vol. 47, no. 1, pp. 177-184, 2015

Authors: Nakamagoe, Kiyotaka | Fujimiya, Suguru | Koganezawa, Tadachika | Kadono, Kotarou | Shimizu, Kotone | Fujizuka, Natsu | Takiguchi, Shino | Ueno, Tomoyuki | Monzen, Tatsuya | Tamaoka, Akira

Article Type: Research Article

Abstract: Background: Falls and fractures due to impaired balance in patients with Alzheimer’s disease (AD) have an adverse effect on the clinical course of the disease. Objective: To evaluate balance impairment in AD from the viewpoint of vestibular functional impairment. Methods: The subjects were 12 patients with AD, 12 dementia-free elderly adults, and 12 younger adults. Vestibular function was assessed using a stepping test, caloric nystagmus, and a visual suppression (VS) test. Results: The stepping test was abnormal in 9 of the 12 patients in the AD group. An abnormal …stepping test was not associated with self-reported dizziness or tendency to fall. Significant VS abnormalities were present in the AD group. The suppression rate of VS was lower in AD patients with either a tendency to fall or constructional apraxia than in AD patients without either. The velocity of the rapid phase of caloric nystagmus before the VS test was similar in the AD group and the elderly control group. Significant abnormalities of both caloric nystagmus and VS were not present in either the elderly or the younger control groups. Conclusion: AD could involve impairments in the vestibular control of balance. The VS test is useful for assessing the tendency to fall in AD. Impairment of VS in AD might arise from cerebral vestibular cortex impairment rather than comorbid peripheral vestibular disorders. Show more

Keywords: Alzheimer’s disease, caloric tests, dementia, eye movements, hippocampus, inferior parietal lobule, vestibular function tests, vestibular imbalance, vestibular stimulation, visual suppression

DOI: 10.3233/JAD-142646

Citation: Journal of Alzheimer's Disease, vol. 47, no. 1, pp. 185-196, 2015

Authors: Nishtala, Arvind | Himali, Jayandra J. | Beiser, Alexa | Murabito, Joanne M. | Seshadri, Sudha | Wolf, Philip A. | Au, Rhoda

Article Type: Research Article

Abstract: Midlife cardiovascular risk, hypertension (HTN) in particular, has been related cross-sectionally to poorer neuropsychological (NP) performance in middle age and older adults. This study investigated whether a similar relationship persists between midlife HTN or systolic blood pressure (SBP) and NP performance approximately 30 years later. 378 Framingham stroke and dementia-free Original cohort participants, with HTN and SBP ascertained between 50–60 years of age (mean age 55 ± 1, 65% women), were administered a NP assessment at age ≥80 years. Tests included Logical Memory, Visual Reproduction, Paired Associate, Hooper Visual Organization Test, Trail Making A & B, Digit Span Forward and …Backward, Controlled Word Association Test (COWAT), and Similarities. Multivariable linear regression, adjusted for age, time interval between risk factor and NP testing, gender, and premorbid intelligence, assessed association between midlife HTN/SBP and NP outcomes. Midlife HTN was not significantly associated with NP outcome measures. Midlife SBP was associated with poorer Digit Span Forward and COWAT performance (p  <  0.05). No significant interaction of age on HTN/SBP to NP associations was found. There was a significant interaction between ApoE4 status and SBP in their effects on COWAT (pinteraction  = 0.074); SBP was negatively associated with COWAT only in those with the ApoE4 allele (p  = 0.025). While midlife HTN is not associated with late life cognitive impairment, midlife SBP is related to late life attention and verbal fluency impairments, particularly among ApoE4+ individuals. These results offer insight into processes that are operative in the absence of overt cognitive impairment and dementia. Show more

DOI: 10.3233/JAD-141881

Citation: Journal of Alzheimer's Disease, vol. 47, no. 1, pp. 197-204, 2015