Journal of Alzheimer's Disease - Volume 74, issue 1

Authors: Chen, Shi-Dong | Li, Hong-Qi | Shen, Xue-Ning | Li, Jie-Qiong | Xu, Wei | Huang, Yu-Yuan | Tan, Lan | Dong, Qiang | Yu, Jin-Tai | on behalf of Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: As cognitive function declines with age, identifying factors affecting the trajectory of cognitive decline is an indispensable step toward developing intervention strategies to improve the quality of the elderly life. Objective: We performed a genome-wide association study (GWAS) focusing on memory function to explore single nucleotide polymorphisms (SNPs) associated with the rate of memory decline. Methods: Seven hundred and nine eligible non-Hispanic Caucasians from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were included for analysis after quality control. GWAS was performed with linear regression. We subsequently tested whether the associations remained significant in subgroup analysis and …also examined the impact of SNPs on the longitudinal changes in other neuropsychological measures and amyloid pathology. Results: We identified rs13374761-A in SLAMF1 gene associated with less memory decline (MAF = 0.071, β= 0.0103, p  = 4.14×10–8 ). Subgroup analysis showed stability of results across groups with different diagnosis at baseline. Rs13374761-A also had protective effects on global cognition (p  = 0.024), episodic memory (p  = 0.024), and semantic memory (p  = 0.042), and exerts protection against a decrease in CSF Aβ42 concentration (p  = 0.0463) and an increase in Aβ loading in cerebral cortex (p  = 0.00666) among minor allele carriers. Conclusion: A novel variant in gene SLAMF1 affects the rate of memory decline in the aged population. Given the protective effect of this variant, SLAMF1 should be further investigated as a potential preventive and therapeutic target for monitoring cognition trajectories. Show more

Keywords: Alzheimer’s disease, amyloid, cognitive decline, genome-wide association study, memory, SLAMF1, SNP

DOI: 10.3233/JAD-191214

Citation: Journal of Alzheimer's Disease, vol. 74, no. 1, pp. 139-149, 2020

Authors: Heser, Kathrin | Kleineidam, Luca | Pabst, Alexander | Wiese, Birgitt | Roehr, Susanne | Löbner, Margrit | Hajek, André | van der Leeden, Carolin | Angermeyer, Matthias C. | Scherer, Martin | König, Hans-Helmut | Maier, Wolfgang | Riedel-Heller, Steffi G. | Wagner, Michael

Article Type: Research Article

Abstract: Background: An association between depression and an increased risk for subsequent dementia is well-established. Sexspecific associations are understudied yet. Objective: We aimed to investigate sex-specific associations between depressive symptoms and dementia risk. Methods: Longitudinal analyses were conducted in a pooled data set (n = 4,255, mean age = 80 years) of two prospective cohort studies (LEILA 75+, AgeCoDe). Depressive symptoms were harmonized by dichotomized scores of two different depression screening scales using established cutoffs. Transition to dementia was used as outcome in Cox proportional hazards models. Results: Depressive symptoms at baseline were associated …with an increased risk for subsequent dementia, and this association was more pronounced in males (interaction of depressive symptoms × sex: HR = 1.64, 95% CI: 1.02–2.64, p = 0.042) in a model adjusted for study, age, and education. After additional adjustment for subjective and objective cognition, depressive symptoms and their interaction with sex (HR = 1.38, 95% CI: 0.85–2.23, p = 0.188) were no longer significantly associated with the risk for subsequent dementia. Sex-stratified analyses showed stronger and significant associations between depressive symptoms and subsequent dementia in men (e.g., HR= 2.10, 95% CI: 1.36–3.23, p = 0.001, compared to HR= 1.28, 95% CI: 1.04–1.58, p = 0.020, in women). Conclusions: Overall, we provide evidence for a stronger association between depression and dementia in men compared to women. Depressive symptoms should be diagnosed, monitored, and treated, not only due to depression, but also with respect to the risk for subsequent dementia, especially in elderly men. Show more

Keywords: Dementia, depression, depressive symptoms, gender, sex

DOI: 10.3233/JAD-190770

Citation: Journal of Alzheimer's Disease, vol. 74, no. 1, pp. 151-161, 2020

Authors: Lai, Michelle M.Y. | Sharman, Matthew J. | Ames, David J. | Ellis, Kathryn A. | Cox, Kay L. | Hepworth, Graham | Desmond, Patricia | Cyarto, Elizabeth V. | Martins, Ralph N. | Masters, Colin L. | Lautenschlager, Nicola T.

Article Type: Research Article

Abstract: Background: There is a paucity of information on the role of microvascular and inflammatory biomarkers in cognitive dysfunction. Objective: This study sought to evaluate the relationships between established and a number of peripheral biomarkers on cognitive patterns in 108 older adults with memory complaints. Methods: Participants in the AIBL Active study aged 60 years and older with at least one vascular risk factor and memory complaints completed a neuropsychological test battery and provided cross-sectional health data. Linear regression models adjusted for covariates examined associations between cognitive performance and a panel of vascular risk factors (Framingham cardiovascular …scores, hs-CRP, homocysteine, fasting glucose, LDL-cholesterol) and peripheral biomarkers (TNF-α , BDNF, VCAM-1, ICAM-1, PAI-1, CD40L). Results: Higher fasting glucose and homocysteine levels were independent factors associated with poorer performance in Trail Making Test (TMT) B (adjusted β= 0.40±0.10 and 0.43±0.09, respectively). Increasing homocysteine levels were weakly associated with poorer global cognition and delayed recall (adjusted β= 0.23±0.10 and –0.20±0.10 respectively). Increasing Framingham cardiovascular scores were related to poorer performance in TMT B (β  = 0.42±0.19). There was early evidence of associations between increasing plasma TNF-α and poorer TMT B (adjusted β  = 0.21±0.10) and between increasing BDNF and better global cognition (β= –0.20±0.09). Conclusion: This study provides evidence to support the associations between vascular risk factors (Framingham scores, fasting glucose, and homocysteine) and poorer cognitive functions. Additionally, we measured several peripheral biomarkers to further investigate their associations with cognition. The relationship between TNF-α , BDNF, and cognitive performance in various domains may offer new insights into potential mechanisms in vascular cognitive impairment. Show more

Keywords: BDNF, biomarkers, cardiovascular disease, cognitive impairment, homocysteine, TNF-α, vascular risk factors, Trial Registration: Australia New Zealand Clinical Trials Registry ACTRN126110006129

DOI: 10.3233/JAD-190953

Citation: Journal of Alzheimer's Disease, vol. 74, no. 1, pp. 163-171, 2020

Authors: Mendes, Fúlvio R. | Leclerc, Jenna L. | Liu, Lei | Kamat, Pradip K. | Naziripour, Arash | Hernandez, Damian | Li, Chris | Ahmad, Abdullah S. | Doré, Sylvain

Article Type: Research Article

Abstract: Background: Neuroinflammation has been recognized as an important factor in the pathogenesis of Alzheimer’s disease (AD). One of the most recognized pathways in mediating neuroinflammation is the prostaglandin E2 -EP1 receptor pathway. Objective: Here, we examined the efficacy of the selective EP1 antagonist ONO-8713 in limiting amyloid-β (Aβ), lesion volumes, and behavioral indexes in AD mouse models after ischemic stroke. Methods: Transgenic APP/PS1, 3xTgAD, and wildtype (WT) mice were subjected to permanent distal middle cerebral artery occlusion (pdMCAO) and sham surgeries. Functional outcomes, memory, anatomical outcomes, and Aβ concentrations were assessed 14 days after surgery. …Results: pdMCAO resulted in significant deterioration in functional and anatomical outcomes in the transgenic mice compared with the WT mice. No relevant differences were observed in the behavioral tests when comparing the ONO-8713 and vehicle-treated groups. Significantly lower cavitation (p  = 0.0373) and percent tissue loss (p  = 0.0247) were observed in APP/PS1 + ONO-8713 mice compared with the WT + ONO-8713 mice. However, the percent tissue injury was significantly higher in APP/PS1 + ONO-8713 mice compared with the WT + ONO-8713 group (p  = 0.0373). Percent tissue loss was also significantly lower in the 3xTgAD + ONO-8713 mice than in the WT + ONO-8713 mice (p  = 0.0185). ONO-8713 treatment also attenuated cortical microgliosis in APP/PS1 mice as compared with the vehicle (p  = 0.0079); however, no differences were observed in astrogliosis across the groups. Finally, APP/PS1 mice presented with characteristic Aβ load in the cortex while 3xTgAD mice exhibited very low Aβ levels. Conclusion: In conclusion, under the experimental conditions, EP1 receptor antagonist ONO-8713 showed modest benefits in anatomical outcomes after stroke, mainly in APP/PS1 mice. Show more

Keywords: Alzheimer’s disease, amyloid-β, EP1 receptor, ischemia, permanent middle cerebral artery occlusion, prostaglandin E2, transgenic mice

DOI: 10.3233/JAD-191069

Citation: Journal of Alzheimer's Disease, vol. 74, no. 1, pp. 173-187, 2020

Authors: Malek-Ahmadi, Michael | Perez, Sylvia E. | Chen, Kewei | Mufson, Elliott J.

Article Type: Research Article

Abstract:  The aim of this study was to determine the interaction between cerebral amyloid angiopathy (CAA) and Braak staging on cognition in the elderly. The study used a total of 141 subjects consisting of 72 non-cognitively impaired (NCI), 33 mild cognitive impairment (MCI), 36 Alzheimer’s disease (AD) cases displaying Braak stages 0-II and III from the Rush Religious Order Study cohort. The association between Braak stage and CAA status and cognition was evaluated using a series of regression models that adjusted for age at death, sex, education, APOE ɛ 4 status, and Consortium to Establish a Registry for Alzheimer’s Disease …(CERAD) neuropathological diagnosis. Individuals with CAA were more likely to be classified as Braak stage III relative to those without CAA [OR = 2.33, 95% CI (1.06, 5.14), p  = 0.04]. A significant interaction was found between Braak stage and CAA status on a global cognitive score (β = –0.58, SE = 0.25, p  = 0.02). Episodic memory also showed a significant association between Braak stage and CAA (β= –0.75, SE = 0.35, p  = 0.03). These data suggest that there is a significant interaction between tau pathology and cerebrovascular lesions on cognition within the AD clinical spectrum. Show more

Keywords: Alzheimer’s disease, Braak stage, cerebral amyloid angiopathy, cognition, cognitive aging, mild cognitive impairment, neurofibrillary tangles

DOI: 10.3233/JAD-191151

Citation: Journal of Alzheimer's Disease, vol. 74, no. 1, pp. 189-197, 2020

Authors: Jia, Jianping | Wei, Cuibai | Chen, Wei | Jia, Longfei | Zhou, Aihong | Wang, Fen | Tang, Yi | Xu, Luoyi

Article Type: Research Article

Abstract: Background: Efficacy and dose-effect relationship of donepezil for treating patients with Alzheimer’s disease (AD) have been proven. However, few studies focused on the safety of donepezil, particularly in Chinese patients. Objective: To assess the safety of donepezil 10 mg/day in Chinese patients with mild-to-moderate AD. Methods: In this single-arm, prospective, multicenter trial, 241 patients with mild to moderate AD who had been treated with donepezil 5 mg/day for at least 4 weeks were enrolled. All patients received donepezil 10 mg/day for 20 weeks. Primary outcome was the incidence of adverse events (AEs). Safety profile was evaluated by physical examinations …including vital signs and weight, clinical laboratory tests and electrocardiograms, and also correlation analysis between AEs and APOE genotypes. Results: 241 patients were enrolled. Of which, 38.59% patients experienced at least one AE and 17.43% discontinued due to AEs. Most AEs were mild to moderate, with diarrhea, vomiting, and nausea the most frequently reported. Risk of AEs was significantly increased by concomitant use of drugs for cardiovascular and cerebrovascular diseases. Mean changes in heart rate and corrected QT relative to baseline were –1.08±6.02 beat/min (p  = 0.009) and –3.91±18.68 ms (p  = 0.0062) at week 4 and –1.48 beat/min±7.18 (p  = 0.0028) and –0.66 ms±19.66 (p  = 0.6561) at week 20, respectively. There were no significant changes in other vital sign parameters. Patients’ MMSE scores improved significantly after treatment (p  = 0.0038), especially for non-APOE ɛ 4 allele carriers and patients ≤75 years. Conclusion: Donepezil 10 mg/day can be tolerated and is effective in Chinese patients with mild-to-moderate AD. Show more

Keywords: Alzheimer’s disease, Chinese, clinical trial, donepezil, safety

DOI: 10.3233/JAD-190940

Citation: Journal of Alzheimer's Disease, vol. 74, no. 1, pp. 199-211, 2020

Authors: Westwood, Sarah | Baird, Alison L. | Anand, Sneha N. | Nevado-Holgado, Alejo J. | Kormilitzin, Andrey | Shi, Liu | Hye, Abdul | Ashton, Nicholas J. | Morgan, Angharad R. | Bos, Isabelle | Vos, Stephanie J.B. | Baker, Susan | Buckley, Noel J. | Ten Kate, Mara | Scheltens, Philip | Teunissen, Charlotte E. | Vandenberghe, Rik | Gabel, Silvy | Meersmans, Karen | Engelborghs, Sebastiaan | De Roeck, Ellen E. | Sleegers, Kristel | Frisoni, Giovanni B. | Blin, Olivier | Richardson, Jill C. | Bordet, Régis | Molinuevo, José L. | Rami, Lorena | Wallin, Anders | Kettunen, Petronella | Tsolaki, Magda | Verhey, Frans | Lléo, Alberto | Sala, Isabel | Popp, Julius | Peyratout, Gwendoline | Martinez-Lage, Pablo | Tainta, Mikel | Johannsen, Peter | Freund-Levi, Yvonne | Frölich, Lutz | Dobricic, Valerija | Legido-Quigley, Cristina | Bertram, Lars | Barkhof, Frederik | Zetterberg, Henrik | Morgan, B. Paul | Streffer, Johannes | Visser, Pieter Jelle | Lovestone, Simon

Article Type: Research Article

Abstract: We have previously investigated, discovered, and replicated plasma protein biomarkers for use to triage potential trials participants for PET or cerebrospinal fluid measures of Alzheimer’s disease (AD) pathology. This study sought to undertake validation of these candidate plasma biomarkers in a large, multi-center sample collection. Targeted plasma analyses of 34 proteins with prior evidence for prediction of in vivo pathology were conducted in up to 1,000 samples from cognitively healthy elderly individuals, people with mild cognitive impairment, and in patients with AD-type dementia, selected from the EMIF-AD catalogue. Proteins were measured using Luminex xMAP, ELISA, and Meso Scale Discovery …assays. Seven proteins replicated in their ability to predict in vivo amyloid pathology. These proteins form a biomarker panel that, along with age, could significantly discriminate between individuals with high and low amyloid pathology with an area under the curve of 0.74. The performance of this biomarker panel remained consistent when tested in apolipoprotein E ɛ 4 non-carrier individuals only. This blood-based panel is biologically relevant, measurable using practical immunocapture arrays, and could significantly reduce the cost incurred to clinical trials through screen failure. Show more

Keywords: Alzheimer’s disease, amyloid-β, biomarkers, plasma, proteomics

DOI: 10.3233/JAD-190434

Citation: Journal of Alzheimer's Disease, vol. 74, no. 1, pp. 213-225, 2020

Authors: Triantafyllou, Areti | Ferreira, João Pedro | Kobayashi, Masatake | Micard, Emilien | Xie, Yu | Kearney-Schwartz, Anna | Hossu, Gabriela | Rossignol, Patrick | Bracard, Serge | Benetos, Athanase

Article Type: Research Article

Abstract: Background: Hippocampal atrophy is associated with cognitive decline. Determining the clinical features associated with hippocampal volume (HV)/atrophy may help in tailoring preventive strategies. Objective: This study was aimed to investigate the association between HV (at visit 2) and vascular status (both at visit 1 and visit 2) in a cohort of individuals aged 60+ with hypertension and without overt cognitive impairment at visit 1 (visit 1 and visit 2 were separated by approximately 8 years). Methods: Hippocampal volume was estimated in brain MRIs as HV both clinically with the Scheltens’ Medial Temporal Atrophy score, and automatically …with the Free Surfer Software application. A detailed medical history, somatometric measurements, cognitive tests, leukoaraiosis severity (Fazekas score), vascular parameters including pulse wave velocity, central blood pressure, and carotid artery plaques, as well as several biochemical parameters were also measured. Results: 113 hypertensive patients, 47% male, aged 75.1±5.6 years, participated in both visit 1 and visit 2 of the ADELAHYDE study. Age (β= –0.30) and hypertension duration (β= –0.20) at visit 1 were independently associated with smaller HV at visit 2 (p  < 0.05 for all). In addition to these variables, low body mass index (β= 0.18), high MRI Fazekas score (β= –0.20), and low Gröber-Buschke total recall (β= 0.27) were associated with smaller HV at visit 2 (p  < 0.05 for all). Conclusion: In a cohort of older individuals without cognitive impairment at baseline, we described several factors associated with lower HV, of which hypertension duration can potentially be modified. Show more

Keywords: Aortic stiffness, brain MRI, cognitive decline, dementia, hippocampus, hypertension, macrovascular, microvascular, white matter lesions

DOI: 10.3233/JAD-190842

Citation: Journal of Alzheimer's Disease, vol. 74, no. 1, pp. 227-235, 2020

Authors: Zhang, Yaxin | Li, Yun | Wang, Rong | Sha, Guiming | Jin, He | Ma, Lina

Article Type: Research Article

Abstract: Background: Hypertension, a common chronic disease, is associated with cognitive impairment. Cognitive impairment, especially Alzheimer’s disease (AD), seriously affects older adults’ quality of life and aggravates the burden of disease on society and families. Elevated Alzheimer-associated neuronal thread protein (AD7c-NTP) has been observed in the urine of patients with AD and mild cognitive impairment; however, it is not clear whether this protein can be used as a biomarker for cognitive impairment in older hypertensive patients. Objective: To explore the value of urinary AD7c-NTP, and the association of urinary AD7c-NTP with cognitive function in older hypertensive patients. …Methods: This was a cross-sectional study. In total, 134 hypertensive patients aged ≥60 years were divided into two groups: Lower Cognitive Function group (LCF group, n  = 89) and Normal Control group (NC group, n  = 45) based on the Montreal Cognitive Assessment (MoCA). Urinary AD7c-NTP, blood glucose, serum insulin, superoxide dismutase (SOD) and malondialdehyde (MDA) levels were measured. Results: Urinary AD7c-NTP level was significantly higher in the LCF group than in the NC group [0.48 (0.21–1.00) versus 0.25 (0.04–0.44) ng/ml, p  < 0.001]. The LCF group had lower SOD level [(43.07±23.74) versus (53.12±25.80) U/ml, p  = 0.026] and higher homeostasis model assessment of insulin resistance (HOMA-IR) [7.17 (3.74–13.94) versus 6.01 (3.78–7.43), p = 0.033] than the NC group. Urinary AD7c-NTP level was associated with MoCA score and HOMA-IR but not with SOD, MDA, blood glucose, and insulin. Conclusion: The level of urinary AD7c-NTP is elevated in older hypertensive patients with lower cognitive function, and insulin resistance may be involved in the process. Show more

Keywords: AD7c-NTP, cognitive function, hypertension, urine

DOI: 10.3233/JAD-190944

Citation: Journal of Alzheimer's Disease, vol. 74, no. 1, pp. 237-244, 2020

Authors: Abdelhamid, Mona | Jung, Cha-Gyun | Zhou, Chunyu | Abdullah, Mohammad | Nakano, Manabu | Wakabayashi, Hiroyuki | Abe, Fumiaki | Michikawa, Makoto

Article Type: Research Article

Abstract: Lactoferrin (LF) is present in senile plaques and neurofibrillary tangles in the brains of Alzheimer’s disease (AD) patients and amyloid-β protein precursor transgenic (AβPP-Tg) mice. LF has anti-inflammatory and antioxidant functions, which exert neuroprotective effects against AD. However, its effects on memory impairment and AD pathogenesis have not been fully examined. In this study, we examined the effects of LF on memory impairment and AD pathogenesis in AβPP-Tg mice (J20 mice). Nine-month-old J20 mice were fed with control, 2% lactoferrin-containing (LF), and 0.5% pepsin-hydrolyzed lactoferrin-containing (LF-hyd) diets for 3 months. We found that both the LF and LF-hyd diets attenuated …memory impairment in J20 mice and decreased brain Aβ40 and Aβ42 levels through the inhibition of amyloidogenic processing of AβPP, as it decreased β-site amyloid protein precursor cleaving enzyme 1 (BACE1) levels. Furthermore, we found for the first time that LF and LF-hyd treatments increased both ApoE secretion and ATP-binding cassette A1 (ABCA1) protein levels in the brains of J20 mice and in primary astrocyte cultures. Moreover, LF and LF-hyd promoted extracellular degradation of Aβ in primary astrocyte cultures. These findings indicate that the reduction in Aβ levels in the brains of mice fed with both the LF and LF-hyd diets may also be mediated by increased ApoE secretion and ABCA1 protein levels, which in turn leads to the enhanced degradation of Aβ in the brains of J20 mice. Our findings suggest that LF and LF-hyd can be used for the treatment and/or prevention of the development of AD. Show more

Keywords: ABCA1, Alzheimer’s disease, amyloid-β, apolipoprotein E, BACE1, ERK1/2 MAPK, lactoferrin

DOI: 10.3233/JAD-191181

Citation: Journal of Alzheimer's Disease, vol. 74, no. 1, pp. 245-259, 2020