Journal of Alzheimer's Disease - Volume 81, issue 1

Authors: Li, Xuanting | Yuan, Junliang | Qin, Wei | Yang, Lei | Yang, Shuna | Li, Yue | Hu, Wenli

Article Type: Research Article

Abstract: Background: Cerebral microbleed (CMB) is an increasingly important risk factor for cognitive impairment due to population aging. Controversies, however, remain regarding the exact association between CMB and cognitive dysfunction. Objective: We aimed to determine the relationship between CMB burden and cognitive impairment, and also explore the characteristics of cognitive decline in CMB patients for middle-aged and elderly people. Methods: The present cross-sectional study included 174 participants (87 CMB patients and 87 controls) who underwent brain magnetic resonance imaging and a battery of neuropsychological test. Global cognitive function was measured using Mini-Mental State Examination (MMSE) and Montreal …Cognitive Assessment (MoCA). Compound z-scores were calculated for three cognitive subdomains: memory, executive function and processing speed. Results: CMB patients had lower scores of MMSE (p  < 0.001) and MoCA (p  < 0.001). Patients at each category of CMB count had worse performance in global cognitive function and all three cognitive subdomains (p  < 0.001). In multiple linear regression models, CMB patients had significantly greater declines in executive function (p  < 0.001), processing speed (p  < 0.001), and MoCA (p  = 0.003) with increasing number of CMB. We found no relationship between CMB location and cognition (p  > 0.05). Conclusion: CMB is associated with impairment in global cognition as well as for all tested subdomains. Strongest effect sizes were seen for tests which rely on executive functioning, where performance deficits increased in proportion to degree of CMB burden. Prospective studies are needed to evaluate whether the association between CMB and executive dysfunction is causal. Show more

Keywords: Cerebral microbleed, cerebral small vessel disease, cognitive impairment, susceptibility weighted imaging

DOI: 10.3233/JAD-201202

Citation: Journal of Alzheimer's Disease, vol. 81, no. 1, pp. 255-262, 2021

Authors: Ma, Ya-Hui | Wang, Ya-Yu | Tan, Lan | Xu, Wei | Shen, Xue-Ning | Wang, Hui-Fu | Hou, Xiao-He | Cao, Xi-Peng | Bi, Yan-Lin | Dong, Qiang | Yang, Jiu-Long | Yu, Jin-Tai

Article Type: Research Article

Abstract: Background: Although social networks are deemed as moderators of incident Alzheimer’s disease (AD), few data are available on the mechanism relevant to AD pathology. Objective: We aimed to investigate whether social networks affect metabolism of cerebrospinal fluid (CSF) AD biomarkers during early stage and identify modification effects of genetic factor and subjective cognitive decline (SCD). Methods: We studied participants from the Chinese Alzheimer’s disease Biomarker and Lifestyle (CABLE) database who received cognition assessments and CSF amyloid-β (Aβ1–42 and Aβ1–40 ) and tau proteins (total-tau [T-tau] and phosphorylated-tau [P-tau]) measurements. The social networks were measured using …self-reported questionnaires about social ties. Linear regression models were used. Results: Data were analyzed from 886 cognitively intact individuals aged 61.91 years (SD = 10.51), including 295 preclinical AD participants and 591 healthy controls. Social networks were mostly associated with CSF indicators of AD multi-pathologies (low P-tau/Aβ1–42 and T-tau/Aβ1–42 and high Aβ1–42 /Aβ1–40 ). Significant differences of genetic and cognitive status were observed for CSF indicators, in which associations of social network scores with CSF P-tau and indicators of multi-pathologies appeared stronger in APOE 4 carriers (versus non-carriers) and participants with SCD (versus controls), respectively. Alternatively, more pronounced associations for CSF T-tau (β= –0.005, p  < 0.001), Aβ1–42 /Aβ1–40 (β= 0.481, p  = 0.001), and T-tau/Aβ1–42 (β= –0.047, p  < 0.001) were noted in preclinical AD stage than controls. Conclusion: These findings consolidated strong links between social networks and AD risks. Social networks as a modifiable lifestyle probably affected metabolisms of multiple AD pathologies, especially among at-risk populations. Show more

Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid, lifestyle, social network

DOI: 10.3233/JAD-201426

Citation: Journal of Alzheimer's Disease, vol. 81, no. 1, pp. 263-272, 2021

Authors: Pan, Danmin | Gu, Jin-Hua | Zhang, Jin | Hu, Yae | Liu, Fei | Iqbal, Khalid | Cekic, Nevena | Vocadlo, David J. | Dai, Chun-Ling | Gong, Cheng-Xin

Article Type: Research Article

Abstract: Background: Abnormal hyperphosphorylation of microtubule-associated protein tau plays a pivotal role in Alzheimer’s disease (AD). We previously found that O-GlcNAcylation inversely correlates to hyperphosphorylation of tau in AD brain, and downregulation of brain O-GlcNAcylation promotes tau hyperphosphorylation and AD-like neurodegeneration in mice. Objective: Herein we investigated the effect of increasing O-GlcNAcylation by using intermittent dosing with low doses of a potent novel O-GlcNAcase (OGA) inhibitor on AD-like brain changes and cognitive function in a mouse model of sporadic AD (sAD) induced by intracerebroventricular (ICV) injection of streptozotocin (STZ). Methods: STZ was injected into the lateral ventricle …of C57BL/6J mice. From the second day, Thiamme2-G (TM2G) or saline, as a vehicle control, was orally administered to the ICV-STZ mice three times per week for five weeks. A separate group of ICV-saline mice treated with saline was used as a baseline control. Behavioral tests, including open field and novel object recognition, were conducted three weeks after the first dose of the TM2G or saline. Protein O-GlcNAcylation, tau hyperphosphorylation, synaptic proteins, and neuroinflammation in the mouse brain were assessed by western blotting. Results: ICV-STZ caused decreased protein O-GlcNAcylation. Enhancement of O-GlcNAcylation to moderate levels by using low-dose OGA inhibitor in ICV-STZ mice prevented STZ-induced body weight loss, rescued cognitive impairments, and restored AD-like pathologies, including hyperphosphorylation of tau and abnormalities in synaptic proteins and neuroinflammation. Conclusion: These findings suggest that moderately increasing protein O-GlcNAcylation by using low doses of OGA inhibitor may be a suitable therapeutic strategy for sAD. Show more

Keywords: Alzheimer’s disease, O-GlcNAcylation, OGA, OGA inhibitor, tau hyperphosphorylation, Thiamme2-G

DOI: 10.3233/JAD-201450

Citation: Journal of Alzheimer's Disease, vol. 81, no. 1, pp. 273-286, 2021

Authors: Byeon, Gihwan | Byun, Min Soo | Yi, Dahyun | Lee, Jun Ho | Jeon, So Yeon | Ko, Kang | Jung, Gijung | Lee, Jun-Young | Kim, Yu Kyeong | Lee, Yun-Sang | Kang, Koung Mi | Sohn, Chul-Ho | Lee, Dong Young | for the KBASE research group

Article Type: Research Article

Abstract: Background: Both elevated blood homocysteine and diabetes mellitus (DM) are related to cognitive impairments or dementia. A previous study also demonstrated that the association between homocysteine and cognitive decline was much stronger in individuals with DM than in those without DM. Objective: This study aimed to examine the interactive effect of blood homocysteine and DM on brain pathological changes including brain atrophy, amyloid-β and tau deposition, and small vessel disease (SVD) related to cognitive impairments. Methods: A total of 430 non-demented older adults underwent comprehensive clinical assessment, measurement of serum homocysteine level, [11 C] Pittsburgh Compound …B (PiB) PET, [18 F] AV-1451 PET, and brain MRI. Results: The interactive effect of homocysteine with the presence of DM on brain atrophy, especially in aging-related brain regions, was significant. Higher homocysteine concentration was associated with more prominent brain atrophy in individuals with DM, but not in those without DM. In contrast, interaction effect of homocysteine and DM was found neither on Alzheimer’s disease (AD) pathologies, including amyloid-β and tau deposition, nor white matter hyperintensity volume as a measure of SVD. Conclusion: The present findings suggest that high blood homocysteine level and DM synergistically aggravate brain damage independently of AD and cerebrovascular disease. With regard to preventing dementia or cognitive decline in older adults, these results support the importance of strictly controlling blood glucose in individuals with hyperhomocysteinemia and lowering blood homocysteine level in those with DM. Show more

Keywords: Brain atrophy, diabetes mellitus, homocysteine, magnetic resonance imaging, positron emission tomography

DOI: 10.3233/JAD-210036

Citation: Journal of Alzheimer's Disease, vol. 81, no. 1, pp. 287-295, 2021

Authors: Morris, Robert | Luboff, Hunter | Jose, Rahul P. | Eckhoff, Kyle | Bu, Kun | Pham, Minh | Rohlsen-Neal, Dekai | Cheng, Feng

Article Type: Research Article

Abstract: Background: Bradycardia is a physiological condition characterized by a decrease in heart rate and is a side effect of many drug classes. Bradycardia has been reported as an adverse event for patients receiving donepezil for Alzheimer’s disease (AD) treatment. Objective: The purpose of the paper is to systematically investigate the association between the occurrence of bradycardia in adults and the usage of donepezil using clinical data derived from the FDA Adverse Event Reporting System (FAERS) database. Methods: The risk of bradycardia in patients who only took donepezil was compared with those of patients who only took …over-the-counter medications, multiple arrhythmia drugs, or other medications for AD treatment. In addition, this study sought to determine if this heightened bradycardia risk was influenced by sex, age, and dosage. Results: The results indicated that there was a significant greater likelihood of reporting bradycardia in patients administered donepezil than most of the drugs investigated. There was no significant association between age or the dosage of donepezil and the likelihood of reporting bradycardia. However, males were found to be more likely than females to report bradycardia as an adverse event. Tumor necrosis factor inhibition and the stimulation of endothelial nitric oxide synthase were proposed to be the primary mechanism of actions which confer elevated bradycardia risk when using donepezil. Conclusion: These findings identified strong association between the usage of donepezil and bradycardia in adults as well as provided insight into the underlying molecular mechanisms that induce bradycardia by donepezil. Show more

Keywords: Acetylcholinesterase inhibitors, AChE, Alzheimer’s disease, bradycardia, donepezil, endothelial nitric oxide synthase

DOI: 10.3233/JAD-201551

Citation: Journal of Alzheimer's Disease, vol. 81, no. 1, pp. 297-307, 2021

Authors: Ikeda, Shunya | Mimura, Masaru | Ikeda, Manabu | Wada-Isoe, Kenji | Azuma, Mie | Inoue, Sachie | Tomita, Kiyoyuki

Article Type: Research Article

Abstract: Background: Alzheimer’s disease dementia (ADD) is the leading cause of long-term care in Japan. Objective: This study estimates the annual healthcare and long-term care costs in fiscal year 2018 for adults over 65 years of age with ADD in Japan and the informal care costs and productivity loss for their families. Methods: Healthcare and long-term care costs for ADD were estimated according to the disease severity classified by the clinical dementia rating (CDR) score, using reports from a literature review. For the costs of time spent on caregiving activities, productivity loss for ADD family caregivers aged …20–69 and informal care costs for all ADD family caregivers were estimated. Results: The total healthcare cost of ADD was JPY 1,073 billion, of which 86% (JPY 923 billion) was attributed to healthcare costs other than ADD drug costs (JPY 151 billion). The healthcare costs other than ADD drug costs by severity were less than JPY 200 billion for CDR 0.5, CDR 1, and CDR 2, respectively, but increased to JPY 447 billion (48%) for CDR 3. The public long-term care costs were estimated to be JPY 4,783 billion, which increased according to the severity. Total productivity loss for ADD family caregivers aged 20–69 was JPY 1,547 billion and the informal care cost for all ADD family caregivers was JPY 6,772 billion. Conclusion: ADD costs have a significant impact on public-funded healthcare, long-term care systems, and families in Japan. To minimize the economic burden of ADD, prolonging healthy life expectancy is the key factor to address. Show more

Keywords: Alzheimer’s disease dementia, burden of illness, clinical dementia rating, healthcare cost, long-term care cost, productivity cost

DOI: 10.3233/JAD-210075

Citation: Journal of Alzheimer's Disease, vol. 81, no. 1, pp. 309-319, 2021

Authors: Jitlal, Mark | Amirthalingam, Guru N.K. | Karania, Tasvee | Parry, Eve | Neligan, Aidan | Dobson, Ruth | Noyce, Alastair J. | Marshall, Charles R.

Article Type: Research Article

Abstract: Background: Socioeconomic deprivation may be an important determinant of dementia risk, mortality, and access to diagnostic services. Premature mortality from other causes and under-representation of deprived individuals in research may lead to this effect being overlooked. Objective: We assessed the relationship between deprivation and dementia mortality using comprehensive death certificate data for England and Wales from 2001 to 2017. Methods: We used standardized mortality ratios (SMR) and a Poisson model to compare likelihood of dying from dementia in each deprivation decile. We also examined the associations of deprivation with age at death from dementia, and with …likelihood of receiving a diagnosis of unspecified dementia. Results: Risk of dying from dementia was higher in more deprived deciles (Mean SMR [95% CI] in decile 1 : 0.528 [0.506 to 0.550], decile 10:0.369 [0.338 to 0.400]). In 2017, 14,837 excess dementia deaths were attributable to deprivation (21.5% of all dementia deaths that year). There were dose-response associations of deprivation with likelihood of being older at death with dementia (odds ratio [95% CI] for decile 10 (least deprived): 1.31 [1.28 to 1.33] relative to decile 1), and with likelihood of receiving a diagnosis of unspecified dementia (odds ratio [95% CI] for decile 10:0.78 [0.76 to 0.80] relative to decile 1). Conclusion: Socioeconomic deprivation in England and Wales is associated with increased dementia mortality, younger age at death with dementia, and poorer access to specialist diagnosis. Reducing social inequality may have a role in the prevention of dementia mortality. Show more

Keywords: Age at death, Alzheimer’s disease, dementia, deprivation, diagnosis, mortality, socioeconomic status

DOI: 10.3233/JAD-210089

Citation: Journal of Alzheimer's Disease, vol. 81, no. 1, pp. 321-328, 2021

Authors: Douros, Antonios | Santella, Christina | Dell’Aniello, Sophie | Azoulay, Laurent | Renoux, Christel | Suissa, Samy | Brassard, Paul

Article Type: Research Article

Abstract: Background: Previous studies suggested a link between various infectious pathogens and the development of Alzheimer’s disease (AD), posing the question whether infectious disease could present a novel modifiable risk factor. Objective: To assess whether infectious disease burden due to clinically apparent infections is associated with an increased risk of AD. Methods: We conducted a population-based nested case-control study using the United Kingdom Clinical Practice Research Datalink. We included all dementia-free subjects ≥50 years of age enrolling in the database between January 1988 and December 2017. Each case of AD identified during follow-up was matched with up …to 40 controls. Conditional logistic regression estimated adjusted odds ratios (ORs) with 95% confidence intervals (CIs) of AD associated with ≥1 infection diagnosed > 2 years before the index date compared with no infection during the study period. We further stratified by time since first infection and cumulative number of infections. Results: The cohort included overall 4,262,092 individuals (mean age at cohort entry 60.4 years; 52% female). During a median follow-up of 10.5 years, 40,455 cases of AD were matched to 1,610,502 controls. Compared with having no burden of infectious disease, having a burden of infectious disease was associated with an increase in the risk of AD (OR, 1.05; 95% CI, 1.02 to 1.08). The risk increased with longer time since first infection, peaking after 12–30 years (OR, 1.11; 95% CI, 1.05–1.17). The risk did not increase with cumulative number of infections. Conclusion: The overall risk of AD associated with infectious disease burden was small but increased gradually with longer time since first infection. Show more

Keywords: Alzheimer’s disease, dementia, epidemiology, infection, neurodegenerative diseases

DOI: 10.3233/JAD-201534

Citation: Journal of Alzheimer's Disease, vol. 81, no. 1, pp. 329-338, 2021

Authors: Edlund, Anna K. | Chen, Kewei | Lee, Wendy | Protas, Hillary | Su, Yi | Reiman, Eric | Caselli, Richard | Nielsen, Henrietta M.

Article Type: Research Article

Abstract: Background: Altered cerebral glucose metabolism, especially prominent in APOE ɛ4 carriers, occurs years prior to symptoms in Alzheimer’s disease (AD). We recently found an association between a higher ratio of plasma apolipoprotein E4 (apoE4) over apoE3, and cerebral glucose hypometabolism in cognitively healthy APOE ɛ3/ɛ4 subjects. Plasma apoE does not cross the blood-brain barrier, hence we speculate that apoE is linked to peripheral glucose metabolism which is known to affect glucose metabolism in the brain. Objective: Explore potential associations between levels of plasma insulin and glucose with previously acquired plasma apoE, cerebral metabolic rate of glucose …(CMRgl), gray matter volume, and neuropsychological test scores. Methods: Plasma insulin and glucose levels were determined by ELISA and a glucose oxidase assay whereas apoE levels were earlier quantified by mass-spectrometry in 128 cognitively healthy APOE ɛ3/ɛ4 subjects. Twenty-five study subjects had previously undergone FDG-PET and structural MRI. Results: Lower plasma apoE3 associated with higher plasma glucose but not insulin in male subjects and subjects with a body mass index above 25. Negative correlations were found between plasma glucose and CMRgl in the left prefrontal and bilateral occipital regions. These associations may have functional implications since glucose levels in turn were negatively associated with neuropsychological test scores. Conclusion: Plasma apoE3 but not apoE4 may be involved in insulin-independent processes governing plasma glucose levels. Higher plasma glucose, which negatively affects brain glucose metabolism, was associated with lower plasma apoE levels in APOE ɛ3/ɛ4 subjects. High plasma glucose and low apoE levels may be a hazardous combination leading to an increased risk of AD. Show more

Keywords: APOE, apolipoprotein E, cerebral glucose metabolism, glucose, insulin

DOI: 10.3233/JAD-210065

Citation: Journal of Alzheimer's Disease, vol. 81, no. 1, pp. 339-354, 2021

Authors: Kleiman, Michael J. | Barenholtz, Elan | Galvin, James E. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Detecting early-stage Alzheimer’s disease in clinical practice is difficult due to a lack of efficient and easily administered cognitive assessments that are sensitive to very mild impairment, a likely contributor to the high rate of undetected dementia. Objective: We aim to identify groups of cognitive assessment features optimized for detecting mild impairment that may be used to improve routine screening. We also compare the efficacy of classifying impairment using either a two-class (impaired versus non-impaired) or three-class using the Clinical Dementia Rating (CDR 0 versus CDR 0.5 versus CDR 1) approach. Methods: Supervised feature selection …methods generated groups of cognitive measurements targeting impairment defined at CDR 0.5 and above. Random forest classifiers then generated predictions of impairment for each group using highly stochastic cross-validation, with group outputs examined using general linear models. Results: The strategy of combining impairment levels for two-class classification resulted in significantly higher sensitivities and negative predictive values, two metrics useful in clinical screening, compared to the three-class approach. Four features (delayed WAIS Logical Memory, trail-making, patient and informant memory questions), totaling about 15 minutes of testing time (∼30 minutes with delay), enabled classification sensitivity of 94.53% (88.43% positive predictive value, PPV). The addition of four more features significantly increased sensitivity to 95.18% (88.77% PPV) when added to the model as a second classifier. Conclusion: The high detection rate paired with the minimal assessment time of the four identified features may act as an effective starting point for developing screening protocols targeting cognitive impairment defined at CDR 0.5 and above. Show more

Keywords: Alzheimer’s disease, data mining, mild cognitive impairment, neuropsychological tests, supervised machine learning

DOI: 10.3233/JAD-201377

Citation: Journal of Alzheimer's Disease, vol. 81, no. 1, pp. 355-366, 2021

Authors: Ashizawa, Takumi | Igarashi, Ataru | Sakata, Yukinori | Azuma, Mie | Fujimoto, Kenichi | Kobayashi, Tsukasa | Takase, Yoshimasa | Ikeda, Shunya

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) increases societal costs and decreases the activities of daily living (ADL) and quality of life (QoL) of the affected individuals. Objective: We assess the impact of AD severity on ADL, QoL, and caregiving costs in Japanese facilities for the elderly. Methods: Patients with AD in facilities for the elderly were included (47 facilities, N = 3,461). The QoL, ADL, and disease severity of patients were assessed using Barthel Index (BI), EuroQoL-5D-5L (EQ-5D-5L), and Mini-Mental State Examination (MMSE), respectively. Annual caregiving costs were estimated using patients’ claims data. The patients were subcategorized into the following …three groups according to the MMSE score: mild (21≤MMSE≤30), moderate (11≤MMSE≤20), and severe (0≤MMSE≤10). Changes among the three groups were evaluated using the Jonckheere-Terpstra test. Results: Four hundred and one participants were on anti-AD medicines, of whom 287 (age: 86.1±6.4 years, 76.7% women) in the mild (n  = 53, 84.0±6.9 years, 71.7%), moderate (n  = 118, 86.6±5.9 years, 76.3%), and severe (n  = 116, 86.6±6.5 years, 79.3%) groups completed the study questionnaires. The mean BI and EQ-5D-5L scores for each group were 83.6, 65.1, and 32.8 and 0.801, 0.662, and 0.436, respectively. The mean annual caregiving costs were 2.111, 2.470, and 2.809 million JPY, respectively. As AD worsened, the BI and EQ-5D-5L scores decreased and annual caregiving costs increased significantly. Conclusion: AD severity has an impact on QoL, ADL, and caregiving costs. Show more

Keywords: Activities of daily living, Alzheimer’s disease, cost of illness, Japan, observational study, quality of life

DOI: 10.3233/JAD-201514

Citation: Journal of Alzheimer's Disease, vol. 81, no. 1, pp. 367-374, 2021

Authors: Wong, Dickson | Broberg, Dana N. | Doad, Jagroop | Umoh, Joseph U. | Bellyou, Miranda | Norley, Chris J. D. | Holdsworth, David W. | Montero-Odasso, Manuel | Beauchet, Olivier | Annweiler, Cedric | Bartha, Robert

Article Type: Research Article

Abstract: Background: Vitamin D deficiency and altered body composition are common in Alzheimer’s disease (AD). Memantine with vitamin D supplementation can protect cortical axons against amyloid-β exposure and glutamate toxicity. Objective: To study the effects of vitamin D deprivation and subsequent treatment with memantine and vitamin D enrichment on whole-body composition using a mouse model of AD. Methods: Male APPswe/PS1dE9 mice were divided into four groups at 2.5 months of age: the control group (n  = 14) was fed a standard diet throughout; the remaining mice were started on a vitamin D-deficient diet at month 6. The vitamin …D-deficient group (n  = 14) remained on the vitamin D-deficient diet for the rest of the study. Of the remaining two groups, one had memantine (n  = 14), while the other had both memantine and 10 IU/g vitamin D (n  = 14), added to their diet at month 9. Serum 25(OH)D levels measured at months 6, 9, 12, and 15 confirmed vitamin D levels were lower in mice on vitamin D-deficient diets and higher in the vitamin D-supplemented mice. Micro-computed tomography was performed at month 15 to determine whole-body composition. Results: In mice deprived of vitamin D, memantine increased bone mineral content (8.7% increase, p  < 0.01) and absolute skeletal tissue mass (9.3% increase, p  < 0.05) and volume (9.2% increase, p  < 0.05) relative to controls. This was not observed when memantine treatment was combined with vitamin D enrichment. Conclusion: Combination treatment of vitamin D and memantine had no negative effects on body composition. Future studies should clarify whether vitamin D status impacts the effects of memantine treatment on bone physiology in people with AD. Show more

Keywords: Adipose tissue, Alzheimer’s disease, animal models, body composition, bone and bones, 3-D imaging, memantine, muscle, vitamin D, x-ray micro-CT

DOI: 10.3233/JAD-201137

Citation: Journal of Alzheimer's Disease, vol. 81, no. 1, pp. 375-388, 2021

Authors: Li, Lin-Lin | Ma, Ya-Hui | Bi, Yan-Lin | Sun, Fu-Rong | Hu, Hao | Hou, Xiao-He | Xu, Wei | Shen, Xue-Ning | Dong, Qiang | Tan, Lan | Yang, Jiu-Long | Yu, Jin-Tai

Article Type: Research Article

Abstract: Background: Serum uric acid (SUA) affects the reaction of oxidative stress and free radicals in the neurodegenerative processes. However, whether SUA impacts Alzheimer’s disease (AD) pathology remains unclear. Objective: We aimed to explore whether high SUA levels can aggravate the neurobiological changes of AD in preclinical AD. Methods: We analyzed cognitively intact participants (n = 839, age 62.16 years) who received SUA and cerebrospinal fluid (CSF) biomarkers (amyloid-β [Aβ], total tau [t-Tau], and phosphorylated tau [p-Tau]) measurements from the Chinese Alzheimer’s Biomarker and LifestylE (CABLE) database using multivariable-adjusted linear models. Results: Levels of …SUA in the preclinical AD elevated compared with the healthy controls (p = 0.007) and subjects with amyloid pathology had higher concentration of SUA than controls (p = 0.017). Roughly, equivalent levels of SUA displayed among cognitively intact individuals with or without tau pathology and neurodegeneration. CSF Aβ1 - 42 (p = 0.019) and Aβ1 - 42 /Aβ1 - 40 (p = 0.027) were decreased and CSF p-Tau/Aβ1 - 42 (p = 0.009) and t-Tau/Aβ1 - 42 (p = 0.043) were increased with the highest (> 75th percentile) SUA when compared to lowest SUA, implying a high burden of cerebral amyloidosis in individuals with high SUA. Sensitivity analyses using the usual threshold to define hyperuricemia and precluding drug effects yielded robust associations. Nevertheless, the quadratic model did not show any U-shaped relationships between them. Conclusion: SUA may aggravate brain amyloid deposition in preclinical AD, which corroborated the detrimental role of SUA. Show more

Keywords: Alzheimer’s disease pathology, biomarkers, cerebrospinal fluid, serum uric acid

DOI: 10.3233/JAD-201192

Citation: Journal of Alzheimer's Disease, vol. 81, no. 1, pp. 389-401, 2021

Authors: Miyagawa, Naoko | Ohkubo, Takayoshi | Fujiyoshi, Akira | Shiino, Akihiko | Chen, Randi | Ross, George Webster | Willcox, Bradley | Miura, Katsuyuki | Ueshima, Hirotsugu | Masaki, Kamal

Article Type: Research Article

Abstract: Background: Few studies have compared factors related to cognitive function among people with similar genetic backgrounds but different lifestyles. Objective: We aimed to identify factors related to lower cognitive scores among older Japanese men in two genetically similar cohorts exposed to different lifestyle factors. Methods: This cross-sectional study of community-dwelling Japanese men aged 71–81 years included 2,628 men enrolled in the Kuakini Honolulu-Asia Aging Study based in Hawaii and 349 men in the Shiga Epidemiological Study of Subclinical Atherosclerosis based in Japan. We compared participant performance through Cognitive Abilities Screening Instrument (CASI) assessment in Hawaii (1991–1993) …and Japan (2009–2014). Factors related to low cognitive scores (history of cardiovascular disease, cardiometabolic factors, and lifestyle factors) were identified with questionnaires and measurements. Multivariable logistic regression analysis was used to calculate the adjusted odds ratios (ORs) of a low (< 82) CASI score based on different factors. Results: CASI scores were lower in Hawaii than in Japan [21.2%(n  = 556) versus 12.3%(n  = 43), p  < 0.001], though this was not significant when adjusted for age and educational attainment (Hawaii 20.3%versus Japan 17.9%, p  = 0.328). History of stroke (OR = 1.65, 95%confidence interval = 1.19–2.29) was positively associated with low cognitive scores in Hawaii. Body mass index ≥25 kg/m2 tended to be associated with low cognitive scores in Japan; there was a significant interaction between the cohorts. Conclusion: Cognitive scores differences between cohorts were mostly explained by differences in educational attainment. Conversely, cardiovascular diseases and cardiometabolic factors differentially impacted cognitive scores among genetically similar older men exposed to different lifestyle factors. Show more

Keywords: Aged, cognitive decline, community dwelling, Japanese, Japanese Americans, men

DOI: 10.3233/JAD-201084

Citation: Journal of Alzheimer's Disease, vol. 81, no. 1, pp. 403-412, 2021

Authors: Nelson, Monica E. | Andel, Ross | Nedelska, Zuzana | Martinkova, Julie | Cechova, Katerina | Markova, Hana | Matuskova, Veronika | Nikolai, Tomas | Lerch, Ondrej | Parizkova, Martina | Laczo, Jan | Vyhnalek, Martin | Hort, Jakub

Article Type: Research Article

Abstract: Background: Identifying modifiable risk factors for cognitive decline can reduce burden of dementia. Objective: We examined whether homocysteine was associated with memory performance, mediated by entorhinal volume, hippocampal volume, total gray matter volume, or white matter lesions, and moderated by APOE ɛ4 allele, B vitamins, creatinine, total cholesterol, or triglycerides. Methods: All 204 members of the Czech Brain Aging Study with subjective cognitive decline (SCD; n  = 60) or amnestic mild cognitive impairment (aMCI; n  = 144) who had valid data were included. Linear regression was used, followed by conditional process modeling to examine mediation and moderation. …Results: Controlling for age, sex, and education, higher homocysteine was related to poorer memory performance overall (b  = –0.03, SE  = 0.01, p  = 0.017) and in participants with SCD (b  = –0.06, SE  = 0.03, p  = 0.029), but less so in aMCI (b  = –0.03, SE  = 0.02, p  = 0.074); though sensitivity analyses revealed a significant association when sample was reduced to aMCI patients with more complete cognitive data (who were also better functioning; b  = –0.04, SE  = 0.02, p  = 0.022). Results were unchanged in fully adjusted models. Neither mediation by markers of brain integrity nor moderation by APOE ɛ4, B vitamins, creatinine, and cardiovascular factors were significant. Memory sub-analyses revealed that results for SCD were likely driven by non-verbal memory. The homocysteine-memory relationship was significant when hippocampal volume was below the median (b  = –0.04, SE  = 0.02, p  = 0.046), but not at/above the median (p  = 0.247). Conclusion: Higher homocysteine levels may adversely influence memory performance, which appears particularly apparent in those without cognitive impairment. Results appear to be independent of brain health, suggesting that homocysteine may represent a good target for intervention. Show more

Keywords: Hippocampus, magnetic resonance imaging, mild cognitive impairment, neuropsychological tests

DOI: 10.3233/JAD-201558

Citation: Journal of Alzheimer's Disease, vol. 81, no. 1, pp. 413-426, 2021