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

Authors: Yang, Heyun | Wang, Wei | Jia, Longfei | Qin, Wei | Hou, Tingting | Wu, Qiaoqi | Li, Haitao | Tian, Yuanruhua | Jia, Jianping

Article Type: Research Article

Abstract: The blood-brain barrier (BBB) can restrict the therapeutic effects of Alzheimer’s disease (AD) medications. While a large number of AD drug treatment trials targeting BBB dynamics have emerged, most have failed due to insufficient permeability. Furthermore, a subset of AD cases, which also feature chronic hypoperfusion are complicated by BBB deficits. We used a mouse model of AD with chronic hypoperfusion—transgenic mice (PS1V97L) with right common carotid artery ligation. In this model, we assessed how chronic cerebral hypoperfusion changed the pathophysiological processes that increase BBB permeability. Compared with control mice, AD mice with chronic hypoperfusion revealed significantly upregulated expression of …the receptor for advanced glycation end products (RAGE) on the BBB. Upregulated RAGE caused increased accumulation of amyloid-β (Aβ) in the brain in these mice. Upregulation of RAGE (or binding to Aβ) can promote activation of the NF-κ B pathway and enhance oxidative stress and increase the release of pro-inflammatory factors. These factors promoted the reduction of tight junction proteins between the endothelial cells in the BBB and increased its permeability. These findings suggest that the transporter RAGE dysregulation on the BBB initiates a series of pathophysiological processes which lead to increased BBB permeability. Taken together, we have shown that chronic hypoperfusion can serve to enhance and aggravate the BBB impairment in AD. Show more

Keywords: Alzheimer’s disease, blood-brain barrier, chronic cerebral hypoperfusion, NF-κB pathway, permeability, transgenic mice

DOI: 10.3233/JAD-191045

Citation: Journal of Alzheimer's Disease, vol. 74, no. 1, pp. 261-275, 2020

Authors: Jääskeläinen, Olli | Hall, Anette | Tiainen, Mika | van Gils, Mark | Lötjönen, Jyrki | Kangas, Antti J. | Helisalmi, Seppo | Pikkarainen, Maria | Hallikainen, Merja | Koivisto, Anne | Hartikainen, Päivi | Hiltunen, Mikko | Ala-Korpela, Mika | Soininen, Pasi | Soininen, Hilkka | Herukka, Sanna-Kaisa

Article Type: Research Article

Abstract: Accurate differentiation between neurodegenerative diseases is developing quickly and has reached an effective level in disease recognition. However, there has been less focus on effectively distinguishing the prodromal state from later dementia stages due to a lack of suitable biomarkers. We utilized the Disease State Index (DSI) machine learning classifier to see how well quantified metabolomics data compares to clinically used cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease (AD). The metabolic profiles were quantified for 498 serum and CSF samples using proton nuclear magnetic resonance spectroscopy. The patient cohorts in this study were dementia (with a clinical AD diagnosis) (N = 359), …mild cognitive impairment (MCI) (N = 96), and control patients with subjective memory complaints (N = 43). DSI classification was conducted for MCI (N = 51) and dementia (N = 214) patients with low CSF amyloid-β levels indicating AD pathology and controls without such amyloid pathology (N = 36). We saw that the conventional CSF markers of AD were better at classifying controls from both dementia and MCI patients. However, quantified metabolic subclasses were more effective in classifying MCI from dementia. Our results show the consistent effectiveness of traditional CSF biomarkers in AD diagnostics. However, these markers are relatively ineffective in differentiating between MCI and the dementia stage, where the quantified metabolomics data provided significant benefit. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, dementia, machine learning, metabolomics

DOI: 10.3233/JAD-191226

Citation: Journal of Alzheimer's Disease, vol. 74, no. 1, pp. 277-286, 2020

Authors: Gezen-Ak, Duygu | Alaylıoğlu, Merve | Genç, Gençer | Şengül, Büşra | Keskin, Ebru | Sordu, Pelin | Güleç, Zeynep Ece Kaya | Apaydın, Hülya | Bayram-Gürel, Çiğdem | Ulutin, Turgut | Yılmazer, Selma | Ertan, Sibel | Dursun, Erdinç

Article Type: Research Article

Abstract: Mitochondrial dysfunctions are significant contributors to neurodegeneration. One result or a cause of mitochondrial dysfunction might be the disruption of mtDNA transcription. Limited data indicated an altered expression of mtDNA encoded transcripts in Alzheimer’s disease (AD) or Parkinson’s disease (PD). The number of mitochondria is high in cells with a high energy demand, such as muscle or nerve cells. AD or PD involves increased risk of cardiomyopathy, suggesting that mitochondrial dysfunction might be systemic. If it is systemic, we should observe it in different cell types. Given that, we wanted to investigate any disruption in the regulation of mtDNA encoded …gene expression in addition to PINK1, PARKIN, and ATP levels in peripheral blood samples of PD cases who are affected by a neurodegenerative disorder that is very well known by its mitochondrial aspects. Our results showed for the first time that: 1) age of onset > 50 PD sporadic (PDS) cases: mtDNA transcription and quality control genes were affected; 2) age of onset <50 PDS cases: only mtDNA transcription was affected; and 3) PD cases with familial background: only quality control genes were affected. mtDNA copy number was not a confounder. Intracellular ATP levels of PD case subgroups were significantly higher than those of healthy subjects. We suggest that a systemic dysregulation of transcription of mtDNA or mitochondrial quality control genes might result in the development of a sporadic form of the disease. Additionally, ATP elevation might be an independent compensatory and response mechanism. Hyperactive cells in AD and PD require further investigation. Show more

Keywords: Alzheimer’s disease, ATP, mitochondrial DNA, OXPHOS, PARKIN, Parkinson’s disease, PINK1

DOI: 10.3233/JAD-191164

Citation: Journal of Alzheimer's Disease, vol. 74, no. 1, pp. 287-307, 2020

Authors: Sinha, Neha | Berg, Chelsie N. | Shaw, Ashlee | Gluck, Mark A.

Article Type: Research Article

Abstract: African Americans are at elevated risk for age-related cognitive decline, with double the prevalence of Alzheimer’s disease (AD) compared to Caucasians Americans. Various behavioral, biological, and lifestyle factors may underlie this health disparity, but little is known about the relative importance and interactions among these different risk factors in African Americans. While the neuroprotective effects of aerobic exercise on biomarkers are well established, few studies have examined the differential benefits of exercise based on genetic risk for AD. Furthermore, evidence is limited regarding the potential moderating effects of ABCA7 , a gene known to confer significantly greater AD risk in …African Americans. In a case-control matched sample of 56 healthy older African Americans, we investigated the effect of an aerobic exercise intervention on a hippocampus-related assessment of generalization following rule learning, in individuals who were carriers of the ABCA7 rs3764650 non-risk (TT) or high-risk (GG) genotype. Following the exercise-intervention, the non-risk group made significantly fewer generalization errors, while there was no improvement in generalization for the high-risk group. For the controls, no changes in generalization scores were observed regardless of genotype status. Our results indicate that the ongoing adverse effects of ABCA7 high-risk genotype may diminish the benefits associated with aerobic exercise. As such, the potential disease-modifying effects of aerobic exercise on AD-related neuropathology may be limited to carriers of the ABCA7 rs3764650 non-risk genotype. Show more

Keywords: ABCA7, aerobic exercise, African American, Alzheimer’s disease

DOI: 10.3233/JAD-190723

Citation: Journal of Alzheimer's Disease, vol. 74, no. 1, pp. 309-318, 2020

Authors: Talaei, Mohammad | Feng, Lei | Barrenetxea, Jon | Yuan, Jian-Min | Pan, An | Koh, Woon-Puay

Article Type: Research Article

Abstract: Background: Few prospective studies with long duration of follow-up have assessed the relations of body mass index (BMI) and weight change with cognitive function, especially in Asian populations. Objective: To investigate whether BMI and weight change in midlife are associated with cognitive impairment in old age. Methods: We used data from 14,691 participants in the Singapore Chinese Health Study and computed weight change as the difference between weight reported at baseline (1993–1998) at mean age of 53.0 years and follow-up 1 (1999–2004) at mean age of 58.6 years. Cognitive impairment was determined using education-specific cut-offs of …the Singapore Modified Mini-Mental State Examination at follow-up 3 (2014–2016) at mean age of 72.9 years. We used multivariable logistic regression models to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) for the associations. Results: Obesity (as defined BMI ≥27.5 kg/m2 ) was associated with a higher risk of cognitive impairment at baseline (OR 1.33, 95% CI 1.12–1.58) and follow-up 1 (OR 1.30, 95% CI 1.10–1.54) compared to BMI of 18.5–22.9 kg/m2 . Underweight (BMI <18.5 kg/m2 ) was not associated with a significant risk either at baseline (OR 0.91, 95% CI 0.73–1.13) or follow-up 1 (OR 1.05, 95% CI 0.85–1.28). Compared to participants with <5% weight change, the ORs (95% CIs) of cognitive impairment were 1.20 (1.03–1.41) for those with 5–9.9% weight loss, 1.53 (1.29–1.81) for ≥10% weight loss, 1.00 (0.85–1.17) for 5–9.9% weight gain, and 1.50 (1.28–1.75) for ≥10% weight gain. Conclusion: Obesity, weight loss, and excessive weight gain at midlife were associated with an increased risk of cognitive impairment at old age. Show more

Keywords: Body mass index, Chinese, cognitive impairment, cohort study, weight change

DOI: 10.3233/JAD-191052

Citation: Journal of Alzheimer's Disease, vol. 74, no. 1, pp. 319-329, 2020

Authors: Benvenutto, Agnès | Guedj, Eric | Felician, Olivier | Eusebio, Alexandre | Azulay, Jean-Philippe | Ceccaldi, Mathieu | Koric, Lejla

Article Type: Research Article

Abstract: Corticobasal syndrome (CBS) is a neuropathologically heterogeneous entity. The use of cerebrospinal fluid and amyloid biomarkers enables detection of underlying Alzheimer’s disease (AD) pathology. We thus compared clinical, eye movement, and 18 FDG-PET imaging characteristics in CBS in two groups of patients divided according to their amyloid biomarkers profile. Fourteen patients presenting with CBS and amyloidosis (CBS-A+ ) were compared with 16 CBS patients without amyloidosis (CBS-A- ). The two groups showed similar motor abnormalities (parkinsonism, dystonia) and global cognitive functions. Unlike CBS-A+ patients who displayed more posterior cortical abnormalities, CBS-A- patients demonstrated more anterior cortical and brain …stem dysfunctions on the basis of neuropsychological testing, study of saccade velocities and brain hypometabolism areas on 18 FDG-PET. Interestingly, Dopamine Transporter SPECT imaging showed similar levels of dopaminergic degeneration in both groups. These findings confirm common and distinct brain abnormalities between the different neurodegenerative diseases that result in CBS. We demonstrate the importance of a multidisciplinary approach to improve diagnosis in vivo in particular on oculomotor examination. Show more

Keywords: Alzheimer’s disease, corticobasal syndrome, DaTSCAN© , eye movements, 18FDG-PET, video-oculography

DOI: 10.3233/JAD-190961

Citation: Journal of Alzheimer's Disease, vol. 74, no. 1, pp. 331-343, 2020

Authors: Goldwaser, Eric L. | Acharya, Nimish K. | Wu, Hao | Godsey, George A. | Sarkar, Abhirup | DeMarshall, Cassandra A. | Kosciuk, Mary C. | Nagele, Robert G.

Article Type: Research Article

Abstract: Blood-brain barrier (BBB) permeability is a recognized early feature of Alzheimer’s disease (AD). In the present study, we examined consequences of increased BBB permeability on the development of AD-related pathology by tracking selected leaked plasma components and their interactions with neurons in vivo and in vitro . Histological sections of cortical regions of postmortem AD brains were immunostained to determine the distribution of amyloid-β1-42 (Aβ42 ), cathepsin D, IgG, GluR2/3, and alpha7 nicotinic acetylcholine receptor (α 7nAChR). Results revealed that chronic IgG binding to pyramidal neurons coincided with internalization of Aβ42, IgG, GluR2/3, and α 7nAChR as …well as lysosomal compartment expansion in these cells in regions of AD pathology. To test possible mechanistic interrelationships of these phenomena, we exposed differentiated SH-SY5Y neuroblastoma cells to exogenous, soluble Aβ42 peptide and serum from AD and control subjects. The rate and extent of Aβ42 internalization in these cells was enhanced by serum containing neuron-binding IgG autoantibodies. This was confirmed by treating cells with individual antibodies specific for α 7nAChR, purified IgG from AD or non-AD sera, and sera devoid of IgG, in the presence of 100 nM Aβ42 . Initial co-localization of IgG, α 7nAChR, and Aβ42 was temporally and spatially linked to early endosomes (Rab11) and later to lysosomes (LAMP-1). Aβ42 internalization was attenuated by treatment with monovalent F(ab) antibody fragments generated from purified IgG from AD serum and then rescued by coupling F(ab) fragments with divalent human anti-Fab. Overall, results suggest that cross-linking of neuron-binding autoantibodies targeting cell surface proteins can accelerate intraneuronal Aβ42 deposition in AD. Show more

Keywords: Aβ1-42 , Alzheimer’s disease, autoantibodies, blood-brain barrier, brain-reactive autoantibodies, cerebrovasculature

DOI: 10.3233/JAD-190962

Citation: Journal of Alzheimer's Disease, vol. 74, no. 1, pp. 345-361, 2020

Authors: Casaletto, Kaitlin B. | Rentería, Miguel Arce | Pa, Judy | Tom, Sarah E. | Harrati, Amal | Armstrong, Nicole M. | Rajan, K. Bharat | Mungas, Dan | Walters, Samantha | Kramer, Joel | Zahodne, Laura B.

Article Type: Research Article

Abstract: Background: Active lifestyles are related to better cognitive aging outcomes, yet the unique role of different types of activity are unknown. Objective: To examine the independent contributions of physical (PA) versus cognitive (CA) leisure activities to brain and cognitive aging. Methods: Independent samples of non-demented older adults from University of California, San Francisco Hillblom Aging Network (UCSF; n  = 344 typically aging) and University of California, Davis Diversity cohort (UCD; n  = 485 normal to MCI) completed: 1) self-reported engagement in current PA and CA (UCSF: Physical Activity Scale for the Elderly and Cognitive Activity Scale; UCD: Life …Experiences Assessment Form); 2) neuropsychological batteries; and 3) neuroimaging total gray matter volume, white matter hyperintensities, and/or global fractional anisotropy. PA and CA were simultaneously entered into multivariable linear regression models, adjusting for demographic characteristics and functional impairment severity. Results: Brain outcomes : In UCSF, only PA was positively associated with gray matter volume and attenuated the relationship between age and fractional anisotropy. In UCD, only CA was associated with less white matter hyperintensities and attenuated the relationship between age and gray matter volume. Cognitive outcomes : In both cohorts, greater CA, but not PA, related to better cognition, independent of age and brain structure. In UCSF, CA attenuated the relationship between fractional anisotropy and cognition. In UCD, PA attenuated the association between white matter hyperintensities and cognition. Conclusions: Although their specificity was not easily teased apart, both PA and CA are clearly related to better brain and cognitive resilience markers across cohorts with differing educational, racial, and disease statuses. PA and CA may independently contribute to converging neuroprotective pathways for brain and cognitive aging. Show more

Keywords: Brain aging, cognitive aging, exercise, mental stimulation, reserve

DOI: 10.3233/JAD-191114

Citation: Journal of Alzheimer's Disease, vol. 74, no. 1, pp. 363-376, 2020

Authors: Whitwell, Jennifer L. | Tosakulwong, Nirubol | Weigand, Stephen D. | Graff-Radford, Jonathan | Duffy, Joseph R. | Clark, Heather M. | Machulda, Mary M. | Botha, Hugo | Utianski, Rene L. | Schwarz, Christopher G. | Senjem, Matthew L. | Strand, Edythe A. | Ertekin-Taner, Nilufer | Jack Jr , Clifford R. | Lowe, Val J. | Josephs, Keith A.

Article Type: Research Article

Abstract: Background: Rates of amyloid-β (Aβ) accumulation have been characterized across the cognitively normal to typical Alzheimer’s dementia spectrum, but little is known about Aβ accumulation in atypical Alzheimer’s disease (AD) and other neurodegenerative diseases, such as frontotemporal lobar degeneration (FTLD). Objective: We aimed tocharacterize longitudinal Aβ accumulation anddetermine the influence of age, apolipoprotein E (APOE) genotype, disease duration, and sexin atypical AD and FTLD. Methods: 322 patients (138 atypical AD, 184 FTLD) underwent Pittsburgh compound B PET scanning, with 73 having serialPiB-PET scans (42 atypical AD, 31 FTLD). Global Aβ standard uptake value ratios were calculated …for every scan. Mixed effects models were used to assess the effect of age, APOE genotype, disease duration, and sex on baseline and change measures of Aβ. Results: Atypical AD showed higher baseline Aβ than FTLD. Rate of Aβ accumulation was not associated with baseline Aβ in either group. Older age was associated with greater baseline Aβ and faster rates of accumulation in FTLD. In patients under age 70, atypical AD showed faster rates of accumulation than FTLD. APOE ɛ 4 genotype was associated with greater baseline Aβ in FTLD but did not influence rates of accumulation. Rates of Aβ accumulation were faster in FTLD patents with time from onset-to-PET≤4 years. Female sex was associated with faster rates of accumulation in atypical AD. Conclusion: Accumulation of Aβ is observed in atypical AD and FTLD, although different demographic factors influence accumulation in these diseases providing insight into potentially different biological mechanisms of Aβ deposition. Show more

Keywords: Alzheimer’s disease, amyloid plaques, frontotemporal lobar degeneration, positron emission tomography

DOI: 10.3233/JAD-190699

Citation: Journal of Alzheimer's Disease, vol. 74, no. 1, pp. 377-389, 2020

Authors: Soares Martins, Tânia | Magalhães, Sandra | Rosa, Ilka Martins | Vogelgsang, Jonathan | Wiltfang, Jens | Delgadillo, Ivonne | Catita, José | da Cruz e Silva, Odete A.B. | Nunes, Alexandra | Henriques, Ana Gabriela

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) diagnosis is based on psychological and imaging tests but can also include monitoring cerebrospinal fluid (CSF) biomarkers. However, CSF based-neurochemical approaches are expensive and invasive, limiting their use to well-equipped settings. In contrast, blood-based biomarkers are minimally invasive, cost-effective, and a widely accessible alternative. Blood-derived exosomes have recently emerged as a reliable AD biomarker source, carrying disease-specific cargo. Fourier-transformed infrared (FTIR) spectroscopy meets the criteria for an ideal diagnostic methodology since it is rapid, easy to implement, and has high reproducibility. This metabolome-based technique is useful for diagnosing a broad range of diseases, although to our knowledge, …no reports for FTIR spectroscopy applied to exosomes in AD exist. In this ground-breaking pilot study, FTIR spectra of serum and serum-derived exosomes from two independent cohorts were acquired and analyzed using multivariate analysis. The regional UA-cohort includes 9 individuals, clinically diagnosed with AD, mean age of 78.7 years old; and the UMG-cohort comprises 12 individuals, clinically diagnosed with AD (based on molecular and/or imaging data), mean age of 73.2 years old. Unsupervised principal component analysis of FTIR spectra of serum-derived exosomes revealed higher discriminatory value for AD cases when compared to serum as a whole. Consistently, the partial least-squares analysis revealed that serum-derived exosomes present higher correlations than serum. In addition, the second derivative peak area calculation also revealed significant differences among Controls and AD cases. The results obtained suggest that this methodology can discriminate cases from Controls and thus be potential useful to assist in AD clinical diagnosis. Show more

Keywords: Alzheimer’s disease, biomarker, blood, diagnosis, exosomes, serum, spectroscopy

DOI: 10.3233/JAD-191034

Citation: Journal of Alzheimer's Disease, vol. 74, no. 1, pp. 391-405, 2020

Article Type: Correction

DOI: 10.3233/JAD-209001

Citation: Journal of Alzheimer's Disease, vol. 74, no. 1, pp. 407-407, 2020

Article Type: Correction

DOI: 10.3233/JAD-199670

Citation: Journal of Alzheimer's Disease, vol. 74, no. 1, pp. 409-409, 2020