Journal of Alzheimer's Disease - Volume Pre-press, issue Pre-press

Authors: Dorey, C. Kathleen | Gierhart, Dennis | Fitch, Karlotta A. | Crandell, Ian | Craft, Neal E.

Article Type: Review Article

Abstract: Background: Oxidative stress contributes to pathogenesis and progression of Alzheimer’s disease (AD). Higher levels of the dietary antioxidants— carotenoids and tocopherols— are associated with better cognitive functions and lower risk for AD, and lower levels of multiple carotenoids are found in serum and plasma of patients with AD. Although brains donated by individuals with mild cognitive impairment had significantly lower levels of lutein and beta-carotene, previous investigators found no significant difference in carotenoid levels of brains with AD and cognitively normal brains. Objective: This study tested the hypothesis that micronutrients are significantly lower in donor brains with AD …than in healthy elderly brains. Methods: Samples of donor brains with confirmed AD or verified health were dissected into grey and white matter, extracted with organic solvents and analyzed by HPLC. Results: AD brains had significantly lower levels of lutein, zeaxanthin, anhydrolutein, retinol, lycopene, and alpha-tocopherol, and significantly increased levels of XMiAD, an unidentified xanthophyll metabolite. No meso-zeaxanthin was detected. The overlapping protective roles of xanthophylls, carotenes, α- and γ -tocopherol are discussed. Conclusion: Brains with AD had substantially lower concentrations of some, but not all, xanthophylls, carotenes, and tocopherols, and several-fold higher concentrations of an unidentified xanthophyll metabolite increased in AD (XMiAD). Show more

Keywords: Alzheimer’s disease, antioxidants, brain, carotenoids, deficiency, lutein, lycopene, meso-zeaxanthin, oxidation, tocopherols, zeaxanthin

DOI: 10.3233/JAD-220460

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2022

Authors: Chen, Liang | Xue, Jun | Zhao, Qianhua | Liang, Xiaoniu | Zheng, Li | Fan, Zhen | Souare, Ibrahima Sory Jnr | Suo, Yuanzhen | Wei, Xunbin | Ding, Ding | Mao, Ying

Article Type: Research Article

Abstract: Background: Laboratory investigations have demonstrated that near-infrared (NIR) light treatment can reduce amyloid-β burden in models of Alzheimer’s disease (AD). However, previous clinical studies are rather insufficient. Objective: Before starting a large-scale clinical trial, we performed a pilot study to characterize the efficacy of NIR light for AD patients. Methods: Twenty participants with mild to moderate AD were assigned randomly to the intervention (1060-1080 nm and 800-820 nm NIR light treatment for 12 weeks) or control group (without sham treatment). Safety and efficacy were evaluated at baseline, week 4, 8, and 12, and 4 weeks after treatment. …Results: In the intervention and control groups at week 12, mean changes from baseline on the Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-Cog) were -3.1 and -1.3 (p  = 0.5689). Mean changes from baseline on the Activities of Daily Living (ADL) were -3.6 versus 3.1 (p  = 0.0437). Mean changes from baseline on the Mini-Mental State Examination (MMSE) were 4.4 versus 1.0 (p  = 0.0253). The percentage of participants who exhibited a change larger than 4 points from baseline to week 12 was determined for the intervention and control groups on the ADAS-Cog (57% versus 29%), ADL (29% versus 0%), and MMSE (57% versus 14%). Treatment with NIR light did not increase the incidence of adverse events in participants. Conclusion: NIR light treatment appears to be safe and potentially beneficial for AD patients. It improved cognitive function and activities of daily living. The preliminary data encouraged us to launch a large-sample, multicenter, double-blind clinical trial. Show more

Keywords: Alzheimer’s disease, clinical study, cognition, pilot project, physical therapy

DOI: 10.3233/JAD-220866

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2022

Authors: Soppela, Helmi | Krüger, Johanna | Hartikainen, Päivi | Koivisto, Anne | Haapasalo, Annakaisa | Borroni, Barbara | Remes, Anne M. | Katisko, Kasper | Solje, Eino

Article Type: Research Article

Abstract: Background: Currently, there are few studies considering possible modifiable risk factors of frontotemporal dementia (FTD). Objective: In this retrospective case-control study, we evaluated whether a history of traumatic brain injury (TBI) associates with a diagnosis of FTD or modulates the clinical phenotype or onset age in FTD patients. Methods: We compared the prevalence of prior TBI between individuals with FTD (N = 218) and age and sex-matched AD patients (N = 214) or healthy controls (HC; N = 100). Based on the patient records, an individual was categorized to the TBI+ group if they were reported to have suffered from TBI during …lifetime. The possible associations of TBI with age of onset and disease duration were also evaluated in the whole FTD patient group or separately in the sporadic and genetic FTD groups. Results: The prevalence of previous TBI was the highest in the FTD group (19.3%) when compared to the AD group (13.1%, p  = 0.050) or HC group (12%, p  = 0.108, not significant). Preceding TBI was more often associated with the sporadic FTD cases than the C9orf72 repeat expansion-carrying FTD cases (p  = 0.003). Furthermore, comparison of the TBI+ and TBI- FTD groups indicated that previous TBI was associated with an earlier onset age in the FTD patients (B = 3.066, p  = 0.010). Conclusion: A preceding TBI associates especially with sporadic FTD and with earlier onset of symptoms. The results of this study suggest that TBI may be a triggering factor for the neurodegenerative processes in FTD. However, understanding the precise underlying mechanisms still needs further studies. Show more

Keywords: Comorbidity, dementia, frontotemporal dementia, head trauma, risk factors, traumatic brain injury

DOI: 10.3233/JAD-220545

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2022

Authors: Hu, Li-Tian | Xie, Xiao-Yong | Zhou, Gui-Feng | Wen, Qi-Xin | Song, Li | Luo, Biao | Deng, Xiao-Juan | Pan, Qiu-Ling | Chen, Guo-Jun

Article Type: Research Article

Abstract: Background: Accumulation of hyperphosphorylated Tau (pTau) contributes to the formation of neurofibrillary tangles in Alzheimer’s disease (AD), and targeting Tau/pTau metabolism has emerged as a therapeutic approach. We have previously reported that mitochondrial 3-hydroxy-3-methylglutaryl-COA synthase 2 (HMGCS2) is involved in AD by promoting autophagic clearance of amyloid-β protein precursor via ketone body-associated mechanism, whether HMGCS2 may also regulate Tau metabolism remains elusive. Objective: The present study was to investigate the role of HMGCS2 in Tau/p degradation. Methods: The protein levels of Tau and pTau including pT217 and pT181, as well as autophagic markers LAMP1 and LC3-II …were assessed by western blotting. The differentially regulated genes by HMGCS2 were analyzed by RNA sequencing. Autophagosomes were assessed by transmission electron microscopy. Results: HMGCS2 significantly decreased Tau/pTau levels, which was paralleled by enhanced formation of autophagic vacuoles and prevented by autophagic regulators chloroquine, bafilomycin A1, 3-methyladenine, and rapamycin. Moreover, HMGCS2-induced alterations of LAMP1/LC3-II and Tau/pTau levels were mimicked by ketone body acetoacetate or β-hydroxybutyrate. Further RNA-sequencing identified ankyrin repeat domain 24 (ANKRD24) as a target gene of HMGCS2, and silencing of ANKRD24 reduced LAMP1/LC3-II levels, which was accompanied by the altered formation of autophagic vacuoles, and diminished the effect of HMGCS2 on Tau/pTau. Conclusion: HMGCS2 promoted autophagic clearance of Tau/pTau, in which ketone body and ANKRD24 played an important role. Show more

Keywords: Alzheimer’s disease, ANKRD24, autophagy, HMGCS2, ketone body, Tau

DOI: 10.3233/JAD-220640

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-20, 2022

Authors: Grobler, Corlia | van Tongeren, Marvi | Gettemans, Jan | Kell, Douglas B. | Pretorius, Etheresia

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a debilitating neurodegenerative disorder affecting 50 million people globally. It is characterized by the presence of extracellular senile plaques and intracellular neurofibrillary tangles, consisting of amyloid-β and hyperphosphorylated tau proteins, respectively. Despite global research efforts, there is currently no cure available, due in part to an incomplete understanding of the disease pathogenesis. Numerous possible mechanisms, or hypotheses, explaining the origins of sporadic or late-onset AD have been proposed, including the amyloid-β, inflammatory, vascular, and infectious hypotheses. However, despite ample evidence, the failure of multiple trial drugs at the clinical stage illuminates the possible pitfalls of these …hypotheses. Systems biology is a strategy which aims to elucidate the interactions between parts of a whole. Using this approach, the current paper shows how the four previously mentioned hypotheses of AD pathogenesis can be intricately connected. This approach allows for seemingly contradictory evidence to be unified in a system-focused explanation of sporadic AD development. Within this view, it is seen that infectious agents, such as P. gingivalis , may play a central role. The data presented here shows that when present, P. gingivalis or its virulence factors, such as gingipains, may induce or exacerbate pathologies underlying sporadic AD. This evidence supports the view that infectious agents, and specifically P. gingivalis , may be suitable treatment targets in AD. Show more

Keywords: Alzheimer’s disease, infectious agents, systemic inflammation, systems biology

DOI: 10.3233/JAD-220720

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-28, 2022

Authors: Königsberg, Alina | Belau, Matthias H. | Ascone, Leonie | Gallinat, Jürgen | Kühn, Simone | Jensen, Märit | Gerloff, Christian | Cheng, Bastian | Thomalla, Götz

Article Type: Research Article

Abstract: Background: Subjective cognitive decline (SCD) is considered to be a preliminary stage of dementia, and its prevalence is increasing with age. Objective: We aimed to study the association of SCD with health-related quality of life (HRQoL) in a large population-based sample. Methods: We analyzed data of the first 10,000 participants from the Hamburg City Health Study in Germany, a single center prospective cohort study, aged between 45 and 74 years that scored higher than 25 points in the Mini-Mental State Examination and had no known pre-existing dementia. HRQoL was assessed by the EQ-5D-5 L index, as well …as the mental (MCS) and physical component summary (PCS) score of the Short Form-8. We computed linear regression analyses with 99% bias-corrected and accelerated (BCa) confidence intervals (CI) from 10,000 bootstrap samples to investigate the association between SCD and different indicators of HRQoL, while controlling for depression (PHQ-9), age, sex, and education as potential confounders. Results: Of 7,799 eligible participants (mean (SD) age 62.01 (8.41) years, 51.1% female), 3,708 (47.5%) reported SCD. Participants with SCD were older (62.7 versus 61.4 years) and more frequently female (54.2% versus 48.2%). SCD was independently associated with a lower EQ-5D-5 L index (β=–0.01, 99% BCa CI = [–0.020, –0.003], p  < 0.001) and PCS (β=–1.00, 99% BCa CI = [–1.48, –0.51], p  < 0.001) but not with MCS score. Conclusion: In a population of middle-aged to elderly participants, there is a significant negative association between SCD and HRQoL across different instruments of HRQoL measurement independent of depression, demographics, and education. Show more

Keywords: Health-related quality of life, population-based study, prospective study, subjective cognitive decline

DOI: 10.3233/JAD-220659

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2022

Authors: Wu, Bang-Sheng | Zhang, Ya-Ru | Yang, Liu | Zhang, Wei | Deng, Yue-Ting | Chen, Shi-Dong | Feng, Jian-Feng | Cheng, Wei | Yu, Jin-Tai

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) patients rank among the highest levels of comorbidities compared to persons with other diseases. However, it is unclear whether the conditions are caused by shared pathophysiology due to the genetic pleiotropy for AD risk genes. Objective: To figure out the genetic pleiotropy for AD risk genes in a wide range of diseases. Methods: We estimated the polygenic risk score (PRS) for AD and tested the association between PRS and 16 ICD10 main chapters, 136 ICD10 level-1 chapters, and 377 diseases with cases more than 1,000 in 312,305 individuals without AD …diagnosis from the UK Biobank. Results: After correction for multiple testing, AD PRS was associated with two main ICD10 chapters: Chapter IV (endocrine, nutritional and metabolic diseases) and Chapter VII (eye and adnexa disorders). When narrowing the definition of the phenotypes, positive associations were observed between AD PRS and other types of dementia (OR = 1.39, 95% CI [1.34, 1.45], p  = 1.96E-59) and other degenerative diseases of the nervous system (OR = 1.18, 95% CI [1.13, 1.24], p  = 7.74E-10). In contrast, we detected negative associations between AD PRS and diabetes mellitus, obesity, chronic bronchitis, other retinal disorders, pancreas diseases, and cholecystitis without cholelithiasis (ORs range from 0.94 to 0.97, FDR <  0.05). Conclusion: Our study confirms several associations reported previously and finds some novel results, which extends the knowledge of genetic pleiotropy for AD in a range of diseases. Further mechanistic studies are necessary to illustrate the molecular mechanisms behind these associations. Show more

Keywords: Alzheimer’s disease, genetic pleiotropy, PheWAS, polygenic risk score

DOI: 10.3233/JAD-220740

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2022

Authors: Maćkowiak, Maria | Libura, Agnieszka | Phillipson, Lyn | Szcześniak, Dorota | Rymaszewska, Joanna

Article Type: Research Article

Abstract: Background: With the increasing incidences of dementia in aging societies, attention should be paid to the social context in which people with dementia live. One of its aspects is language transmitting beliefs, perceptions, and behavioral patterns. An analysis of understanding the diagnostic label of dementia may reveal the role of semantics in the process of social cognition of this disease. Objective: The overall aim of this study was to investigate the understanding of the word dementia (otępienie ) in the Polish language. Methods: Frame semantics approach was applied. The structure of semantic information was uncovered with …the concept of frame utilizing The National Corpus of Polish (the biggest corpus of contemporary Polish language of 1,500 million words). Additional data was collected from Polish speaking adults in Poland. Results: The analyses allowed to identify the otępienie frame for Polish and verify how its elements are filled in by the general population, indicating the selectivity of colloquial knowledge about dementia. Dementia deviates from the prototypical disease. Need to care for the person with dementia outweighs treatment options. The cognitive symptoms and characteristics of the subject are salient. The perceptions of people with dementia embedded in semantics of the diagnostic label might create a basis for prejudicial attitudes among lay part of the society. Conclusion: Findings give foundation to further studies on relationship between semantics and social cognition of dementia which has a real impact on the social and clinical situation of people with dementia and may facilitate formulation of tailored messages aimed at building dementia-friendly society. Show more

Keywords: Dementia, language, semantics, social cognition, social stigma

DOI: 10.3233/JAD-220633

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2022

Authors: Khezri, Mohammad Rafi | Ghasemnejad-Berenji, Morteza

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is the most common neurodegenerative disorder worldwide. Although the main cause of the onset and development of AD is not known yet, neuronal death due to pathologic changes such as amyloid-β (Aβ) deposition, tau aggregation, neuroinflammation, oxidative stress, and calcium dyshomeostasis are considered to be the main cause. At the present, there is no cure for this insidious disorder. However, accurate identification of molecular changes in AD can help provide new therapeutic goals. Caspases are a group of proteases which are known because of their role in cellular apoptosis. In addition, different caspases are involved in other …cellular responses to the environment, such as induction of inflammation. Emerging evidence suggest that these proteases play a central role in AD pathophysiology due to their role in the processing of amyloid-β protein precursor, tau cleavage, and neuroinflammation. Therefore, it seems that targeting caspases may be a suitable therapeutic option to slow the progression of AD. This review focuses on the role of caspases in AD pathophysiology and introduce results from studies targeted caspases in different models of AD. Show more

Keywords: Alzheimer’s disease, caspase, neurodegeneration

DOI: 10.3233/JAD-220873

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-20, 2022

Authors: Abbate, Carlo | Trimarchi, Pietro D. | Fumagalli, Giorgio G. | Gallucci, Alessia | Tomasini, Emanuele | Fracchia, Stefania | Rebecchi, Isabella | Morello, Elisabetta | Fontanella, Anna | Parisi, Paola M.R. | Tartarone, Federica | Giunco, Fabrizio | Ciccone, Simona | Nicolini, Paola | Lucchi, Tiziano | Arosio, Beatrice | Inglese, Silvia | Rossi, Paolo D.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is clinically heterogeneous, including the classical-amnesic (CA-) phenotype and some variants. Objective: We aim to describe a further presentation we (re)named confabulation-misidentification (CM-) phenotype. Methods: We performed a retrospective longitudinal case-series study of 17 AD outpatients with the possible CM-phenotype (CM-ADs). Then, in a cross-sectional study, we compared the CM-ADs to a sample of 30 AD patients with the CA-phenotype (CA-ADs). The primary outcome was the frequency of cognitive and behavioral features. Data were analyzed as differences in percentage by non-parametric Chi Square and mean differences by parametric T-test. …Results: Anterograde amnesia (100%) with early confabulation (88.2%), disorientation (88.2%) and non-infrequently retrograde amnesia (64.7%) associated with reduced insight (88.2%), moderate prefrontal executive impairment (94.1%) and attention deficits (82.3%) dominated the CM-phenotype. Neuropsychiatric features with striking misidentification (52.9%), other less-structured delusions (70.6%), and brief hallucinations (64.7%) were present. Marked behavioral disturbances were present early in some patients and very common at later stages. At the baseline, the CM-ADs showed more confabulation (p  <  0.001), temporal disorientation (p  <  0.02), misidentification (p  = 0.013), other delusions (p  = 0.002), and logorrhea (p  = 0.004) than the CA-ADs. In addition, more social disinhibition (p  = 0.018), reduction of insight (p  = 0.029), and hallucination (p  = 0.03) persisted at 12 months from baseline. Both the CA- and CM-ADs showed anterior and medial temporal atrophy. Compared to HCs, the CM-ADs showed more right fronto-insular atrophy, while the CA-ADs showed more dorsal parietal, precuneus, and right parietal atrophy. Conclusion: We described an AD phenotype resembling diencephalic rather than hippocampal amnesia and overlapping the past-century description of presbyophrenia. Show more

Keywords: Alzheimer’s disease, amnesia, confabulation, delusions, memory rehabilitation, misidentification, presbyophrenia

DOI: 10.3233/JAD-220919

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-26, 2022