Journal of Alzheimer's Disease - Volume 90, issue 2

Authors: Hrincu, Viorica | An, Zijian | Joseph, Kenneth | Jiang, Yu Fei | Robillard, Julie M.

Article Type: Review Article

Abstract: Background: Social media is a powerful tool for engaging diverse audiences in dementia research. However, there is little data summarizing current content exchange in this context. Objective: To inform ethical dementia research engagement on social media, we characterized current practices by analyzing public social media posts. Methods: We retrieved Facebook (2-year period, N  = 7,896) and Twitter (1-year period, N  = 9,323) posts containing dementia research-related keywords using manual and machine learning-based search strategies. We performed qualitative and quantitative content and sentiment analyses on random samples (10%) of the posts. Results: Top Facebook users were advocacy …(45%) and health organizations (25%). On Twitter, academics/researchers were the largest user group. Prevention was the most frequently coded theme (Facebook 30%; Twitter 26%), followed by treatment (Facebook 15%; Twitter 18%). Diagnostics had the highest Facebook engagement. Sharing knowledge was the primary form of content exchange (Facebook 63%; Twitter 80%). Most shared journal articles were peer-reviewed and open access. Emotional tone was overall more positive on Facebook. Justice was a prominent ethics topic regarding inequalities related to identity and intersecting modes of marginalization in dementia research. Conclusion: The findings indicate the importance of social media as an engagement tool of current topics in health research and reveal areas of potential for increased engagement. These data can inform consensus-based best practices for ethical social media application in dementia research. Show more

Keywords: Access to information, Alzheimer’s disease, dementia, internet, qualitative research, social media

DOI: 10.3233/JAD-220525

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 447-459, 2022

Authors: Joshi, Mahesh S. | Galvin, James E.

Article Type: Review Article

Abstract: With the expected rise in Alzheimer’s disease and related dementias (ADRD) in the coming decades due to the aging population and a lack of effective disease-modifying treatments, there is a need for preventive strategies that may tap into resilience parameters. A wide array of resilience strategies has been proposed including genetics, socioeconomic status, lifestyle modifications, behavioral changes, and management of comorbid disease. These different strategies can be broadly classified as distinguishing between modifiable and non-modifiable risk factors, some of which can be quantified so that their clinical intervention can be effectively accomplished. A clear shift in research focus from dementia …risk to addressing disease resistance and resilience is emerging that has provided new potential therapeutic targets. Here we review and summarize the latest investigations of resilience mechanisms and methods of quantifying resilience for clinical research. These approaches include identifying genetic variants that may help identify novel pathways (e.g., lipid metabolism, cellular trafficking, synaptic function, inflammation) for therapeutic treatments and biomarkers for use in a precision medicine-like regimen. In addition, innovative structural and molecular neuroimaging analyses may assist in detecting and quantifying pathological changes well before the onset of clinical symptoms setting up the possibility of primary and secondary prevention trials. Lastly, we summarize recent studies demonstrating the study of resilience in caregivers of persons living with dementia may have direct and indirect impact on the quality of care and patient outcomes. Show more

Keywords: Alzheimer’s disease, biomarkers, brain health, cognition, cognitive reserve, dementia, neuroimaging, resilience

DOI: 10.3233/JAD-220755

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 461-473, 2022

Authors: Downey, Jocelyn | Lam, Jacqueline C.K. | Li, Victor O.K. | Gozes, Illana

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) represents a global health challenge, with an estimated 55 million people suffering from the non-curable disease across the world. While amyloid-β plaques and tau neurofibrillary tangles in the brain define AD proteinopathy, it has become evident that diverse coding and non-coding regions of the genome may significantly contribute to AD neurodegeneration. The diversity of factors associated with AD pathogenesis, coupled with age-associated damage, suggests that a series of triggering events may be required to initiate AD. Since somatic mutations accumulate with aging, and aging is a major risk factor for AD, there is a great potential for …somatic mutational events to drive disease. Indeed, recent data from the Gozes team/laboratories as well as other leading laboratories correlated the accumulation of somatic brain mutations with the progression of tauopathy. In this review, we lay the current perspectives on the principal genetic factors associated with AD and the potential causes, highlighting the contribution of somatic mutations to the pathogenesis of late onset Alzheimer’s disease. The roles that artificial intelligence and big data can play in accelerating the progress of causal somatic mutation markers/biomarkers identification, and the associated drug discovery/repurposing, have been highlighted for future AD and other neurodegenerations, with the aim to bring hope for the vulnerable aging population. Show more

Keywords: Alzheimer’s disease, amyloid-β peptide, artificial intelligence, big data, late onset Alzheimer’s disease, somatic mutations, tau

DOI: 10.3233/JAD-220643

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 475-493, 2022

Authors: Xu, Chang | Zhao, Li | Dong, Chunbo

Article Type: Review Article

Abstract: The number of patients with Alzheimer’s disease (AD) and non-Alzheimer’s disease (non-AD) has drastically increased over recent decades. The amyloid cascade hypothesis attributes a vital role to amyloid-β protein (Aβ) in the pathogenesis of AD. As the main pathological hallmark of AD, amyloid plaques consist of merely the 42 and 40 amino acid variants of Aβ (Aβ42 and Aβ40 ). The cerebrospinal fluid (CSF) biomarker Aβ42/40 has been extensively investigated and eventually integrated into important diagnostic tools to support the clinical diagnosis of AD. With the development of highly sensitive assays and technologies, blood-based Aβ42/40 , which was …obtained using a minimally invasive and cost-effective method, has been proven to be abnormal in synchrony with CSF biomarker values. This paper presents the recent progress of the CSF Aβ42/40 ratio and plasma Aβ42/40 for AD as well as their potential clinical application as diagnostic markers or screening tools for dementia. Show more

Keywords: Alzheimer’s disease, amyloid-β, biomarker, cerebrospinal fluid, plasma

DOI: 10.3233/JAD-220673

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 495-512, 2022

Authors: Rai, Harleen Kaur | Kernaghan, David | Schoonmade, Linda | Egan, Kieren J. | Pot, Anne Margriet

Article Type: Systematic Review

Abstract: Background: Dementia poses significant and sustained challenges to global society. Diagnosis can lead to increased feelings of loneliness and social isolation. People with dementia living alone are particularly at risk. Considering the growing number of technologies proposed to aid people with dementia address social isolation and loneliness, we reviewed the existing literature. Objective: To collate and summarize current evidence for digital technologies to prevent social isolation and loneliness for people with dementia. Methods: Following the PRISMA guidelines, we systematically searched five databases to identify studies of digital technologies designed to support or prevent social isolation or …loneliness for people with dementia. Pre-specified outcomes included social isolation, loneliness, and quality of life. We used deductive thematic analysis to synthesize the major themes emerging from the studies. Results: Ten studies met our inclusion criteria where all studies reported improvements in quality of life and seven reported benefits regarding social inclusion or a reduction in loneliness. Technologies were varied across purpose, delivery format, theoretical models, and levels of personalization. Two studies clearly described the involvement of people with dementia in the study design and five technologies were available outside the research context. Conclusion: There is limited— but increasing— evidence that technologies hold potential to improve quality of life and reduce isolation/loneliness for people with dementia. Results presented are largely based in small-scale research studies. Involvement of people with dementia was limited and few research concepts are reaching implementation. Closer collaboration with people with dementia to provide affordable, inclusive, and person-centered solutions is urgently required. Show more

Keywords: Dementia, digital technology, loneliness, quality of life, social isolation

DOI: 10.3233/JAD-220438

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 513-528, 2022

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

Article Type: Research Article

Abstract: In recent years, the association between the activity of platelets and risk of Alzheimer’s disease (AD) risk has been noticed in numerous studies. However, there in no investigations on the role of specific intracellular pathways to explain this connection. The phosphatidylinositol 3 kinase (PI3K)/AKT pathway is one of the main regulators of cell survival which regulates cellular responses to environmental changes. This pathway also regulates the activity of platelets, and its aberrant activity has been linked to platelet dysfunction in different pathologies. On the other hand, the PI3K/AKT pathway regulates amyloid-β (Aβ) production through regulation of amyloid-β protein precursor (AβPP), …BACE-1, ADAMs, and γ -secretase. In addition, alterations in the activity of all of these factors in platelets has been shown in AD-related pathologies. Therefore, this paper aims to introduce the PI3K/AKT pathway as a molecular inducer of platelet dysfunction during aging and AD progression. Show more

Keywords: Alzheimer’s disease, amyloid, PI3K/AKT, platelet

DOI: 10.3233/JAD-220663

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 529-534, 2022

Authors: Palmer, Jacqueline A. | Kaufman, Carolyn S. | Vidoni, Eric D. | Honea, Robyn A. | Burns, Jeffrey M. | Billinger, Sandra A.

Article Type: Short Communication

Abstract: Sex as a biological variable appears to contribute to the multifactorial etiology of Alzheimer’s disease. We tested sex-based interactions between cerebrovascular function and APOE4 genotype on resistance and resilience to brain pathology and cognitive executive dysfunction in cognitively-normal older adults. Female APOE4 carriers had higher amyloid-β deposition yet achieved similar cognitive performance to males and female noncarriers. Further, female APOE4 carriers with robust cerebrovascular responses to exercise possessed lower amyloid-β. These results suggest a unique cognitive resilience and identify cerebrovascular function as a key mechanism for resistance to age-related brain pathology in females with high genetic vulnerability …to Alzheimer’s disease. Show more

Keywords: Aging, Apolipoproteins E, amyloid, cardiovascular system, cerebrovascular circulation, cognition, female, hemodynamics, ultrasound

DOI: 10.3233/JAD-220359

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 535-542, 2022

Authors: Vipin, Ashwati | Koh, Chen Ling | Wong, Benjamin Yi Xin | Zailan, Fatin Zahra | Tan, Jayne Yi | Soo, See Ann | Satish, Vaynii | Kumar, Dilip | Wang, Brian Zhiyang | Ng, Adeline Su Lyn | Chiew, Hui Jin | Ng, Kok Pin | Kandiah, Nagaendran

Article Type: Short Communication

Abstract: We examined amyloid-tau-neurodegeneration biomarker effects on cognition in a Southeast-Asian cohort of 84 sporadic young-onset dementia (YOD; age-at-onset <65 years) patients. They were stratified into A+N+, A– N+, and A– N– profiles via cerebrospinal fluid amyloid-β1–42 (A), phosphorylated-tau (T), MRI medial temporal atrophy (neurodegeneration– N), and confluent white matter hyperintensities cerebrovascular disease (CVD). A, T, and CVD effects on longitudinal Mini-Mental State Examination (MMSE) were evaluated. A+N+ patients demonstrated steeper MMSE decline than A– N+ (β = 1.53; p  = 0.036; CI 0.15:2.92) and A– N– (β = 4.68; p  = 0.001; CI 1.98:7.38) over a mean follow-up of 1.24 years. Within A– N+, T– …CVD+ patients showed greater MMSE decline compared to T+CVD– patients (β = – 2.37; p  = 0.030; CI – 4.41:– 0.39). A+ results in significant cognitive decline, while CVD influences longitudinal cognition in the A– sub-group. Show more

Keywords: ATN profile, cognition, longitudinal, Southeast Asian cohort, young-onset dementia

DOI: 10.3233/JAD-220448

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 543-551, 2022

Authors: Crockett, Rachel A. | Hsu, Chun Liang | Dao, Elizabeth | Tam, Roger | Eng, Janice J. | Handy, Todd C. | Liu-Ambrose, Teresa

Article Type: Research Article

Abstract: Background: White matter hyperintensities (WMH) are associated with impaired cognition and increased falls risk. Resistance training (RT) is a promising intervention to reduce WMH progression, improve executive functions, and reduce falls. However, the underlying neurobiological process by which RT improves executive functions and falls risk remain unclear. We hypothesized that: 1) RT reduces the level of WMH-related disruption to functional networks; and 2) reduced disruption to the sensorimotor and attention networks will be associated with improved executive function and reduced falls risk. Objective: Investigate the impact of 52 weeks of RT on WMH-related disruption to functional networks. …Methods: Thirty-two older females (65–75 years) were included in this exploratory analysis of a 52-week randomized controlled trial. Participants received either twice-weekly RT or balance and tone training (control). We used lesion network mapping to assess changes in WMH-related disruption to the sensorimotor, dorsal attention, and ventral attention networks. Executive function was measured using the Stroop Colour-Word Test. Falls risk was assessed using the Physiological Profile Assessment (PPA) and the foam sway test. Results: RT significantly reduced the level of WMH-related disruption to the sensorimotor network (p  = 0.012). Reduced disruption to the dorsal attention network was associated with improvements in Stroop performance (r  = 0.527, p  = 0.030). Reduced disruption to the ventral attention network was associated with reduced PPA score (r  = 0.485, p  = 0.049) Conclusion: RT may be a promising intervention to mitigate WMH-related disruption to the sensorimotor network. Additionally, reducing disruption to the dorsal and ventral attention networks may contribute to improved executive function and reduced falls risk respectively. Show more

Keywords: Cognition, executive functions, exercise, falls risk, functional connectivity, resistance training

DOI: 10.3233/JAD-220142

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 553-563, 2022

Authors: Dentoni, Giacomo | Naia, Luana | Portal, Benjamin | Leal, Nuno Santos | Nilsson, Per | Lindskog, Maria | Ankarcrona, Maria

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) research has relied on mouse models overexpressing human mutant A βPP ; however, newer generation knock-in models allow for physiological expression of amyloid-β protein precursor (AβPP) containing familial AD mutations where murine AβPP is edited with a humanized amyloid-β (Aβ) sequence. The AppNL -F mouse model has shown substantial similarities to AD brains developing late onset cognitive impairment. Objective: In this study, we aimed to characterize mature primary cortical neurons derived from homozygous AppNL -F embryos, especially to identify early mitochondrial alterations in this model. …Methods: Primary cultures of AppNL -F neurons kept in culture for 12–15 days were used to measure Aβ levels, secretase activity, mitochondrial functions, mitochondrial-ER contacts, synaptic function, and cell death. Results: We detected higher levels of Aβ42 released from AppNL -F neurons as compared to wild-type neurons. AppNL -F neurons, also displayed an increased Aβ42 /Aβ40 ratio, similar to adult AppNL -F mouse brain. Interestingly, we found an upregulation in mitochondrial oxygen consumption with concomitant downregulation in glycolytic reserve. Furthermore, AppNL -F neurons were more susceptible to cell death triggered by mitochondrial electron transport chain inhibition. Juxtaposition between ER and mitochondria was found to be substantially upregulated, which may account for upregulated mitochondrial-derived ATP production. However, anterograde mitochondrial movement was severely impaired in this model along with loss in synaptic vesicle protein and impairment in pre- and post-synaptic function. Conclusion: We show that widespread mitochondrial alterations can be detected in AppNL -F neurons in vitro , where amyloid plaque deposition does not occur, suggesting soluble and oligomeric Aβ-species being responsible for these alterations. Show more

Keywords: Alzheimer’s disease, AppNL-F knock-in mice, mitochondria, mitochondria-ER contact sites, synapses

DOI: 10.3233/JAD-220383

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 565-583, 2022

Authors: Zarbock, Katie R. | Han, Jessica H. | Singh, Ajay P. | Thomas, Sydney P. | Bendlin, Barbara B. | Denu, John M. | Yu, John-Paul J. | Rey, Federico E. | Ulland, Tyler K.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the most common aging-associated neurodegenerative disease; nevertheless, the etiology and progression of the disease is still incompletely understood. We have previously shown that the microbially-derived metabolite trimethylamine N -oxide (TMAO) is elevated in the cerebrospinal fluid (CSF) of individuals with cognitive impairment due to AD and positively correlates with increases in CSF biomarkers for tangle, plaque, and neuronal pathology. Objective: We assessed the direct impact of TMAO on AD progression. Methods: To do so, transgenic 5XFAD mice were supplemented with TMAO for 12 weeks. Neurite density was assessed through quantitative brain …microstructure imaging with neurite orientation dispersion and density imaging magnetic resonance imaging (MRI). Label-free, quantitative proteomics was performed on cortex lysates from TMAO-treated and untreated animals. Amyloid-β plaques, astrocytes, and microglia were assessed by fluorescent immunohistochemistry and synaptic protein expression was quantified via western blot. Results: Oral TMAO administration resulted in significantly reduced neurite density in several regions of the brain. Amyloid-β plaque mean intensity was reduced, while plaque count and size remained unaltered. Proteomics analysis revealed that TMAO treatment impacted the expression of 30 proteins (1.5-fold cut-off) in 5XFAD mice, including proteins known to influence neuronal health and amyloid-β precursor protein processing. TMAO treatment did not alter astrocyte and microglial response nor cortical synaptic protein expression. Conclusion: These data suggest that elevated plasma TMAO impacts AD pathology via reductions in neurite density. Show more

Keywords: Alzheimer’s disease, neurites, trimethylamine N-oxide

DOI: 10.3233/JAD-220413

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 585-597, 2022

Authors: Chino, Brenda | Zegarra-Valdivia, Jonathan | de Frutos-Lucas, Jaisalmer | Paredes-Manrique, Carmen | Custodio, Nilton

Article Type: Research Article

Abstract: Background: Cognitive impairment and dementia may result from a combination of modifiable and nonmodifiable risk and protective factors, such as the environment, educational attainment, time devoted to cognitively stimulating activities, and physical activity. Objective: This study aimed to investigate the mediating role of sociodemographic characteristics and lifestyle factors in the years of education and cognitive performance in Peruvian adults. Methods: This cross-sectional study included 1,478 subjects assessed by Addenbrooke’s Cognitive Examination Revised (ACE-R). Using mediation models, we evaluated the mediation role of parents’ educational level, reading time (RT), and physical activity time (PAT) in the years …of education (IYE) and cognitive performance. Results: People who reported having lived in an urban area during their childhood are estimated to have, on average, 2.085 years more formal education than those who lived in rural areas. In addition, 49% of cognitive performance scores are explained by the mediation effect of reading and physical activity time in the IYE. This implies that higher levels of education, mediated by RT and PAT per week, are 1.596 units associated with higher scores on the ACE-R. Conclusion: Despite the fact that nonmodifiable factors (i.e., childhood residence area, parents’ educational level) seem to exert an effect on older adults’ cognition, their influence is mediated by other factors that are indeed modifiable (i.e., reading time, physical activity engagement). In this sense, lifestyle changes could help prevent or decrease the risk of cognitive impairment and reduce the disease’s impact on vulnerable environments in Latin American and Caribbean countries. Show more

Keywords: Aging, cognitive performance, lifestyle, sociodemographic characteristics, vulnerable populations

DOI: 10.3233/JAD-220428

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 599-608, 2022

Authors: Wang, Zhuo | Wang, Jie | Liu, Ning | Liu, Caiyan | Li, Xiuxing | Dong, Liling | Zhang, Rui | Mao, Chenhui | Duan, Zhichao | Zhang, Wei | Gao, Jing | Wang, Jianyong

Article Type: Research Article

Abstract: Background: Accurate, cheap, and easy to promote methods for dementia prediction and early diagnosis are urgently needed in low- and middle-income countries. Integrating various cognitive tests using machine learning provides promising solutions. However, most effective machine learning models are black-box models that are hard to understand for doctors and could hide potential biases and risks. Objective: To apply cognitive-test-based machine learning models in practical dementia prediction and diagnosis by ensuring both interpretability and accuracy. Methods: We design a framework adopting Rule-based Representation Learner (RRL) to build interpretable diagnostic rules based on the cognitive tests selected by …doctors. According to the visualization and test results, doctors can easily select the final rules after analysis and trade-off. Our framework is verified on the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset (n  = 606) and Peking Union Medical College Hospital (PUMCH) dataset (n  = 375). Results: The predictive or diagnostic rules learned by RRL offer a better trade-off between accuracy and model interpretability than other representative machine learning models. For mild cognitive impairment (MCI) conversion prediction, the cognitive-test-based rules achieve an average area under the curve (AUC) of 0.904 on ADNI. For dementia diagnosis on subjects with a normal Mini-Mental State Exam (MMSE) score, the learned rules achieve an AUC of 0.863 on PUMCH. The visualization analyses also verify the good interpretability of the learned rules. Conclusion: With the help of doctors and RRL, we can obtain predictive and diagnostic rules for dementia with high accuracy and good interpretability even if only cognitive tests are used. Show more

Keywords: Deep learning, dementia, interpretability, machine learning, neuropsychological tests

DOI: 10.3233/JAD-220502

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 609-624, 2022

Authors: Rovčanin Dragović, Isidora | Popović, Nataša | Ždralević, Maša | Radulović, Ljiljana | Vuković, Tijana | Marzano, Flaviana | Tullo, Apollonia | Radunović, Miodrag

Article Type: Research Article

Abstract: Background: Pathological and clinical features of Alzheimer’s disease (AD) are in temporal discrepancy and currently accepted clinical tests provide the diagnosis decades after the initial pathophysiological events. In order to enable a more timely detection of AD, research efforts are directed to identification of biomarkers of the early symptomatic stage. Neuroinflammatory signaling pathways and inflammation-related microRNAs (miRNAs) could possibly have a crucial role in AD, making them promising potential biomarkers. Objective: We examined the expression of circulatory miRNAs with a documented role in AD pathophysiology: miR-29a/b, miR-101, miR-125b, miR-146a, and miR-155 in the plasma of AD patients (AD, …n  = 12), people with mild cognitive impairment (MCI, n  = 9), and normocognitive group (CTRL, n  = 18). We hypothesized that these miRNA expression levels could correlate with the level of participants’ cognitive decline. Methods: The study participants completed the standardized interview, neurological examination, neuropsychological assessment, and biochemical analyses. miRNA expression levels were assessed by RT-PCR. Results: Neurological and laboratory findings could not account for MCI, but miR-146a and -155 were upregulated in the MCI group compared to the control. miR-146a, known to mediate early neuroinflammatory AD events, was also upregulated in the MCI compared to AD group. ROC curve analysis for miRNA-146a showed 77.8% sensitivity and 94.4% specificity and 66.7% sensitivity and 88.9% specificity for miR-155. Conclusion: Determination of circulatory inflamma-miRs-146a and -155 expression, together with neuropsychological screening, could become a non-invasive tool for detecting individuals with an increased risk for AD, but research on a larger cohort is warranted. Show more

Keywords: Alzheimer’s disease, mild cognitive impairment, miR-146a, miR-155, neuroinflammation

DOI: 10.3233/JAD-220676

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 625-638, 2022

Authors: Godefroy, Valérie | Batrancourt, Bénédicte | Charron, Sylvain | Bouzigues, Arabella | Sezer, Idil | Bendetowicz, David | Carle, Guilhem | Rametti-Lacroux, Armelle | Bombois, Stéphanie | Cognat, Emmanuel | Migliaccio, Raffaella | Levy, Richard

Article Type: Research Article

Abstract: Background: Apathy is highly frequent in behavioral variant frontotemporal dementia (bvFTD). It is presumed to involve different pathophysiological mechanisms and neuroanatomical regions. Objective: We explored the hypothesis that subgroups showing distinct profiles of apathy and distinct patterns of atrophy within frontal lobes could be disentangled in bvFTD. Methods: Using data-driven clustering applied to 20 bvFTD patients, we isolated subgroups according to their profiles on the three subscales of the Dimensional Apathy Scale (DAS). We explored their apathy profiles and atrophy patterns. Apathy profiles were characterized through both subjective measures of apathy by questionnaires and measures including …objective behavioral metrics. Atrophy patterns were obtained by voxel-based morphometry, contrasting each bvFTD subgroup with healthy controls (N = 16). Results: By clustering based on DAS dimensions, we disentangled three subgroups of bvFTD patients, with distinct apathy profiles and atrophy patterns. One subgroup, which presented the smallest pattern of atrophy (including orbitofrontal cortex) with a right asymmetry, was characterized by high self-reported emotional and initiation apathy and by a self-initiation deficit reversible by external guidance. In other subgroups showing more diffuse bilateral atrophies extending to lateral prefrontal cortex, apathy was not reversible by external guidance and more difficulty to focus on goal-management was observed, especially in the subgroup with the largest atrophy and highest levels of executive apathy. Conclusion: Distinct clinical profiles of apathy, corresponding to distinct anatomical subtypes of bvFTD, were identified. These findings have implications for clinicians in a perspective of precision medicine as they could contribute to personalize treatments of apathy. Show more

Keywords: Apathy, apathy subtypes, exploratory clustering, frontotemporal dementia, grey matter atrophy, voxel-based morphometry

DOI: 10.3233/JAD-220370

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 639-654, 2022

Authors: Zhang, Yanchun | Li, Chenxi | Chen, Deqiang | Tian, Rui | Yan, Xinyue | Zhou, Yingwen | Song, Yancheng | Yang, Yanlong | Wang, Xiaoxuan | Zhou, Bo | Gao, Yuhong | Jiang, Yujuan | Zhang, Xi

Article Type: Research Article

Abstract: Background: Early intervention of amnestic mild cognitive impairment (aMCI) may be the most promising way for delaying or even preventing the progression to Alzheimer’s disease. Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that has been recognized as a promising approach for the treatment of aMCI. Objective: In this paper, we aimed to investigate the modulating mechanism of tDCS on the core neurocognitive networks of brain. Methods: We used repeated anodal high-definition transcranial direct current stimulation (HD-tDCS) over the left dorsolateral prefrontal cortex and assessed the effect on cognition and dynamic functional brain …network in aMCI patients. We used a novel method called temporal variability to depict the characteristics of the dynamic brain functional networks. Results: We found that true anodal stimulation significantly improved cognitive performance as measured by the Montreal Cognitive Assessment after simulation. Meanwhile, the Mini-Mental State Examination scores showed a clear upward trend. More importantly, we found significantly altered temporal variability of dynamic functional connectivity of regions belonging to the default mode network, central executive network, and the salience network after true anodal stimulation, indicating anodal HD-tDCS may enhance brain function by modulating the temporal variability of the brain regions. Conclusion: These results imply that ten days of anodal repeated HD-tDCS over the LDLPFC exerts beneficial effects on the temporal variability of the functional architecture of the brain, which may be a potential neural mechanism by which HD-tDCS enhances brain functions. Repeated HD-tDCS may have clinical uses for the intervention of brain function decline in aMCI patients. Show more

Keywords: High-definition transcranial direct current stimulation (HD-tDCS), mild cognitive disorder, temporal variability, triple network model

DOI: 10.3233/JAD-220539

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 655-666, 2022

Authors: Morrow, Autumn | Panyard, Daniel J. | Deming, Yuetiva K. | Jonaitis, Erin | Dong, Ruocheng | Vasiljevic, Eva | Betthauser, Tobey J. | Kollmorgen, Gwendlyn | Suridjan, Ivonne | Bayfield, Anna | Van Hulle, Carol A. | Zetterberg, Henrik | Blennow, Kaj | Carlsson, Cynthia M. | Asthana, Sanjay | Johnson, Sterling C. | Engelman, Corinne D.

Article Type: Research Article

Abstract: Background: Sphingomyelin (SM) levels have been associated with Alzheimer’s disease (AD), but the association direction has been inconsistent and research on cerebrospinal fluid (CSF) SMs has been limited by sample size, breadth of SMs examined, and diversity of biomarkers available. Objective: Here, we seek to build on our understanding of the role of SM metabolites in AD by studying a broad range of CSF SMs and biomarkers of AD, neurodegeneration, and neuroinflammation. Methods: Leveraging two longitudinal AD cohorts with metabolome-wide CSF metabolomics data (n  = 502), we analyzed the relationship between the levels of 12 CSF SMs, …and AD diagnosis and biomarkers of pathology, neurodegeneration, and neuroinflammation using logistic, linear, and linear mixed effects models. Results: No SMs were significantly associated with AD diagnosis, mild cognitive impairment, or amyloid biomarkers. Phosphorylated tau, neurofilament light, α -synuclein, neurogranin, soluble triggering receptor expressed on myeloid cells 2, and chitinase-3-like-protein 1 were each significantly, positively associated with at least 5 of the SMs. Conclusion: The associations between SMs and biomarkers of neurodegeneration and neuroinflammation, but not biomarkers of amyloid or diagnosis of AD, point to SMs as potential biomarkers for neurodegeneration and neuroinflammation that may not be AD-specific. Show more

Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid, metabolomics, neurodegeneration, neuroinflammation, sphingolipid, sphingomyelin

DOI: 10.3233/JAD-220349

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 667-680, 2022

Authors: Song, Yang | Quan, Meina | Li, Tingting | Jia, Jianping

Article Type: Research Article

Abstract: Background: Although elevated levels of homocysteine (Hcy) are associated with cognitive impairment and dementia, the relevance of Hcy, vitamin B12 , and folate levels to subtypes of dementia are still unknown. Objective: To investigate the changes of Hcy, vitamin B12 , and folate levels in mild cognitive impairment (MCI) and subtypes of dementia including Alzheimer’s disease (AD), vascular dementia (VaD), frontotemporal dementia (FTD), and Lewy body dementia (LBD), and their relationships with cognitive function and magnetic resonance imaging (MRI) markers. Methods: We measured serum levels of Hcy, vitamin B12 , and folate in 257 subjects. Each …subject underwent cognitive function assessment and brain MRI test. The Fazekas and temporal lobe atrophy (MTA) visual rating scales were used to assess the degree of white matter hyperintensities and MTA, respectively. Results: Serum levels of Hcy was higher and vitamin B12 was lower in AD, VaD, FTD, and LBD groups than cognitively normal controls. No significant differences of folate levels were found among 6 groups. Hcy levels were positively correlated with MTA total score in AD (r  = 0.448, p  < 0.001). Vitamin B12 levels were positively correlated with MoCA in VaD (r  = 0.497), and negatively correlated with MTA total score in AD (r  = – 0.325) (p s < 0.05). Hyperhomocysteinemia may increase the risk of AD (OR = 2.744), VaD (OR = 3.600), and FTD (OR = 3.244) in the adjusted model (p s < 0.05). Conclusion: Hcy and vitamin B12 levels are associated with MTA in AD. Vitamin B12 levels are associated with general cognition in VaD. Hyperhomocysteinemia is a risk factor for not only AD and VaD but also FTD. Show more

Keywords: Alzheimer’s disease, B vitamin, dementia, frontotemporal dementia, homocysteine, Lewy body dementia, mild cognitive impairment, vascular dementia

DOI: 10.3233/JAD-220410

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 681-691, 2022

Authors: Yamada, Yasunori | Kobayashi, Masatomo | Shinkawa, Kaoru | Nemoto, Miyuki | Ota, Miho | Nemoto, Kiyotaka | Arai, Tetsuaki

Article Type: Research Article

Abstract: Background: Early differential diagnosis of Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) is important for treatment and disease management, but it remains challenging. Although computer-based drawing analysis may help differentiate AD and DLB, it has not been studied. Objective: We aimed to identify the differences in features characterizing the drawing process between AD, DLB, and cognitively normal (CN) individuals, and to evaluate the validity of using these features to identify and differentiate AD and DLB. Methods: We collected drawing data with a digitizing tablet and pen from 123 community-dwelling older adults in three clinical …diagnostic groups of mild cognitive impairment or dementia due to AD (n  = 47) or Lewy body disease (LBD; n  = 27), and CN (n  = 49), matched for their age, sex, and years of education. We then investigated drawing features in terms of the drawing speed, pressure, and pauses. Results: Reduced speed and reduced smoothness in speed and pressure were observed particularly in the LBD group, while increased pauses and total durations were observed in both the AD and LBD groups. Machine-learning models using these features achieved an area under the receiver operating characteristic curve (AUC) of 0.80 for AD versus CN, 0.88 for LBD versus CN, and 0.77 for AD versus LBD. Conclusion: Our results indicate how different types of drawing features were particularly discriminative between the diagnostic groups, and how the combination of these features can facilitate the identification and differentiation of AD and DLB. Show more

Keywords: Cognitive impairment, dementia, digital biomarker, handwriting, machine learning

DOI: 10.3233/JAD-220546

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 693-704, 2022

Authors: Alvarez, X. Anton | Winston, Charisse N. | Barlow, James W. | Sarsoza, Floyd M. | Alvarez, Irene | Aleixandre, Manuel | Linares, Carlos | García-Fantini, Manuel | Kastberger, Birgit | Winter, Stefan | Rissman, Robert A.

Article Type: Research Article

Abstract: Background: Plasma neuronal-derived extracellular vesicles (NDEV) contain proteins of pathological, diagnostic, and therapeutic relevance. Objective: We investigated the associations of six plasma NDEV markers with Alzheimer’s disease (AD) severity, cognition and functioning, and changes in these biomarkers after Cerebrolysin®, donepezil, and a combination therapy in AD. Methods: Plasma NDEV levels of Aβ42 , total tau, P-T181-tau, P-S393-tau, neurogranin, and REST were determined in: 1) 116 mild to advanced AD patients and in 20 control subjects; 2) 110 AD patients treated with Cerebrolysin®, donepezil, or combination therapy in a randomized clinical trial (RCT). Samples for NDEV determinations …were obtained at baseline in the NDEV study and at baseline and study endpoint in the RCT. Cognition and functioning were assessed at the same time points. Results: NDEV levels of Aβ42 , total tau, P-T181-tau, and P-S393-tau were higher and those of neurogranin and REST were lower in mild-to-moderate AD than in controls (p  < 0.05 to p  < 0.001). NDEV total tau, neurogranin, and REST increased with AD severity (p  < 0.05 to p  < 0.001). NDEV Aβ42 and P-T181-tau correlated negatively with serum BDNF (p  < 0.05), and total-tau levels were associated to plasma TNF-α (p  < 0.01) and cognitive impairment (p  < 0.05). Combination therapy reduced NDEV Aβ42 with respect to monotherapies (p  < 0.05); and NDEV total tau, P-T181-tau, and P-S396-tau were decreased in Cerebrolysin-treated patients compared to those on donepezil monotherapy (p  < 0.05). Conclusion: The present results demonstrate the utility of NDEV determinations of pathologic and synaptic proteins as effective AD biomarkers, as markers of AD severity, and as potential tools for monitoring the effects of anti-AD drugs. Show more

Keywords: Aβ42 , Alzheimer disease, Cerebrolysin®, combination therapy, donepezil, plasma neuronal-derived extracellular vesicles, tau

DOI: 10.3233/JAD-220575

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 705-717, 2022

Authors: Villarejo-Galende, Alberto | García-Arcelay, Elena | Piñol-Ripoll, Gerard | del Olmo-Rodríguez, Antonio | Viñuela, Félix | Boada, Mercè | Franco-Macías, Emilio | Ibañez de la Peña, Almudena | Riverol, Mario | Puig-Pijoan, Albert | Abizanda-Soler, Pedro | Arroyo, Rafael | Baquero-Toledo, Miquel | Feria-Vilar, Inmaculada | Balasa, Mircea | Berbel, Ángel | Rodríguez-Rodríguez, Eloy | Vieira-Campos, Alba | García-Ribas, Guillermo | Rodrigo-Herrero, Silvia | Terrancle, Ángeles | Prefasi, Daniel | Lleó, Alberto | Maurino, Jorge

Article Type: Research Article

Abstract: Background: There is a need to better understand the experience of patients living with Alzheimer's disease (AD) in the early stages. Objective: The aim of the study was to evaluate the perception of quality of life in patients with early-stage AD. Methods: A multicenter, non-interventional study was conducted including patients of 50–90 years of age with prodromal or mild AD, a Mini-Mental State Examination (MMSE) score ≥22, and a Clinical Dementia Rating-Global score (CDR-GS) of 0.5.–1.0. The Quality of Life in Alzheimer ’s Disease (QoL-AD) questionnaire was used to assess health-related quality of life. A battery …of self-report instruments was used to evaluate different psychological and behavioral domains. Associations between the QoL-AD and other outcome measures were analyzed using Spearman’s rank correlations. Results: A total of 149 patients were included. Mean age (SD) was 72.3 (7.0) years and mean disease duration was 1.4 (1.8) years. Mean MMSE score was 24.6 (2.1). The mean QoL-AD score was 37.9 (4.5). Eighty-three percent (n = 124) of patients had moderate-to-severe hopelessness, 22.1% (n = 33) had depressive symptoms, and 36.9% (n = 55) felt stigmatized. The quality of life showed a significant positive correlation with self-efficacy and negative correlations with depression, emotional and practical consequences, stigma, and hopelessness. Conclusion: Stigma, depressive symptoms, and hopelessness are frequent scenarios in AD negatively impacting quality of life, even in a population with short disease duration and minimal cognitive impairment. Show more

Keywords: Alzheimer’s disease, amyloid, biomarkers, cerebrospinal fluid, magnetic resonance imaging, tau proteins, white matter hyperintensities, white matter lesions

DOI: 10.3233/JAD-220696

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 719-726, 2022

Authors: Sabbir, Mohammad Golam | Speth, Robert C. | Albensi, Benedict C.

Article Type: Research Article

Abstract: Background: Dysfunction of cholinergic neurotransmission is a hallmark of Alzheimer’s disease (AD); forming the basis for using acetylcholine (ACh) esterase (AChE) inhibitors to mitigate symptoms of ACh deficiency in AD. The Cholinergic Receptor Muscarinic 1 (CHRM1) is highly expressed in brain regions impaired by AD. Previous analyses of postmortem AD brains revealed unaltered CHRM1 mRNA expression compared to normal brains. However, the CHRM1 protein level in AD and other forms of dementia has not been extensively studied. Reduced expression of CHRM1 in AD patients may explain the limited clinical efficacy of AChE inhibitors. Objective: To quantify CHRM1 protein …in the postmortem hippocampus and temporal cortex of AD, Parkinson’s disease (PD), and frontotemporal dementia (FTD) patients. Methods: Western blotting was performed on postmortem hippocampus (N  = 19/73/7/9: unaffected/AD/FTD/PD) and temporal cortex (N  = 9/74/27: unaffected/AD/PD) using a validated anti-CHRM1 antibody. Results: Quantification based on immunoblotting using a validated anti-CHRM1 antibody revealed a significant loss of CHRM1 protein level (<50%) in the hippocampi (78% AD, 66% PD, and 85% FTD) and temporal cortices (56% AD and 42% PD) of dementia patients. Loss of CHRM1 in the temporal cortex was significantly associated with early death (<65–75 years) for both AD and PD patients. Conclusion: Severe reduction of CHRM1 in a subset of AD and PD patients can explain the reported low efficacy of AChE inhibitors as a mitigating treatment for dementia patients. Based on this study, it can be suggested that future research should prioritize therapeutic restoration of CHRM1 protein levels in cholinergic neurons. Show more

Keywords: Alzheimer’s disease, β-arrestin, Cholinergic Receptor Muscarinic 1, CHRM1, frontotemporal dementia, Parkinson’s disease, survival

DOI: 10.3233/JAD-220766

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 727-747, 2022

Authors: McClannahan, Katrina S. | Mainardi, Amelia | Luor, Austin | Chiu, Yi-Fang | Sommers, Mitchell S. | Peelle, Jonathan E.

Article Type: Research Article

Abstract: Background: Difficulty understanding speech is a common complaint of older adults. In quiet, speech perception is often assumed to be relatively automatic. However, higher-level cognitive processes play a key role in successful communication in noise. Limited cognitive resources in adults with dementia may therefore hamper word recognition. Objective: The goal of this study was to determine the impact of mild dementia on spoken word recognition in quiet and noise. Methods: Participants were 53–86 years with (n  = 16) or without (n  = 32) dementia symptoms as classified by the Clinical Dementia Rating scale. Participants performed a word identification …task with two levels of word difficulty (few and many similar sounding words) in quiet and in noise at two signal-to-noise ratios, +6 and +3 dB. Our hypothesis was that listeners with mild dementia symptoms would have more difficulty with speech perception in noise under conditions that tax cognitive resources. Results: Listeners with mild dementia symptoms had poorer task accuracy in both quiet and noise, which held after accounting for differences in age and hearing level. Notably, even in quiet, adults with dementia symptoms correctly identified words only about 80% of the time. However, word difficulty was not a factor in task performance for either group. Conclusion: These results affirm the difficulty that listeners with mild dementia may have with spoken word recognition, both in quiet and in background noise, consistent with a role of cognitive resources in spoken word identification. Show more

Keywords: Cognition, dementia, hearing, speech intelligibility, word processing

DOI: 10.3233/JAD-215606

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 749-759, 2022

Authors: Aerqin, Qiaolifan | Jia, Sha-Sha | Shen, Xue-Ning | Li, Quan | Chen, Ke-Liang | Ou, Ya-Nan | Huang, Yu-Yuan | Dong, Qiang | Chen, Shu-Fen | Yu, Jin-Tai

Article Type: Research Article

Abstract: Background: Excessive oxidative stress may contribute to neurodegeneration by leading to protein aggregation and mitochondrial dysfunction. Uric acid (UA) is an important endogenous antioxidant that protects against oxidative stress, yet its exact role in neurodegeneration remains unclear. Objective: To explore the performance of serum UA in neurodegenerative disorders. Methods: A total of 839 controls and 840 patients, including Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), dementia with Lewy bodies (DLB), motor neuron disease (MND), Creutzfeldt-Jakob disease (CJD), and mixed dementia (MixD) were enrolled. Fasting serum UA …levels were measured in all participants and compared between patients and controls. Linear regression models were utilized to explore possible relationships of serum UA with cognition, disease duration, age, and age of onset. Results: Compared to controls (355.48 ± 85.38 μmol/L), serum UA was significantly lower in AD (291.29 ± 83.49 μmol/L, p  < 0.001), PD (286.95 ± 81.78 μmol/L, p  < 0.001), PSP (313.32 ± 88.19 μmol/L, p  < 0.001), FTD (313.89 ± 71.18 μmol/L, p  = 0.001), and DLB (279.23 ± 65.51 μmol/L, p  < 0.001), adjusting for confounding factors including age, gender, education, etc. In addition, serum UA was positively correlated with cognitive levels in all patients (Mini-Mental State Examination: r = 0.136, p  = 0.001; and Montreal Cognitive Assessment Scale: r = 0.108, p  = 0.009). Conclusion: Decreased levels of serum UA were correlated with AD, PD, PSP, FTD, and DLB, offering significant potential as a promisingly relevant, less-invasive marker of multiple neurodegenerative disorders. Show more

Keywords: Cognition, neurodegeneration, oxidative stress, uric acid

DOI: 10.3233/JAD-220432

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 761-773, 2022

Authors: Shepherd-Banigan, Megan E. | Ford, Cassie B. | Smith, Valerie A. | Belanger, Emmanuelle | Wetle, Terrie T. | Plassman, Brenda L. | Burke, James R. | DePasquale, Nicole | O’Brien, Emily C. | Sorenson, Corinna | Van Houtven, Courtney H.

Article Type: Research Article

Abstract: Background: Diagnostic tests, such as amyloid-β positron emission tomography (PET) scans, can increase appropriate therapeutic management for the underlying causes of cognitive decline. To evaluate the full utility of this diagnostic tool, information is needed on whether results from amyloid-β PET scans influence care-partner outcomes. Objective: This study examines the extent to which previous disclosure of elevated amyloid (suggestive of Alzheimer’s disease (AD) etiology) versus not-elevated amyloid (not suggestive of AD etiology) is associated with changes in care-partner wellbeing. Methods: The study used data derived from a national longitudinal survey of Medicare beneficiaries (n  = 921) with …mild cognitive impairment (MCI) or dementia and their care-partners. Care-partner wellbeing outcomes included depressive symptoms (PHQ-8), subjective burden (4-item Zarit burden score), and a 3-item measure of loneliness. Change was measured between 4 (Time 1) and 18 (Time 2) months after receiving the scan results. Adjusted linear regression models regressed change (Time 2-Time 1) in each outcome on scan result. Results: Care-partners were primarily white, non-Hispanic, college-educated, and married to the care recipient. Elevated amyloid was not associated with statistically significant Time 1 differences in outcomes or with statistically significant changes in depressive symptoms 0.22 (–0.18, 0.61), subjective burden 0.36 (–0.01, 0.73), or loneliness 0.15 (–0.01, 0.32) for care-partners from one time point to another. Conclusion: Given advances in AD biomarker testing, future research in more diverse samples is needed to understand the influence of scan results on care-partner wellbeing across populations. Show more

Keywords: Amyloid-β, caregiver, dementia, depression, mild cognitive impairment, positron emission tomography

DOI: 10.3233/JAD-220611

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 775-782, 2022

Authors: Lin, Junhan | Yang, Siyu | Wang, Chao | Yu, Erhan | Zhu, Zhibao | Shi, Jinying | Li, Xiang | Xin, Jiawei | Chen, Xiaochun | Pan, Xiaodong

Article Type: Research Article

Abstract: Background: DNA methylation is expected to become a kind of new diagnosis and treatment method of Alzheimer’s disease (AD). Neuroinflammation- and immune-related pathways represent one of the major genetic risk factors for AD. Objective: We aimed to investigate DNA methylation levels of 7 key immunologic-related genes in peripheral blood and appraise their applicability in the diagnosis of AD. Methods: Methylation levels were obtained from 222 participants (101 AD, 72 MCI, 49 non-cognitively impaired controls). Logistic regression models for diagnosing AD were established after least absolute shrinkage and selection operator (LASSO) and best subset selection (BSS), evaluated …by respondent working curve and decision curve analysis for sensitivity. Results: Six differentially methylated positions (DMPs) in the MCI group and 64 in the AD group were found, respectively. Among them, there were 2 DMPs in the MCI group and 30 DMPs in the AD group independent of age, gender, and APOE4 carriers (p  <  0.05). AD diagnostic prediction models differentiated AD from normal controls both in a training dataset (LASSO: 8 markers, including methylation levels at ABCA7 1040077 , CNR1 88166293 , CX3CR1 39322324 , LRRK2 40618505 , LRRK2 40618493 , NGFR 49496745 , TARDBP 11070956 , TARDBP 11070840 area under the curve [AUC] = 0.81; BSS: 2 markers, including methylation levels at ABCA7 1040077 and CX3CR1 39322324 , AUC = 0.80) and a testing dataset (AUC = 0.84, AUC = 0.82, respectively). Conclusion: Our work indicated that methylation levels of 7 key immunologic-related genes (ABCA7 , CNR1 , CX3CR1 , CSF1R , LRRK2 , NGFR , and TARDBP ) in peripheral blood was altered in AD and the models including methylation of immunologic-related genes biomarkers improved prediction of AD. Show more

Keywords: Alzheimer’s disease, clinical prediction model, immunologic-related genes, methylation, mild cognitive impairment

DOI: 10.3233/JAD-220701

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 783-794, 2022

Authors: Guo, Qian | Cai, Qinfeng | Huang, Fang | Wei, Zhen | Wang, Jian-Zhi | Zhang, Bin | Liu, Rong | Yang, Yang | Wang, Xiaochuan | Li, Hong-Lian

Article Type: Research Article

Abstract: Background: As an acetylcholinesterase inhibitor (AChEI), Huperzine-A (Hup-A) is marketed for treatment of mild to moderate Alzheimer’s disease (AD) for decades in China. However, Hup-A causes some side effects. To search for new analogs or derivatives of Hup-A, we produced five Lycopodium alkaloids and two analogues by chemical synthesis: Lyconadins A-E, H-R-NOB, and 2JY-OBZ4. Objective: To systematically evaluate the therapeutic effects of the seven compounds on AD cell models. Methods: We assessed the effects of the seven compounds on cell viability via CCK-8 kit and used HEK293-hTau cells and N2a-hAPP cells as AD cell models to …evaluate their potential therapeutic effects. We examined their effects on cholinesterase activity by employing the mice primary neuron. Results: All compounds did not affect cell viability; in addition, Lyconadin A and 2JY-OBZ4 particularly increased cell viability. Lyconadin D and Lyconadin E restored tau phosphorylation at Thr231, and H-R-NOB and 2JY-OBZ4 restored tau phosphorylation at Thr231 and Ser396 in GSK-3β-transfected HEK293-hTau cells. 2JY-OBZ4 decreased the level of PP2Ac-pY307 and increased the level of PP2Ac-mL309, supporting that 2JY-OBZ4 may activate PP2A. Lyconadin B, Lyconadin D, Lyconadin E, H-R-NOB, and 2JY-OBZ4 increased sAβPPα level in N2a-hAPP cells. 2JY-OBZ4 decreased the levels of BACE1 and sAβPPβ, thereby reduced Aβ production. Seven compounds exhibited weaker AChE activity inhibition efficiency than Hup-A. Among them, 2JY-OBZ4 showed the strongest AChE inhibition activity with an inhibition rate of 17% at 10μM. Conclusion: Among the seven Lycopodium compounds, 2JY-OBZ4 showed the most expected effects on promoting cell viability, downregulating tau hyperphosphorylation, and Aβ production and inhibiting AChE in AD. Show more

Keywords: Alzheimer’s disease, beta-Secretase 1, cholinesterase inhibitor, Lycopodium alkaloid, protein phosphatase-2A

DOI: 10.3233/JAD-220704

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 795-809, 2022

Authors: Blivet, Guillaume | Relano-Gines, Aroa | Wachtel, Mélanie | Touchon, Jacques

Article Type: Research Article

Abstract: Background: Recent innovative non-pharmacological interventions and neurostimulation devices have shown potential for application in the treatment of Alzheimer’s disease (AD). These include photobiomodulation (PBM) therapy. Objective: This pilot study assesses the safety, compliance with, and efficacy of a brain-gut PBM therapy for mild-to-moderate AD patients. Methods: This double-blind, randomized, monocentric sham-controlled study started in 2018 and ended prematurely in 2020 due to the COVID-19 pandemic. Fifty-three mild-to-moderate AD patients were randomized, 27 in the PBM group and 26 in the sham group. All patients had 40 treatment sessions lasting 25 min each over 8 weeks and were …followed for 4 weeks afterwards. Compliance with the treatment was recorded. Safety was assessed by recording adverse events (AEs), and efficacy was evaluated using neuropsychological tests. Results: The PBM therapy proved to be safe in regard to the number of recorded AEs (44% of the patients), which were balanced between the PBM and sham groups. AEs were mainly mild, and no serious AEs were reported. The majority of the patients (92.5%) were highly compliant, which confirms the feasibility of the PBM treatment. Compared to the sham patients, the PBM patients showed lower ADAS-Cog comprehension subscores, higher forward verbal spans, and lower TMT-B execution times, which suggests an improvement in cognitive functions. Conclusion: This study demonstrates the tolerability of and patient compliance with a PBM-based treatment for mild-to-moderate AD patients. It highlights encouraging efficacy trends and provides insights for the design of the next phase trial in a larger AD patient sample. Show more

Keywords: Alzheimer’s disease, brain-gut axis, cognition, dementia, memory, neurodegenerative diseases, optics and photonics, photobiomodulation

DOI: 10.3233/JAD-220467

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 811-822, 2022

Authors: Valles-Salgado, María | Cabrera-Martín, María Nieves | Curiel-Cid, Rosie E. | Delgado-Álvarez, Alfonso | Delgado-Alonso, Cristina | Gil-Moreno, María José | Matías-Guiu, Jorge | Loewenstein, David A. | Matias-Guiu, Jordi A.

Article Type: Research Article

Abstract: Background: LASSI-L is a novel neuropsychological test specifically designed for the early diagnosis of Alzheimer’s disease (AD) based on semantic interference. Objective: To examine the cognitive and neural underpinnings of the failure to recover from proactive semantic and retroactive semantic interference. Methods: One hundred and fifty-five patients consulting for memory loss were included. Patients underwent neuropsychological assessment, including the LASSI-L, and FDG-PET imaging. They were categorized as subjective memory complaints (SMC) (n=32), pre-mild cognitive impairment (MCI) due to AD (Pre-MCI) (n=39), MCI due to AD (MCI-AD) (n=71), and MCI without evidence of neurodegeneration (MCI-NN) (n=13). Voxel-based …brain mapping and metabolic network connectivity analyses were conducted. Results: A significant group effect was found for all the LASSI-L scores. LASSI-L scores measuring failure to recover from proactive semantic interference and retroactive semantic interference were predicted by other neuropsychological tests with a precision of 64.1 and 44.8%. The LASSI-L scores were associated with brain metabolism in the bilateral precuneus, superior, middle and inferior temporal gyri, fusiform, angular, superior and inferior parietal lobule, superior, middle and inferior occipital gyri, lingual gyrus, and posterior cingulate. Connectivity analysis revealed a decrease of node degree and centrality in posterior cingulate in patients showing frPSI. Conclusion: Episodic memory dysfunction and the involvement of the medial temporal lobe, precuneus and posterior cingulate constitute the basis of the failure to recover from proactive semantic interference and retroactive semantic interference. These findings support the role of the LASSI-L in the detection, monitoring and outcome prediction during the early stages of AD. Show more

Keywords: Alzheimer’s disease, connectivity, FDG-PET, interference, memory, mild cognitive impairment, neuropsychological assessment

DOI: 10.3233/JAD-220754

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 823-840, 2022

Authors: Shen, Wei-Bin | Elahi, Montasir | Wang, Bingbing | Zhan, Min | Yang, Penghua | Yang, Peixin

Article Type: Research Article

Abstract: Background: The cascade of events that lead to Alzheimer’s disease (AD) consists of several possible underlying signal transduction pathways. Apoptosis signal-regulating kinase 1 (ASK1) and insulin receptor (IR) signaling are implicated in AD. Objective: We aimed to determine whether ASK1 activation and IR signaling impairment occurred prior to and during overt AD. Methods: Immunostaining, immunoblotting, and quantitative PCR were used to assess the levels of ASK1 and IR signaling intermediates. Glucose uptake was determined in AD-patient derived inducible pluripotent stem cells (iPSCs). Results: ASK1 signaling was activated in postmortem brain tissues acquired from APOE4 …carriers, a causative heritable factor, and in brain tissues of AD subjects in comparison with those harboring the normal APOE3 variant, which was manifested with an increased phosphorylated ASK1 (p-ASK1) and reduced thioredoxin 1 (TRX1). ASK1 downstream signaling effectors were also significantly elevated in these APOE4 carriers and AD brain tissues. Increased insulin receptor substrate 1 (IRS1) phosphorylation at serine residues, and decreased p-AKT1, p-IRβ, and GLUT3 expression were present in all APOE4 carriers and AD samples, suggesting impaired IR signaling leading to insulin resistance. ASK1 activation, IR signaling impairment, and GLUT3 reduction were also present in young AD transgenic mice prior to AD syndromes, AD mice at AD neuropathology onset, and AD iPSCs and their derived neurons prior to p-Tau aggregation. Conclusion: We conclude that the activation of oxidative stress-responsive kinases and reduced IR signaling precede and are persistent in AD pathogenesis. Our data further suggest possible crosstalk between ASK1 signaling and insulin resistance in AD etiology. Show more

Keywords: Alzheimer’s disease, ASK1 signaling, GLUT3, insulin resistance, metabolic dysregulation, neuropathology, oxidative stress

DOI: 10.3233/JAD-215687

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 841-857, 2022

Authors: Souza, Melyssa Alves | Peres Bomfim, Larissa Gomes | de Barros, Vinicius Lúcio | Medeiros Jr , Reinaldo Coelho | Ginsicke, Danielle Cristine | Colovati, Mileny Esbravatti Stephano | Daly, Timothy | Zanesco, Angelina

Article Type: Research Article

Abstract: Background: Modifiable risk factors exert crucial impact on dementia. Objective: We sought to answer the question: do two modifiable risk factors, schooling level and physical activity (PA), affect cognitive function similarly in each sex? Methods: This cross-sectional study was conducted in 2019 and 2021, and the survey was applied to the residents of the metropolitan area of Santos, a seashore of Sao Paulo State. Four hundred and twenty-two participants (women = 254 and men = 168) were eligible. Baecke questionnaire for the elderly was applied for the classification as physically inactive (PI) or active (PA). Cognitive function was assessed by …the Mini-Mental State Examination (MMSE) and the Clinical Dementia Rating (CDR). Participants were also stratified by schooling status for both sexes. Results: Higher education had a sex-independent positive influence on MMSE and CDR (p  < 0.001). PA influences positively MMSE in older women (PI: 25±5 and PA: 27±3, p  < 0.03), but has no effect in older men (26±5 and 25±5, p  > 0.05). Concordantly, older women who were PA (1.7 and 0 %) showed a lower prevalence of dementia compared with PI (6.2 and 2.1%), for mild and moderate respectively. Active older women had higher odds of improving the MMSE score (OR: 1.093; 95% CI: 1.008–1.186) than men (OR: 0.97 (95% CI: 0.896–1.051). Conclusion: Education affects cognitive function equally in Brazilian elderly whereas older women are more responsive to the beneficial effects of PA for dementia than men. Show more

Keywords: Cognitive function, physical activity, schooling status, sex difference

DOI: 10.3233/JAD-220517

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 859-867, 2022

Authors: Rabi, Rahel | Chow, Ricky | Paracha, Shahier | Hasher, Lynn | Gardner, Sandra | Anderson, Nicole D. | Alain, Claude

Article Type: Research Article

Abstract: Background: Amnestic mild cognitive impairment (aMCI), a prodromal phase of Alzheimer’s disease (AD), is characterized by episodic memory dysfunction, but inhibitory deficits have also been commonly reported. Time of day (TOD) effects have been confirmed in 1) healthy aging on cognitive processes such as inhibitory control, and 2) on behavior in AD (termed the sundowning effect), but no such research has addressed aMCI. Objective: The present study examined the impact of TOD on the behavioral and electrophysiological correlates of inhibition in 54 individuals with aMCI and 52 healthy controls (HCs), all of morning chronotype. Methods: Participants …were randomly assigned to complete two inhibition tasks (Go-NoGo and Flanker) during their optimal (morning) or non-optimal (evening) TOD, while electroencephalography was recorded. Results: Both tasks elicited changes in N2 and P3 event-related potential (ERP) components, which commonly index inhibitory functioning. Analyses showed that the Go-NoGo difference in P3 amplitude was reduced in individuals with aMCI relative to HCs. Compared to HCs, the Flanker difference in P3 amplitude was also reduced and coincided with more errors in the aMCI group. Notably, these behavioral and ERP differences were exaggerated in the non-optimal TOD relative to the optimal TOD. Conclusion: Findings confirm the presence of inhibition deficits in aMCI and provide novel evidence of sundowning effects on inhibitory control in aMCI. Results reinforce the need to consider the influences of TOD in clinical assessments involving individuals with aMCI. Show more

Keywords: Amnestic mild cognitive impairment, circadian rhythms, chronotype, executive functions, Flanker task, Go-NoGo task

DOI: 10.3233/JAD-220580

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 869-890, 2022

Authors: Wu, Xinxing | Peng, Chong | Nelson, Peter T. | Cheng, Qiang

Article Type: Research Article

Abstract: Background: The progression of Alzheimer’s disease (AD) varies in different patients at different stages, which makes predicting the time of disease conversions challenging. Objective: We established an algorithm by leveraging machine learning techniques to predict the probability of the conversion time to next stage for different subjects during a given period. Methods: Firstly, we used Kaplan-Meier (KM) estimation to get the transition curves of different AD stages, and calculated Log-rank statistics to test whether the progression rate between different stages was identical. This quantitatively confirmed the progression rates known in the literature. Then, we developed an …approach based on deep learning model, DeepSurv, to predict the probabilities of time-to-conversion. Finally, to help interpret the deep learning model in our approach, we identified important variables contributing the most to the DeepSurv prediction, whose significance were validated with the analysis of variance (ANOVA). Results: Our machine learning approach predicted the time to conversion with a high accuracy. For each of the different stages, the concordance index (CI) of our approach was at least 86%, and the integrated Brier score (IBS) was less than 0.1. To facilitate interpretability of the prediction results, our approach identified the top 10 variables for each disease conversion scenario, which were clinicopathologically meaningful, and most of them were also statistically significant. Conclusion: Our study has the potential to provide individualized prediction for future time course of AD conversions years before their actual occurrence, thus facilitating personalized prevention and intervention strategies to slow down the progression of AD. Show more

Keywords: Analysis of variance, dementia, machine learning, survival analysis

DOI: 10.3233/JAD-220590

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 891-903, 2022

Authors: O’Bryant, Sid E. | Petersen, Melissa | Hall, James | Johnson, Leigh A. | Barber, Robert | Phillips, Nicole | Braskie, Meredith N. | Yaffe, Kristine | Rissman, Robert | Toga, Arthur

Article Type: Research Article

Abstract: Background: Despite tremendous advancements in the field, our understanding of mild cognitive impairment (MCI) and Alzheimer’s disease (AD) among Mexican Americans remains limited. Objective: The aim of this study was to characterize MCI and dementia among Mexican Americans and non-Hispanic whites. Methods: Baseline data were analyzed from n  = 1,705 (n  = 890 Mexican American; n  = 815 non-Hispanic white) participants enrolled in the Health and Aging Brain Study-Health Disparities (HABS-HD). Results: Among Mexican Americans, age (OR = 1.07), depression (OR = 1.09), and MRI-based neurodegeneration (OR = 0.01) were associated with dementia, but none of these factors were associated with MCI. Among …non-Hispanic whites, male gender (OR = 0.33), neighborhood deprivation (OR = 1.34), depression (OR = 1.09), and MRI-based neurodegeneration (OR = 0.03) were associated with MCI, while depression (OR = 1.09) and APOE ɛ 4 genotype (OR = 4.38) were associated with dementia. Conclusion: Findings from this study revealed that the demographic, clinical, sociocultural and biomarker characteristics of MCI and dementia are different among Mexican Americans as compared to non-Hispanic whites. Show more

Keywords: Alzheimer’s disease, health disparities, Hispanic, mild cognitive impairment

DOI: 10.3233/JAD-220300

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 905-915, 2022

Authors: Yang, Yuan-Han | Hsieh, Sun-Wung | Chang, Hsi-Wen | Sung, Jia-Li | Chuu, Chih-Pin | Yen, Chen-Wen | Hour, Tzyh-Chyuan

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) was the main cause of dementia in an aging society; unfortunately, there is no effective treatment for AD now. Meditation has been reported to thicken the cerebral cortex, and gamma wave at a frequency of 40 hertz (Hz) was recorded during the meditation process from the brain. Previous study showed that non-invasive scintillation gamma frequency oscillation increased the space in recognition and memory of auditory cortex hippocampal gyrus in AD mice model. However, the AD-related molecular change by exposure of 40 Hz gamma frequency in brain cells was still unclear. Objective: We investigated the AD-related …molecular change by exposure of 40 Hz gamma frequency in SH-SY5Y cells. Methods: We designed the light and sound generators at 40 Hz gamma frequency for this study. SH-SY5Y cells were exposed to sound or light of 40 Hz gamma frequency, respectively. The concentrations of amyloid-β40 (Aβ40 ) and amyloid-β42 (Aβ42 ) were quantified by enzyme-linked immunosorbent assay. The protein levels were examined by Western blotting. The aggregation of Aβ42 was examined by thioflavin T assay. Results: Our results showed that the secretion of Aβ, phosphorylation of AKT, mTOR, and tau, and aggregation of Aβ42 were significantly inhibited by 40 Hz gamma frequency in SH-SY5Y cells. The phosphorylation of 4E-BP1, downstream of mTOR, was induced by 40 Hz gamma frequency in SH-SY5Y cells. Conclusion: Our study showed 40 Hz gamma frequency involved in the inhibition of secretion and aggregation of Aβ and inhibition of p-Tau protein expression through the mTOR/4E-BP1/Tau signaling pathway. Show more

Keywords: Alzheimer disease, amyloid-β, gamma frequency, mTOR, tau

DOI: 10.3233/JAD-220307

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 917-928, 2022

Authors: Schaffert, Jeff | Bue, Christian Lo | Hynan, Linda S. | Hart Jr., John | Rossetti, Heidi | Carlew, Anne R. | Lacritz, Laura | White III, Charles L. | Cullum, C. Munro

Article Type: Correction

DOI: 10.3233/JAD-229015

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 929-929, 2022

Article Type: Correction

DOI: 10.3233/JAD-229016

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 931-931, 2022