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

Authors: Shinagawa, Shunichiro | Kawakami, Ito | Takasaki, Emi | Shigeta, Masahiro | Arai, Tetsuaki | Ikeda, Manabu

Article Type: Research Article

Abstract: Background: It is important to make accurate clinical diagnosis of frontotemporal lobar degeneration (FTLD), which in turn, leads to future therapic approaches. The FTLD cases are frequently inaccurately identified, but the frequency of this misidentification according to the underlying pathological subtypes is still unclear. Objective: We aimed to quantify the accuracy of behavioral variant frontotemporal dementia (bvFTD) and semantic variant primary progressive aphasia (svPPA) diagnoses by both the patients’ referring physicians and hospital expert psychiatrists, and we investigated whether the physicians’ and psychiatrists’ diagnostic patterns are associated with a specific neuropathology. Methods: We retrospectively analyzed the …cases of a series of Japanese patients with pathologically diagnosed FTLD (n  = 55): the bvFTD group (n  = 47) consisted of patients with FTLD-tau (n  = 20), FTLD-TDP (TAR DNA-binding protein of 43-kDA) (n  = 19), and FTLD-FUS (fused in sarcoma) (n  = 8). The svPPA patients (n  = 8) all had FTLD-TDP. Results: Only 31% of the patients’ referring physicians mentioned FTD syndrome. The referring psychiatrists and neurologists showed similar diagnostic accuracy. High diagnostic accuracy was observed for the TDP pathology group (mainly svPPA patients). The FTLD-FUS patients were more likely to be diagnosed as having a psychiatric disorder by referring physicians. The hospital expert psychiatrists’ accuracy for identifying FTLD-tau pathology was low. Conclusion: The results of our analyses revealed a specific diagnostic pattern associated with particular FTLD pathological subtypes, which will help to improve non-specialists’ diagnostic ability. Show more

Keywords: Frontotemporal dementia, frontotemporal lobar degeneration, hospital expert psychiatrist, misdiagnosis, referring physician, semantic variant

DOI: 10.3233/JAD-215516

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

Authors: Serwer, Philip | Wright, Elena T. | Hunter, Barbara

Article Type: Research Article

Abstract: Protein amyloid-β (Aβ) oligomers with β-sheet-like backbone (β-structured) form extracellular amyloid plaques associated with Alzheimer’s disease (AD). However, the relationship to AD is not known. Some investigations suggest that the toxic Aβ component has α -sheet-like backbone (α -structured) subsequently detoxified by intracellular α -to-β conversion before plaque formation. Our objective is to compare this latter hypothesis with observations made by electron microscopy of thin sections of AD-cerebral cortex. We observe irregular, 200–2,000 nm, intracellular, lipofuscin-like inclusions. Some are light-staining and smooth. Others are dark-staining and made granular by fibers that are usually overlapping and are sometimes individually seen. Aspects unusual …for lipofuscin include 1) dark and light inclusions interlocking as though previously one inclusion, 2) dark inclusion-contained 2.6 nm thick sub-fibers that are bent as though α -structured, and 3) presence of inclusions in lysosomes and apparent transfer of dark inclusion material to damaged, nearby lysosomal membranes. These data suggest the following additions to α -structure-based hypotheses: 1) Lipofuscin-associated, α -structured protein toxicity to lysosomal membranes is in the chain of AD causation; 2) α -to-β detoxification of α -structured protein occurs in lipofuscin and causes dark-to-light transition that, when incomplete, is the origin of cell-to-cell transmission essential for development of AD. Show more

Keywords: Alpha-sheet, amyloid, electron microscopy, lipofuscin, molecular model, thin sectioning

DOI: 10.3233/JAD-220311

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

Authors: Gonzalez-Moreno, Jesús | Satorres, Encarnacion | Soria-Urios, Gema | Meléndez, Juan C.

Article Type: Research Article

Abstract: Background: Cognitive stimulation is one of the non-pharmacological therapies recommended for intervention in dementia, consisting of activities involving different cognitive domains and involving brain activation. New technologies can be very useful in this field, favoring intervention tasks. Objective: The objective of this work is to test the effectiveness of a cognitive stimulation intervention mediated with new technologies on a group of people with moderate dementia. Methods: This is a quantitative, quasi-experimental study with a control and treatment group, with three measurement times (pre, post, and follow-up months after the end of the intervention). Ninety-eight subjects with …moderate dementia were randomly assigned to the treatment group (N = 50) and the control group (N = 48). The treatment group received 16 intervention sessions including attention, executive function, and memory tasks, which were presented using new technologies and the activity was conducted in a group setting. Control group remained on a waiting list. The evaluators did not know which group each subject belonged to. All participants were assessed with a battery of neuropsychological tests. Results: The results show an improvement in post-intervention outcomes in the treatment group compared to the control group on cognitive variables. No differences were found in mood depression. These results fade overtime after a few months without intervention. Conclusion: This type of intervention is useful to maintain cognitive functioning using new technologies and in a group setting, which favors the intervention. The improvements of the intervention disappear at follow-up, which would indicate the need to maintain the intervention over time. Show more

Keywords: Cognitive function, dementia, intervention, new technologies

DOI: 10.3233/JAD-220245

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2022

Authors: Wang, Yilin | Li, Lei | Zhao, Xiaodong | Sui, Shaomei | Wang, Qi | Shi, Guizhi | Xu, Huilian | Zhang, Xiujun | He, Yan | Gu, Jinsong

Article Type: Research Article

Abstract: Background: Understanding the relationship between Alzheimer’s disease (AD) and intestinal flora is still a major scientific topic that continues to advance. Objective: To determine characterized changes in the intestinal microbe community of patients with mild AD. Methods: Comparison of the 16S ribosomal RNA (rRNA) high-throughput sequencing data was obtained from the Illumina MiSeq platform of fecal microorganisms of the patients and healthy controls (HC) which were selected from cohabiting caregivers of AD patients to exclude environmental and dietary factors. Results: We found that the abundance of several bacteria taxa in AD patients was different …from that in HC at the genus level, such as Anaerostipes , Mitsuokella , Prevotella , Bosea , Fusobacterium , Anaerotruncus , Clostridium , and Coprobacillus . Interestingly, the abundance of Akkermansia , an emerging probiotic, increased significantly in the AD group compared with that in the HC group. Meanwhile, the quantity of traditional probiotic Bifidobacteria of the AD group also rose. Conclusion: These alterations in fecal microbiome of the AD group indicate that patients with mild AD have unique gut microbial characteristics. These specific AD-associated intestinal microbes could serve as novel potential targets for early intervention of AD. Show more

Keywords: Akkermansia , Bifidobacteria , intestinal microflora, mild Alzheimer’s disease, therapeutic targets

DOI: 10.3233/JAD-220076

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2022

Authors: Riphagen, Joost M. | van Hooren, Roy W.E. | Kenis, Gunter | Verhey, Frans R.J. | Jacobs, Heidi I.L.

Article Type: Short Communication

Abstract: The brain-derived neurotropic growth factor (BDNF ) gene has been linked to dementia, inflammation, and Apolipoprotein E (APOE ) ɛ4 status. We used cerebrospinal fluid (CSF) amyloid-β (Aβ)42 and phosphorylated tau (p-tau) to investigate associations with BDNF polymorphisms and modifications by APOE ɛ4 or inflammation in a memory clinic population (n  = 114; subjective cognitive decline, mild cognitive impairment, Alzheimer’s disease). We found distinct pathways to Alzheimer’s disease pathology: Val-Met displayed lower CSF-Aβ 42 in APOE ɛ4+ carriers, independent of p-tau, while Val-Val displayed greater p-tau at higher IL-6 and sub-threshold Aβ 42 . This may …contribute to resolving some inconsistencies in the BDNF literature and provide possible inroads to specific Aβ and tau interventions depending on BDNF polymorphism. Show more

Keywords: Alzheimer’s disease, amyloid-β, brain-derived neurotropic growth factor, inflammation, interleukin 6, phosphorylated tau

DOI: 10.3233/JAD-215353

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2022

Authors: Fowler, Mackenzie E. | Wright, Nicole C. | Triebel, Kristen | Rocque, Gabrielle B. | Irvin, Ryan | Kennedy, Richard E.

Article Type: Research Article

Abstract: Background: Cancer-related cognitive impairment (CRCI), a frequent effect of cancer and its treatments, shares common cognitive symptoms with dementia syndromes. Cross-sectional studies demonstrate an inverse relationship between cancer and dementia. However, the longitudinal relationship between dementia decline and cancer has not been investigated. Objective: To evaluate the association between cancer and longitudinal progression of dementia. Methods: We extracted electronic health record data from July 2003 to February 2020 from a single academic medical center. We identified dementia and cancer history prior to dementia using ICD-9/10 codes. We measured cognitive decline with the Alabama Brief Cognitive Screener …(ABCs). We used adjusted linear mixed models to estimate baseline cognition and rate of progression by cancer history, including differences by race. Results: The study included 3,809 participants with dementia, of which 672 (17.6%) had cancer history. Those with cancer history had higher baseline cognition (β: 0.62, 95% CI: –0.02–1.25), but similar rate of decline. Non-Hispanic Blacks had lower cognitive scores at baseline and throughout follow-up regardless of cancer status compared to non-Hispanic Whites and other races/ethnicities with and without cancer history. Conclusion: In this longitudinal retrospective study, participants with cancer history demonstrate better cognition at dementia diagnosis and no difference in cognitive decline than those without cancer history. Smoking and comorbidities attenuate this association and results indicate non-Hispanic Blacks have worse cognitive outcomes in dementia regardless of cancer history than other race/ethnicity groups. Further exploration of the role of smoking, comorbidities, and race/ethnicity on cancer and dementia-related cognitive decline is needed. Show more

Keywords: Aging, cancer, cognitive dysfunction, dementia

DOI: 10.3233/JAD-220054

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2022

Authors: Stephan, Blossom C.M. | Tang, Eugene Y.H. | Pakpahan, Eduwin | Biswas, Bijetri | Gupta, Alisha | McGrattan, Andrea | Bosco, Alessandro | Richardson, Connor D. | Robinson, Louise | Siervo, Mario

Article Type: Systematic Review

Abstract: Background: Although numerous studies have reported a decrease in dementia risk in the last two decades, it is unclear whether dementia-free cognitive function is also changing across generations. Objective: The objective was to systematically evaluate the published data on generational differences in cognitive function in the older population. Methods: Searches were performed on PubMed, Embase, and PsychInfo for articles published in English before 20 June 2021. Included studies were from population-based samples that reported generational differences in cognition in individuals without dementia, aged ≥60 years. Results: 28,101 studies were identified and 15 selected covering …the period from 1971 to 2015: including studies from China, Europe, and the USA. The results show generally consistent findings of improvements or stability in dementia free cognitive function in later versus earlier born generations, but not for all cognitive domains. Prevalence of mild cognitive impairment and cognitive impairment no dementia has remained stable in the USA, UK, and China over the last two decades. Results: Prevalence of vascular related mild cognitive impairment has increased in China. Improvements in cognition may only partially be explained by increased educational attainment across generations. Conclusion: This review provides evidence for generational effects in dementia-free cognitive function, predominately stability or improvements in performance, in later compared to earlier born individuals across different world regions. There is an urgent need to determine the factors driving such changes and whether they are being experienced in all world regions, particularly low- and middle-income countries where the burden of cognitive impairment is greatest and rising. Show more

Keywords: Cognitive function, epidemiology, generational effects, secular trends

DOI: 10.3233/JAD-220162

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2022

Authors: McGrattan, Andrea | Stewart, Christopher J. | Cassidy, Aedín | Woodside, Jayne V. | McEvoy, Claire T.

Article Type: Review Article

Abstract: Given the complex bidirectional communication system that exists between the gut microbiome and the brain, there is growing interest in the gut microbiome as a novel and potentially modifiable risk factor for Alzheimer’s disease (AD). Gut dysbiosis has been implicated in the pathogenesis and progression of AD by initiating and prolonging neuroinflammatory processes. The metabolites of gut microbiota appear to be critical in the mechanism of the gut-brain axis. Gut microbiota metabolites, such as trimethylamine-n-oxide, lipopolysaccharide, and short chain fatty acids, are suggested to mediate systemic inflammation and intracerebral amyloidosis via endothelial dysfunction. Emerging data suggest that the fungal microbiota …(mycobiome) may also influence AD pathology. Importantly,  60% of variation in the gut microbiome is attributable to diet, therefore modulating the gut microbiome through dietary means could be an effective approach to reduce AD risk. Given that people do not eat isolated nutrients and instead consume a diverse range of foods and combinations of nutrients that are likely to be interactive, studying the effects of whole diets provides the opportunity to account for the interactions between different nutrients. Thus, dietary patterns may be more predictive of real-life effect on gut microbiome and AD risk than foods or nutrients in isolation. Accumulating evidence from experimental and animal studies also show potential effects of gut microbiome on AD pathogenesis. However, data from human dietary interventions are lacking. Well-designed intervention studies are needed in diverse populations to determine the influence of diet on gut microbiome and inform the development of effective dietary strategies for prevention of AD. Show more

Keywords: Gut microbiome, gut metabolites, dietary patterns, Alzheimer’s disease

DOI: 10.3233/JAD-220205

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2022

Authors: Gamble, Laura D. | Parker, Sophie | Quinn, Catherine | Bennett, Holly Q. | Martyr, Anthony | Sabatini, Serena | Pentecost, Claire | Collins, Rachel | Dawson, Eleanor | Hunt, Anna | Allan, Louise | Burns, Alistair | Litherland, Rachael | Victor, Christina | Matthews, Fiona E. | Clare, Linda

Article Type: Research Article

Abstract: Background: Social restriction measures imposed to curb the spread of COVID-19 in the United Kingdom impacted on carers of people with dementia, limiting access to support services and increasing perceived burden of caring. Few studies have compared data collected both during and before the pandemic to examine the effect of these changes. Objective: To explore whether the COVID-19 pandemic affected the well-being of carers of people with dementia living in the community, and their ability to cope with their caring responsibilities. Methods: Analysis was conducted on two groups of carers who were enrolled in the IDEAL …programme; the ‘pre-pandemic group’ (n  = 312), assessed at two time points prior to the pandemic, and the ‘pandemic group’, assessed prior to and several months into the pandemic (n  = 156). For the pre-pandemic group, carers were matched 2:1 to carers in the pandemic group on certain characteristics. Differences in change over time between the two groups on self-reported well-being, quality of life, coping, perceived competence, and role captivity, was investigated using mixed effect modelling. Results: Compared to the pre-pandemic group, those in the pandemic group appeared to cope better and had more stable self-rated competency and role captivity. They did not differ in terms of well-being or quality of life. Conclusions: Despite reports of negative impacts on carers early in the pandemic, the findings suggest the pandemic had little negative longer-term impact on carers of people with dementia, and in fact they appeared to have a more positive attitude towards coping several months into the pandemic. Show more

Keywords: Alzheimer’s disease, competence, coping, quality of life, role captivity, well-being

DOI: 10.3233/JAD-220221

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2022

Authors: García-Roldán, Ernesto | Arriola-Infante, José Enrique | Méndez-Barrio, Carlota | Montiel-Herrera, Fátima | Mendoza-Vázquez, Gonzalo | Marín-Cabañas, Alba Marta | Rodrigo-Herrero, Silvia | Luque-Tirado, Andrea | Sánchez-Arjona, María Bernal | Maillet, Didier | Franco-Macías, Emilio

Article Type: Research Article

Abstract: Background: TMA-93 examines relational binding using images. The test has been proven to be discriminative for diagnosing early Alzheimer’s disease by biomarkers. Norms for this test are available, but the elderly, at high risk for Alzheimer’s disease, have not yet been widely represented. Objective: To extend normative data on the TMA-93 for people aged 75 and over. Methods: An extension of the Spanish TMA-93 normative study was undertaken. Only cognitively unimpaired people aged 75 and over were included. Age, gender, and educational attainment were registered as socio-demographic variables. Using histograms analysis, median comparisons, and linear regression …analysis, we selected variables that demonstrated influence on TMA-93 total scores and provided percentile-base reference data according to combinations of those variables. Results: We included 431 new participants, resulting in a total sample of 657 individuals (median age = 78, interquartile range = 76–81, range = 75–93). Percentile-base reference data stratified by a combination of age ranges (75–79, n  = 428; and ≥80 years, n  = 229), and educational attainment (<  first grade, n  = 253; first grade, n  = 209; >  first grade, n  = 195) revealed that participants achieved a minimum TMA-93 total score of 26/30 at the 50th-percentile regardless of stratum. At the 10th-percentile, a maximum of 24/30 was achieved in the more educated stratum contrasting with a minimum of 19/30 in the less educated stratum. Conclusion: Although mitigated by lower levels of education, performance on the TMA-93 is widely preserved in cognitively unimpaired people aged 75 and over. The test could facilitate the screening of elderly patients with memory complaints. Show more

Keywords: Alzheimer’s disease, binding, elderly, illiterate, normative data, TMA-93

DOI: 10.3233/JAD-220099

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

Authors: Frame, Gabrielle | Schuller, Adam | Smith, Matthew A. | Crish, Samuel D. | Dengler-Crish, Christine M.

Article Type: Research Article

Abstract: Background: Visual disturbances often precede cognitive dysfunction in patients with Alzheimer’s disease (AD) and may coincide with early accumulation of amyloid-β (Aβ) protein in the retina. These findings have inspired critical research on in vivo ophthalmic Aβ imaging for disease biomarker detection but have not fully answered mechanistic questions on how retinal pathology affects visual signaling between the eye and brain. Objective: The goal of this study was to provide a functional and structural assessment of eye-brain communication between retinal ganglion cell (RGCs) and their primary projection target, the superior colliculus, in female and male 3xTg-AD mice …across disease stages. Methods: Retinal electrophysiology, axonal transport, and immunofluorescence were used to determine RGC projection integrity, and retinal and collicular Aβ levels were assessed with advanced protein quantitation techniques. Results: 3xTg mice exhibited nuanced deficits in RGC electrical signaling, axonal transport, and synaptic integrity that exceeded normal age-related decrements in RGC function in age- and sex-matched healthy control mice. These deficits presented in sex-specific patterns among 3xTg mice, differing in the timing and severity of changes. Conclusion: These data support the premise that retinal Aβ is not just a benign biomarker in the eye, but may contribute to subtle, nuanced visual processing deficits. Such disruptions might enhance the biomarker potential of ocular amyloid and differentiate patients with incipient AD from patients experiencing normal age-related decrements in visual function. Show more

Keywords: Amyloidosis, dementia, pattern electroretinogram, preclinical, presymptomatic, retina, vision

DOI: 10.3233/JAD-220016

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-22, 2022

Authors: Wanigatunga, Amal A. | Liu, Fangyu | Wang, Hang | Urbanek, Jacek K. | An, Yang | Spira, Adam P. | Dougherty, Ryan J. | Tian, Qu | Moghekar, Abhay | Ferrucci, Luigi | Simonsick, Eleanor M. | Resnick, Susan M. | Schrack, Jennifer A.

Article Type: Research Article

Abstract: Background: Gradual disengagement from daily physical activity (PA) could signal present or emerging mild cognitive impairment (MCI) or Alzheimer’s disease (AD). Objective: This study examined whether accelerometry-derived patterns of everyday movement differ by cognitive diagnosis in participants of the Baltimore Longitudinal Study of Aging (BLSA). Methods: Activity patterns, overall and by time-of-day, were cross-sectionally compared between participants with adjudicated normal cognition (n  = 549) and MCI/AD diagnoses (n  = 36; 6 participants [17%] living with AD) using covariate-adjusted regression models. Results: Compared to those with normal cognition, those with MCI/AD had 2.1% higher activity fragmentation (SE = 1.0%, …p  = 0.036) but similar mean total activity counts/day (p  = 0.075) and minutes/day spent active (p  = 0.174). Time-of-day analyses show MCI/AD participants had lower activity counts and minutes spent active during waking hours (6:00 am–5:59 pm; p  <  0.01 for all). Also, they had lower activity fragmentation from 12:00–5:59 am (p  <  0.001), but higher fragmentation from 12:00–5:59 pm (p  = 0.026). Conclusion: Differences in the timing and patterns of physical activity throughout the day linked to MCI/AD diagnoses warrant further investigation into potential clinical utility. Show more

Keywords: Accelerometry, Alzheimer’s disease, diurnal patterns, mild cognitive impairment

DOI: 10.3233/JAD-215544

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

Authors: Tsai, Yi-Liang | Yen, Chieh-Tsung | Wang, Yuh-Feng

Article Type: Research Article

Abstract: The typical symptoms of patients with Alzheimer’s disease (AD) are amyloid-β (Aβ) plaques and tau hyperphosphorylation. However, recent studies show that these symptoms are not the cause of the disease but are generated after the pathogenesis. Compared with other types of dementia, AD has the obvious features of pineal gland calcification and decreased melatonin production. The pineal gland is mainly composed of pinealocytes that release melatonin and astrocytes. Astrocytes function to maintain a balanced concentration of calcium ions, provide nerve cell nutrients, and migrate nutrients in vivo . Calcium ions are among the most important neurotransmitters. Once triggered, a calcium …wave can be formed between astrocytes to activate other astrocytes to transmit information. Most calcium is stored in the skeleton. Bone tissue is composed mainly of osteocytes, osteoblasts, and osteoclasts. Of these, osteocyte is a kind of astrocyte which regulates the activity of osteoclasts and osteoblasts. The pineal gland is composed mainly of astrocytes; osteocytes are also a kind of astrocyte. Therefore, we conclude that when astrocytes are gradually disabled, calcium may be lost from the bones, prompting osteoporosis. The calcium ions then released into the blood may accumulate and cause ectopic calcification in the pineal gland, which promotes the occurrence of AD. Finally, this study used aspects of drugs and hormones (bone and calcium metabolism hormones and melatonin) to infer the hypothesis, which proposes that astrocyte dysregulation promotes the long-term imbalance of calcium ions in vivo and leads to osteoporosis and AD. Show more

Keywords: Alzheimer’s disease, astrocyte, bone, calcium ion, osteoporosis

DOI: 10.3233/JAD-220218

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2022

Authors: Zhang, Kaixia | Ma, Xiaoying | Zhang, Rui | Liu, Zanchao | Jiang, Lei | Qin, Yushi | Zhang, Di | Tian, Pei | Gao, ZhaoYu | Zhang, Nan | Shi, Zhongli | Xu, Shunjiang

Article Type: Research Article

Abstract: Background: The interactions between environmental factors and genetic variants have been implicated in the pathogenesis of Alzheimer’s disease (AD). The altered gut microbiota (GM) and vitamin D deficiency are closely associated with the higher risk of AD. Objective: This study was performed to evaluate whether the crosstalk between GM and single nucleotide polymorphisms (SNPs) of vitamin D receptor (VDR) or vitamin D binding protein (VDBP) have a link with the risk of amnestic mild cognitive impairment (aMCI) in the Chinese elderly population. Methods: A total of 171 aMCI patients and 261 cognitive normal controls (NC) were …enrolled in this study. Six tag SNPs of VDR and VDBP were genotyped by PCR-RFLP. The serum levels of vitamin D, Aβ1-42 , and p-tau (181P) were determined by using of ELISA kits. The alterations in the GM were analyzed by full-length 16S ribosomal RNA (rRNA) gene sequencing. Results: The frequencies of AG genotype and A allele of VDR rs1544410 in aMCI group were significantly higher than that in NC group (genotype: p  = 0.002, allele: p  = 0.003). Patients with aMCI showed an abnormal GM composition compared with NC group. Interestingly, significant differences in GM composition were found between aMCI and NC group among individuals with AG genotype, as well as between individuals with AG and GG genotype of VDR rs1544410 among patients with aMCI. Conclusion: These results implicated that the crosstalk between gut microflora and vitamin D receptor variants are associated with the risk of aMCI in Chinese elderly population. Show more

Keywords: Amnestic mild cognitive impairment, full-length 16S rRNA sequencing, gut microbiota, single nucleotide polymorphisms, vitamin D receptor

DOI: 10.3233/JAD-220101

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2022

Authors: Baazaoui, Narjes | Iqbal, Khalid

Article Type: Review Article

Abstract: COVID-19 emerged as a global pandemic starting from Wuhan in China and spread at a lightning speed to the rest of the world. One of the potential long-term outcomes that we speculate is the development of neurodegenerative diseases as a long-term consequence of SARS-CoV-2 especially in people that have developed severe neurological symptoms. Severe inflammatory reactions and aging are two very strong common links between neurodegenerative diseases and COVID-19. Thus, patients that have very high viral load may be at high risk of developing long-term adverse neurological consequences such as dementia. We hypothesize that people with neurodegenerative diseases such as …Alzheimer’s disease, Parkinson’s disease, and aged people are at higher risk of getting the COVID-19 than normal adults. The basis of this hypothesis is the fact that SARS-CoV-2 uses as a receptor angiotensin-converting enzyme 2 to enter the host cell and that this interaction is calcium-dependent. This could then suggest a direct relationship between neurodegenerative diseases, ACE-2 expression, and the susceptibility to COVID-19. The analysis of the available literature showed that COVID-19 virus is neurotropic and was found in the brains of patients infected with this virus. Furthermore, that the risk of having the infection increases with dementia and that infected people with severe symptoms could develop dementia as a long-term consequence. Dementia could be developed following the acceleration of the spread of prion-like proteins. In the present review we discuss current reports concerning the prevalence of COVID-19 in dementia patients, the individuals that are at high risk of suffering from dementia and the potential acceleration of prion-like proteins spread following SARS-CoV-2 infection. Show more

Keywords: ACE receptors, Alzheimer’s disease, dementia, Parkinson’s disease, prion-like proteins, SARS-CoV-2

DOI: 10.3233/JAD-220105

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

Authors: Hao, Jing | Guo, Yanping | Guo, Keke | Yang, Qingcheng

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a neurodegenerative disease of unknown pathological origin. The clinical diagnosis of AD is time-consuming and needs to a combination of clinical evaluation, psychological testing, and imaging assessments. Biomarkers may be good indicators for the clinical diagnosis of AD; hence, it is important to identify suitable biomarkers for the diagnosis and treatment of AD. Peripheral inflammatory biomarkers have been the focus of research in recent years. This review summarizes the role of inflammatory biomarkers in the disease course of AD.

Keywords: Alzheimer’s disease, biomarkers, inflammatory, neurodegeneration

DOI: 10.3233/JAD-215422

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

Authors: Roddick, Kyle M. | Fertan, Emre | Schellinck, Heather M. | Brown, Richard E

Article Type: Short Communication

Abstract: Although Alzheimer’s disease is most often studied in terms of memory impairments, olfactory dysfunction begins in the early stages. We tested olfactory learning, sensitivity, and response bias using signal detection methods in 12-month-old male and female 5xFAD mice and their wildtype controls in the operant olfactometer. Odor detection was not reduced in the 5xFAD mice, but learning was, which was worse in female 5xFAD mice than in males. Female mice were more conservative in their response strategy. Signal detection analysis allows us to discriminate between cognitive and sensory deficits of male and female mouse models of AD.

Keywords: Accuracy, Alzheimer model mice, false alarms, olfactory learning, response bias, sensitivity, signal detection

DOI: 10.3233/JAD-220049

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

Authors: Høilund-Carlsen, Poul F. | Revheim, Mona-Elisabeth | Alavi, Abass

Article Type: Article Commentary

Abstract: Three decades with the amyloid hypothesis, nearly two with amyloid-PET imaging, and one with testing of anti-amyloid therapy have not yielded benefits to patients with Alzheimer’s disease (AD). It is time to focus on more promising options, e.g., infection, low dose radiation, and atherosclerosis. The relevance of the latter in managing AD has fluctuated from being significant to insignificant. Current methodologies for detecting cerebral atherosclerosis reflect advanced changes in only major arteries. In contrast, 18 F-sodium fluoride PET imaging assessing early-stage cerebral atherosclerosis regionally or in the entire vascular bed may provide new insight in this age-related process in dementia.

Keywords: Alzheimer’s disease, amyloid-β, dementia, 18F-sodium fluoride PET, NaF

DOI: 10.3233/JAD-220190

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-4, 2022

Authors: Cheng, Yuan | Jian, Jie-Ming | He, Chen-Yang | Ren, Jun-Rong | Xu, Man-Yu | Jin, Wang-Sheng | Tan, Cheng-Rong | Zeng, Gui-Hua | Shen, Ying-Ying | Chen, Dong-Wan | Li, Hui-Yun | Yi, Xu | Zhang, Yuan | Zeng, Fan | Wang, Yan-Jiang

Article Type: Research Article

Abstract: Background: The dysregulation of lipid metabolism plays an important role in the pathogenesis of Alzheimer’s disease (AD). Liver-type fatty acid-binding protein (L-FABP, also known as FABP1) is critical for fatty acid transport and may be involved in AD. Objective: To investigate whether the FABP1 level is altered in patients with AD, and its associations with levels of amyloid-β (Aβ) and tau in the plasma and cerebrospinal fluid (CSF). Methods: A cross-sectional study was conducted in a Chinese cohort consisting of 39 cognitively normal controls and 47 patients with AD. The …levels of FABP1 in plasma, and Aβ and tau in CSF, were measured by enzyme-linked immunosorbent assay (ELISA). A single-molecule array (SIMOA) was used to detect plasma Aβ levels. Results: The level of plasma FABP1 was significantly elevated in the AD group (p  = 0.0109). Further analysis showed a positive correlation of FABP1 with CSF total tau (t-tau) and phosphorylated tau (p-tau) levels. Besides, plasma FABP1/Aβ 42 (AUC = 0.6794, p  = 0.0071) and FABP1/t-tau (AUC = 0.7168, p  = 0.0011) showed fair diagnostic efficacy for AD. When combined with other common AD biomarkers including plasma Aβ 42 , Aβ 40 , and t-tau, both FABP1/Aβ 42 and FABP1/t-tau showed better diagnostic efficacy than using these biomarkers alone. Among all AUC analyses, the combination of plasma FABP1/t-tau and Aβ 42 had the highest diagnostic value (AUC = 0.8075, p  <  0.0001). Conclusion: These findings indicate that FABP1 may play a role in AD pathogenesis and be worthy of further investigation in the future. Show more

Keywords: Alzheimer’s disease, amyloid-β, liver-type fatty acid-binding protein, tau

DOI: 10.3233/JAD-220126

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2022

Authors: Tancheva, Lyubka | Lazarova, Maria | Velkova, Lyudmila | Dolashki, Alexander | Uzunova, Diamara | Minchev, Borislav | Petkova-Kirova, Polina | Hassanova, Yozljam | Gavrilova, Petja | Tasheva, Krasimira | Taseva, Teodora | Hodzhev, Yordan | Atanasov, Atanas G. | Stefanova, Miroslava | Alexandrova, Albena | Tzvetanova, Elina | Atanasov, Ventseslav | Kalfin, Reni | Dolashka, Pavlina

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a complex neurodegenerative disease with multifactorial etiology, unsatisfactory treatment, and a necessity for broad-spectrum active substances for cure. The mucus from Helix aspersa snail is a mixture of bioactive molecules with antimicrobial, anti-inflammatory, antioxidant, and anti-apoptotic effects. So far there are no data concerning the capacity of snail extract (SE) to affect neurodegenerative disorders. Objective: The effects of SE from Helix aspersa on learning and memory deficits in Alzheimer’s type dementia (ATD) induced by scopolamine (Sco) in male Wistar rats were examined and some mechanisms of action underlying these effects were …evaluated. Methods: SE (0.5 mL/100 g) was applied orally through a food tube for 16 consecutive days: 5 days before and 11 days simultaneously with Sco (2 mg/kg, intraperitoneally). At the end of Sco treatment, using behavioral methods, we evaluated memory performance. Additionally, in cortex and hippocampus the acetylcholinesterase (AChE) activity, acetylcholine and monoamines (dopamine, noradrenaline, and serotonin) content, levels of main oxidative stress markers, and expression of brain-derived neurotrophic factor (BDNF) and cAMP response element-binding protein (CREB) were determined. Results: We demonstrated that, according to all behavioral tests used, SE significantly improved the cognitive deficits induced by Sco. Furthermore, SE possessed AChE inhibitory activity, moderate antioxidant properties and the ability to modulate monoamines content in two brain structures. Moreover, multiple SE applications not only restored the depressed by Sco expression of CREB and BDNF, but significantly upregulated it. Conclusion: Summarizing results, we conclude that complex mechanisms underlie the beneficial effects of SE on impaired memory in Alzheimer’s type dementia. Show more

Keywords: Antioxidant system, BDNF, cholinergic function, CREB, scopolamine, snail Helix aspersa

DOI: 10.3233/JAD-215693

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-21, 2022

Authors: Wittfeld, Katharina | Raman, Mekala R. | Conner, Sarah C. | Aslam, Asra | Teumer, Alexander | Nauck, Matthias | Hosten, Norbert | Habes, Mohamad | DeCarli, Charles | Vasan, Ramachandran S. | Beiser, Alexa S. | Himali, Jayandra J. | Seshadri, Sudha | Grabe, Hans J. | Satizabal, Claudia L.

Article Type: Research Article

Abstract: Background: Insulin-like growth factor 1 (IGF-1) signaling has been implicated in Alzheimer’s disease pathogenesis, and further evidence suggests inflammation can be a moderator of this association. However, most research to date has been conducted on older adults. Objective: To investigate the association of serum IGF-1 and IGF binding protein 3 (IGFBP-3) concentrations with MRI markers of Alzheimer’s disease in predominantly middle-aged adults, and further assess moderation by chronic inflammation. Methods: We included participants from the Framingham Heart Study (n  = 1,852, mean age 46±8, 46% men) and the Study of Health in Pomerania (n  = 674, mean age …50±13, 42% men) with available serum IGF-1, IFGBP-3, as well as brain MRI. IGF-1 and IFGBP-3 were related to MRI outcomes (i.e., total brain, cortical gray matter, white matter, white matter hyperintensities (WMH), and hippocampal volumes) using multivariable regression models adjusting for potential confounders. Subgroup analyses by C-reactive protein (CRP) concentrations were also performed. Cohort-specific summary statistics were meta-analyzed using random-effects models and corrected for multiple comparisons. Results: Meta-analysis results revealed that higher IGF-1 concentrations were associated with lower WMH (estimate [β] [95% CI], –0.05 [–0.09, –0.02], p  = 0.006) and larger hippocampal volumes (0.07 [0.02, 0.12], p  = 0.01), independent of vascular risk factors. These associations occurred predominantly in individuals with CRP concentrations < 75th percentile. We did not observe associations between IGFBP-3 and MRI outcomes. Conclusion: Our findings suggest that IGF-1-related signaling may be implicated in brain health as early as midlife. Show more

Keywords: Alzheimer’s disease endophenotype, C-reactive protein, cohort study, epidemiology, hippocampus, insulin-like growth factor, neuroimaging, white matter hyperintensity

DOI: 10.3233/JAD-220356

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2022

Authors: Vásquez, Priscilla M. | Tarraf, Wassim | Li, Yuyi | Jenkins, Derek | Soria-Lopez, Jose | Zlatar, Zvinka Z. | Marquine, Maria J. | Stickel, Ariana M. | Estrella, Mayra L. | Gallo, Linda C. | Lipton, Richard B. | Isasi, Carmen R. | Cai, Jianwei | Zeng, Dongling | Daviglus, Martha L. | Schneiderman, Neil | González, Hector M.

Article Type: Research Article

Abstract: Background: Population-based studies typically rely on self-reported medical diagnosis (SRMD) of mild cognitive impairment (MCI)/dementia; however, links to objective neurocognitive function have not been established. Objective: Examine the association between SRMD of MCI/dementia and objective neurocognitive function among Hispanic/Latino adults. Methods: We conducted a case-control study using the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) baseline data and its ancillary SOL-Investigation of Neurocognitive Aging (SOL-INCA) at visit 2. Hispanic/Latino adults aged 50 years and older (n  = 593) were administered neurocognitive tests: the Six-Item Screener (SIS), Brief-Spanish English Verbal Learning Test (B-SVELT Sum), B-SVELT Recall, Word Fluency …Test (WF), Digit Symbol Substitution Test (DSS), and Trail Making Test A and B. Individual and global neurocognitive function scores were used for analyses. Propensity matching techniques and survey generalized linear regression models were used to compare SRMD of MCI/dementia with demographic, psychological, and cardiovascular risk matched controls. Complex survey design methods were applied. Results: There were 121 cases of SRMD of MCI/dementia and 472 propensity matched controls. At baseline, compared to matched controls, cases showed no differences in neurocognitive function (p  > 0.05). At SOL-INCA visit 2, cases had poorer scores in global neurocognitive function (p  < 0.05), B-SEVLT Sum, B-SEVLT Recall, WF, DSS, and Trail A (p  < 0.01). Conclusion: Observed differences in neurocognitive test scores between SRMD of MCI/dementia cases and matched controls were present at visit 2, but not at baseline in middle-aged and older Hispanic/Latino adults. These findings present initial evidence of the potential utility of SRMD of MCI/dementia in epidemiologic studies, where obtaining confirmation of diagnosis may not be feasible. Show more

Keywords: Cognition, dementia, hispanic, latino, mild cognitive impairment, neurocognition

DOI: 10.3233/JAD-215060

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

Authors: Tsiakiri, Anna | Vlotinou, Pinelopi | Terzoudi, Aikaterini | Heliopoulos, Ioannis | Vadikolias, Konstantinos

Article Type: Research Article

Abstract: Background: Prolonged periods of social deprivation, such as COVID-19-related lockdowns, are associated with deleterious effects on cognitive functions. Objective: The aim of this study was to gauge the effect of prolonged social isolation on the cognitive function of older adults with neurocognitive disorders. Methods: We recruited 125 older adults with minor or major neurocognitive disorders divided into two groups. The control group was tested at the first period of the study (October 2018–May 2019), whereas the experimental group was evaluated at the second chronological period of the study (October 2020–May 2021) during the second wave of …COVID-19. Neuropsychological tests were performed at baseline and six months after baseline. Results: In the control group, significant changes in the scores from the Montreal Cognitive Assessment (MoCA; p  = 0.049) and the Functional Rating Scale for Symptoms of Dementia (FRSSD; p  = 0.005) were found between baseline and follow-up assessments, whereas no changes were identified in Mini-Mental State Examination (MMSE; p  = 0.229) and Geriatric Depression Scale (GDS; p  = 0.619) scores. In the experimental group, the scores from all neuropsychological tests (MoCA, MMSE, GDS, and FRSSD; p  < 0.001 for all) were significantly different at follow-up when compared with those at baseline measurements. Moreover, significant deterioration of specific functions assessed in MMSE and FRSSD was detected, especially in the experimental group. Conclusion: This study highlights cognitive functions directly affected by social deprivation of individuals with neurocognitive disorders. The findings can be used in the rehabilitation from confinement and its negative consequences. Show more

Keywords: Cognitive functions, COVID-19, emotional status, neurocognitive disorders

DOI: 10.3233/JAD-220118

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

Authors: Wolfova, Katrin | Creese, Byron | Aarsland, Dag | Ismail, Zahinoor | Corbett, Anne | Ballard, Clive | Hampshire, Adam | Cermakova, Pavla

Article Type: Research Article

Abstract: Background: While the gender/sex differences in neuropsychiatric symptoms in dementia population are well described, gender/sex differences in mild behavioral impairment (MBI) in dementia-free populations and the relationship to cognitive performance and to subsequent cognitive decline have not been studied. Objective: We aimed to explore gender/sex differences in the association of MBI with the level of cognitive performance and its rate of decline in a dementia-free cohort. Methods: We studied 8,181 older adults enrolled in the online PROTECT UK Study. MBI was assessed using the MBI Checklist and cognition was measured by digit span, paired associate learning, …spatial working memory, and verbal reasoning. Statistical analysis was conducted using linear regression models and linear mixed-effects models. Results: Out of 8,181 individuals (median age 63 years, 73% females), 11% of females and 14% of males had MBI syndrome. Females exhibited less often symptoms of decreased motivation (45% versus 36% in males), impulse dyscontrol (40% versus 44% in males; p  = 0.001) and social inappropriateness (12% versus 15% ; p  <  0.001), while they showed more often symptoms of emotional dysregulation (45% versus 36% ; p  <  0.001). The associations of MBI domains with some measures of cognitive performance and decline were stronger in males than females, with the exception of the association of emotional dysregulation with the rate of cognitive decline in verbal reasoning, which was present exclusively in females. Conclusion: MBI may influence cognition to a greater extent in males than in females. We propose that predictors and biomarkers of dementia should consider gender/sex as an effect modifier. Show more

Keywords: Behavioral symptoms, cognition, dementia, gender differences, sex differences

DOI: 10.3233/JAD-220040

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

Authors: Yeung, Michael K. | Lee, Tsz-lok | Chan, Agnes S.

Article Type: Research Article

Abstract: Background: Identifying individuals at increased risks for developing Alzheimer’s disease (AD) is crucial for early intervention. Memory complaints are associated with brain abnormalities characteristic of AD in cognitively normal older people. However, the utility of memory complaints for predicting mild cognitive impairment (MCI) or AD onset remains controversial, likely due to the heterogeneous nature of this construct. Objective: We investigated whether prefrontal oxygenation changes measured by functional near-infrared spectroscopy (fNIRS) during an arduous cognitive task, previously shown to be associated with the AD syndrome, could differentiate memory abilities among individuals with memory complaints. Episodic memory performance was adopted …as a proxy for MCI/AD risks since it has been shown to predict AD progression across stages. Methods: Thirty-six adults self-reporting memory complaints in the absence of memory impairment completed a verbal list learning test and underwent a digit n -back paradigm with an easy (0-back) and a difficult (2-back) condition. K-means clustering was applied to empirically derive memory complaint subgroups based on fNIRS-based prefrontal oxygenation changes during the effortful 2-back task. Results: Cluster analysis revealed two subgroups characterized by high (n  = 12) and low (n  = 24) bilateral prefrontal activation during the 2-back but not a 0-back task. The low activation group was significantly less accurate across the n -back task and recalled significantly fewer words on the verbal memory test compared to the high activation group. Conclusion: fNIRS may have the potential to differentiate verbal memory abilities in individuals with self-reported memory complaints. Show more

Keywords: Episodic memory, fNIRS, k-means, memory complaints, n-back, prefrontal cortex

DOI: 10.3233/JAD-220130

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

Authors: Agger, Mikkel Pejstrup | Carstensen, Marcus Schultz | Henney, Mark Alexander | Hansen, Luna Skytte | Baandrup, Anders Ohlhues | Nguyen, Mai | Petersen, Paul Michael | Madsen, Kristoffer Hougaard | Kjær, Troels Wesenberg

Article Type: Research Article

Abstract: Background: Exposure to 40 Hz stroboscopic light, for one hour a day, has previously been published as a potential treatment option for Alzheimer’s disease in animal models. However, exposure for an hour a day to 40 Hz stroboscopic light can be strenuous and examining other types of 40 Hz inducing stimuli is paramount if chronic treatment is wanted. Objective: A core assumption behind ensuring a therapeutic outcome is that the visual stimuli can induce 40 Hz gamma entrainment. Here, we examine whether a specific visual stimulus, 40 Hz invisible spectral flicker (ISF), can induce gamma entrainment and how it differs from both continuous …light (CON) and 40 Hz stroboscopic light (STROBE). Methods: The study included non-simultaneous EEG-fMRI neuroimaging of 13 young healthy volunteers during light exposure. Each light condition (i.e., CON, ISF, or STROBE) was active for 30 seconds followed immediately by the next. Results: Entrainment of 40 Hz neural activity were significantly higher signal-to-noise ratio during exposure to ISF (mean: 3.03, 95% CI 2.07 to 3.99) and STROBE (mean: 12.04, 95% CI 10.18 to 13.87) compared to CON. Additionally STROBE had a higher entrainment than ISF (mean: 9.01, 95% CI 7.16 to 12.14). Conclusion: This study presents a novel method of 40 Hz entrainment using ISF. This enables the possibility of future randomized placebo-controlled clinical trials with acceptable double blinding due to the essentially imperceivable flicker, which is expected to substantially reduce discomfort compared to interventions with stroboscopic flicker. Show more

Keywords: 40 Hz, Alzheimer’s disease, electroencephalograph, functional MRI, gamma entrainment, GENUS, invisible spectral flicker, light-based neurostimulation, steady state visually evoked potentials

DOI: 10.3233/JAD-220081

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

Authors: Hendriks, Stevie | Peetoom, Kirsten | Tange, Huibert | van Bokhoven, Marloes A. | van der Flier, Wiesje M. | Bakker, Christian | Papma, Janne M. | Koopmans, Raymond | Verhey, Frans | Köhler, Sebastian | de Vugt, Marjolein

Article Type: Research Article

Abstract: Background: Young-onset dementia (YOD) has many underlying etiologies, leading to a large heterogeneity in first symptoms. This makes it difficult for general practitioners (GPs) to recognize YOD. Objective: Identify early symptoms that are more common in the pre-diagnostic phase of YOD. Methods: We performed a case-control study nested in a primary-care registry on 89 cases and 162 matched controls, where we compared symptoms of people with YOD up to 5 years before diagnosis to their matched control group without YOD. The variables included in this study were International Classification of Primary Care codes and symptoms extracted …from written GP notes and categorized in groups. We used Generalized Equation Estimation to analyze symptom’s time-trajectories and logistic regression and ROC-curves to analyze differences in number of symptom categories reported. Results: Cognitive symptoms were more common in people with YOD 5 years before diagnosis, affective symptoms 4 years before diagnosis, social symptoms 3 years, behavioral symptoms 2 years, and daily functioning disturbances 1 year before diagnosis. The ROC-curve suggested that reporting two or more symptom categories at the GP gave the best trade-off between sensitivity (85%) and specificity (77% ), for the highest percentage of correctly diagnosed persons. Conclusion: This study showed people with YOD present differently than people without YOD. However, it may still be difficult for GPs to use these symptom categories to distinguish people with YOD, since the symptoms also occur in people with other diseases. A combination of reported symptom categories increases the probability of an underlying cause of YOD. Show more

Keywords: Case-control study, dementia, general practice, middle aged

DOI: 10.3233/JAD-220215

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

Authors: Liang, Yajun | Gao, Ya | Wang, Rui | Grande, Giulia | Monastero, Roberto | Dong, Yanhong | Jiang, Xin | Lv, Peiyuan | Qiu, Chengxuan

Article Type: Research Article

Abstract: Background: The potential impact of migraine on cognitive aging among older adults remains controversial. Objective: To examine the relationship of migraine and subtypes with cognitive decline and dementia in an older Swedish population. Methods: This population-based study included 3069 participants (age≥60) from the Swedish National study on Aging and Care in Kungsholmen, Stockholm. Baseline examination was conducted in 2001–2004, and participants were followed every 3 or 6 years until 2013–2016. Data were collected through face-to-face interviews, clinical examinations, laboratory tests, and linkage with registers. Global cognitive function was measured with the Mini-Mental State Examination (MMSE). Dementia …was diagnosed according to the DSM-IV criteria. Migraine and subtypes were defined following the international classification system. Data were analyzed using logistic regression, Cox regression, and linear mixed-effects models. Results: At baseline, 305 participants were defined with non-migraine headache and 352 with migraine. The cross-sectional analysis showed that the multivariable-adjusted odds ratio (95% confidence interval) of prevalent dementia was 0.49 (0.20–1.21) for migraine and 0.66 (0.26–1.66) for migraine without aura. The longitudinal analysis showed that the multivariable-adjusted hazard ratios of incident dementia associated with migraine and subtypes ranged 0.68–0.89 (p  > 0.05). Furthermore, migraine and subtypes were not significantly associated with either baseline MMSE score or MMSE changes during follow-ups (p  > 0.05). The nonsignificant associations did not vary substantially by age, APOE ɛ 4 allele, cerebrovascular disease, and antimigraine treatment (p for interactions > 0.05). Conclusion: This study shows no evidence supporting the associations of migraine and its subtypes with cognitive decline and dementia among older adults. Show more

Keywords: Cognitive aging, dementia, headache, migraine, population-based study

DOI: 10.3233/JAD-220013

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2022

Authors: Drouin, Shannon M. | McFall, G. Peggy | Potvin, Olivier | Bellec, Pierre | Masellis, Mario | Duchesne, Simon | Dixon, Roger A. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Hippocampal atrophy is a well-known biomarker of neurodegeneration, such as that observed in Alzheimer’s disease (AD). Although distributions of hippocampal volume trajectories for asymptomatic individuals often reveal substantial heterogeneity, it is unclear whether interpretable trajectory classes can be objectively detected and used for prediction analyses. Objective: To detect and predict hippocampal trajectory classes in a computationally competitive context using established AD-related risk factors/biomarkers. Methods: We used biomarker/risk factor and longitudinal MRI data in asymptomatic adults from the AD Neuroimaging Initiative (n  = 351; Mean  = 75 years; 48.7% female). First, we applied latent class growth analyses to …left (LHC) and right (RHC) hippocampal trajectory distributions to identify distinct classes. Second, using random forest analyses, we tested 38 multi-modal biomarkers/risk factors for their relative importance in discriminating the lower (potentially elevated atrophy risk) from the higher (potentially reduced risk) class. Results: For both LHC and RHC trajectory distribution analyses, we observed three distinct trajectory classes. Three biomarkers/risk factors predicted membership in LHC and RHC lower classes: male sex, higher education, and lower plasma Aβ1–42 . Four additional factors selectively predicted membership in the lower LHC class: lower plasma tau and Aβ1–40 , higher depressive symptomology, and lower body mass index. Conclusion: Data-driven analyses of LHC and RHC trajectories detected three classes underlying the heterogeneous distributions. Machine learning analyses determined three common and four unique biomarkers/risk factors discriminating the higher and lower LHC/RHC classes. Our sequential analytic approach produced evidence that the dynamics of preclinical hippocampal trajectories can be predicted by AD-related biomarkers/risk factors from multiple modalities. Show more

Keywords: Biomarker predictions, hippocampal atrophy, latent class growth analyses, random forest analyses, trajectory classes

DOI: 10.3233/JAD-215289

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-19, 2022

Authors: Zhang, Xingxing | Guan, Qing | Li, Yingjia | Zhang, Jianfeng | Zhu, Wanlin | Luo, Yuejia | Zhang, Haobo | Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: BOLD signals in the gray matter (GM) and white matter (WM) are tightly coupled. However, our understanding of the cross-tissue functional network in Alzheimer’s disease (AD) is limited. Objective: We investigated the changes of cross-tissue functional connectivity (FC) metrics for the GM regions susceptible to AD damage. Methods: For each GM region in the default mode (DMN) and limbic networks, we obtained its low-order static FC with any WM region, and the high-order static FC between any two WM regions based on their FC pattern similarity with multiple GM regions. The dynamic and directional properties …of cross-tissue FC were then acquired, specifically for the regional pairs whose low- or high-order static FCs showed significant differences between AD and normal control (NC). Moreover, these cross-tissue FC metrics were correlated with voxel-based GM volumes and MMSE in all participants. Results: Compared to NC, AD patients showed decreased low-order static FCs between the intra-hemispheric GM-WM pairs (right ITG-right fornix ; left MoFG-left posterior corona radiata ), and increased low-order static, dynamic, and directional FCs between the inter-hemispheric GM-WM pairs (right MTG-left superior/posterior corona radiata ). The high-order static and directional FCs between the left cingulate bundle -left tapetum were increased in AD, based on their FCs with the GMs of DMN. Those decreased and increased cross-tissue FC metrics in AD had opposite correlations with memory-related GM volumes and MMSE (positive for the decreased and negative for the increased). Conclusion: Cross-tissue FC metrics showed opposite changes in AD, possibly as useful neuroimaging biomarkers to reflect neurodegenerative and compensatory mechanisms. Show more

Keywords: Alzheimer’s disease, directional, dynamic, functional connectivity, gray matter, high-order, static, white matter

DOI: 10.3233/JAD-215649

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

Authors: Contador, Israel | Alzola, Patricia | Bermejo-Pareja, Félix | del Ser, Teodoro | Llamas-Velasco, Sara | Fernández-Calvo, Bernardino | Benito-León, Julián

Article Type: Research Article

Abstract: Background: A protective effect of education on cognitive decline after stroke has been claimed, but evidence from prospective population-based cohorts is very limited. The differential role of literacy and education on dementia after stroke remains unexplored. Objective: This research addresses the role of education and literacy in dementia incidence after stroke and transient ischemic attack (TIA). Methods: 131 participants with stroke or TIA were identified within the population-based NEDICES study (N  = 5,278 persons). Participants were fully assessed at baseline (1994–1995) and incident dementia diagnosis was made by expert neurologists (DSM-IV criteria) after a mean follow-up of …3.4 years. Adjusted Cox regression analyses were applied to test the association between education, literacy, and dementia risk. Results: Within the 131 subjects with stroke or TIA, 19 (14%) developed dementia at follow-up. The Cox’s regression model (age and sex adjusted) showed that low education (HR = 3.48, 95% CI = 1.28, 9.42, p  = 0.014) and literacy (HR = 3.16, 95% CI = 1.08, 9.22, p  = 0.035) were significantly associated with a higher dementia risk. Low education was also associated with dementia when main confounders (i.e., cognitive/functional performance) were considered in the Cox’s model. However, after including stroke recurrence, only low/null literacy (versus education) remained as significant predictor of dementia. Finally, low/null literacy showed an effect over-and-above education on dementia risk when both factors were introduced in the adjusted Cox’s regression. Conclusion: These findings underline the importance of literacy to estimate cognitive decline after stroke in low-educated populations. Show more

Keywords: Cognitive reserve, illiteracy, low education, stroke, transient ischemic attack

DOI: 10.3233/JAD-220109

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2022

Authors: Wu, Fen | Davey, Samuel | Clendenen, Tess V. | Koenig, Karen L. | Afanasyeva, Yelena | Zhou, Boyan | Bedi, Sukhleen | Li, Huilin | Zeleniuch-Jacquotte, Anne | Chen, Yu

Article Type: Research Article

Abstract: Background: Epidemiological studies that investigate alterations in gut microbial composition associated with cognitive dysfunction are limited. Objective: To examine the association between the gut microbiota and subjective memory complaints (SMCs), a self-reported, validated indicator of cognitive dysfunction. Methods: In this cross-sectional study of 95 older women selected from the New York University Women’s Health Study (NYUWHS), we characterized the gut microbial composition using 16S rRNA gene sequencing. We estimated odds ratio (OR) from beta regression which approximates the ratio of mean relative abundances of individual bacterial taxon from phylum to genus levels by binary (2+ versus …< 2) and continuous SMCs. Results: Women reporting 2 or more SMCs had higher relative abundances of genus Holdemania and family Desulfovibrionaceae compared with those reporting one or no complaint. Compared with women with < 2 SMCs, the relative abundances of Holdemania and family Desulfovibrionaceae were 2.09 times (OR: 2.09, 95% confidence interval [CI]: 1.38–3.17) and 2.10 times (OR: 2.10, 95% CI: 1.43–3.09) higher in women with 2+ SMCs, respectively (false discovery rate (FDR)-adjusted p = 0.038 and 0.010, respectively). A dose-response association was observed for genus Sutterella and family Desulfovibrionaceae . Every one-unit increase in SMCs was associated with 25% and 27% higher relative abundances of Sutterella (OR: 1.25; 95% CI: 1.11–1.40) and Desulfovibrionaceae (OR: 1.27; 95% CI: 1.13–1.42), respectively (FDR-adjusted p  = 0.018 and 0.006, respectively). Conclusion: Our findings support an association between alterations in the gut bacterial composition and cognitive dysfunction. Show more

Keywords: 16S RNA gene sequencing, cross-sectional, gut microbiota, NYUWHS, subjective memory complaints

DOI: 10.3233/JAD-220011

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2022

Authors: Ang, Su Fen | Low, Serena | Ng, Tze Pin | Tan, Clara S.H. | Ang, Keven | Lim, Ziliang | Tang, Wern Ee | Subramaniam, Tavintharan | Sum, Chee Fang | Lim, Su Chi

Article Type: Research Article

Abstract: Background: Type 2 diabetes mellitus (T2DM) has been shown to increase the risks of cognitive decline and dementia. Paired box gene 4 (PAX4), a transcription factor for beta cell development and function, has recently been implicated in pathways intersecting Alzheimer’s disease and T2DM. Objective: In this report, we evaluated the association of the ethnic-specific PAX4 R192H variant, a T2DM risk factor for East Asians which contributes to earlier diabetes onset, and cognitive function of Chinese T2DM patients. Methods: 590 Chinese patients aged 45–86 from the SMART2D study were genotyped for PAX4 R192H variation using …Illumina OmniExpress-24 Array. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) which had been validated in the Singapore population was administered to assess five cognitive domains: immediate memory, visuospatial/constructional, language, attention, and delayed memory. Multiple linear regression was used to assess the association of the R192H risk allele and cognitive domains. Results: Patients with two PAX4 R192H risk alleles showed significantly lower attention index score (β= –8.46, 95% CI [–13.71, –3.21], p  = 0.002) than patients with wild-type alleles after adjusting for age, gender, diabetes onset age, HbA1c, body-mass index, renal function, lipid profiles, systolic blood pressure, metformin usage, smoking history, education level, Geriatric Depression Scale score, and presence of APOE ɛ 4 allele. Conclusion: Ethnic-specific R192H variation in PAX4 is associated with attention-specific cognitive impairment in Chinese with T2DM. Pending further validation studies, determining PAX4 R192H genotype may be helpful for early risk assessment of early-onset T2DM and cognitive impairment to improve diabetes care. Show more

Keywords: Cognitive impairment, ethnic-specific, PAX4, type 2 diabetes

DOI: 10.3233/JAD-220036

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2022

Authors: Fernandes, Mariana | Chiaravalloti, Agostino | Manfredi, Natalia | Placidi, Fabio | Nuccetelli, Marzia | Izzi, Francesca | Camedda, Riccardo | Bernardini, Sergio | Schillaci, Orazio | Mercuri, Nicola Biagio | Liguori, Claudio

Article Type: Research Article

Abstract: Background: Sleep disorders may cause dysregulation of cerebral glucose metabolism and synaptic functions, as well as alterations in cerebrospinal fluid (CSF) biomarker levels. Objective: This study aimed at measuring sleep, CSF Alzheimer’s disease (AD) biomarkers, and cerebral glucose consumption in patients with obstructive sleep apnea syndrome (OSAS) and patients with periodic limb movement disorder (PLMD), compared to controls. Methods: OSAS and PLMD patients underwent 18 F-fluoro-2-deoxy-D-glucose positron emission tomography (18 F-FDG PET), polysomnographic monitoring, and lumbar puncture to quantify CSF levels of amyloid-β42 (Aβ42 ), total tau, and phosphorylated tau. All patients were compared to …controls, who were not affected by sleep or neurodegenerative disorders. Results: Twenty OSAS patients, 12 PLMD patients, and 15 controls were included. Sleep quality and sleep structure were altered in both OSAS and PLMD patients when compared to controls. OSAS and PLMD patients showed lower CSF Aβ42 levels than controls. OSAS patients showed a significant increase in glucose uptake in a wide cluster of temporal-frontal areas and cerebellum, as well as a reduced glucose consumption in temporal-parietal regions compared to controls. PLMD patients showed increased brain glucose consumption in the left parahippocampal gyrus and left caudate than controls. Conclusion: Sleep dysregulation and nocturnal hypoxia present in OSAS patients, more than sleep fragmentation in PLMD patients, were associated with the alteration in CSF and 18 F-FDG PET AD biomarkers, namely reduction of CSF Aβ42 levels and cerebral glucose metabolism dysregulation mainly in temporal areas, thus highlighting the possible role of sleep disorders in driving neurodegenerative processes typical of AD pathology. Show more

Keywords: Alzheimer’s disease, amyloid-β , brain glucose consumption, cerebrospinal fluid, positron emission tomography, sleep

DOI: 10.3233/JAD-215734

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2022

Authors: Zhang, Yinghan | Hu, Yazhuo | Han, Zhitao | Geng, Yan | Xia, Zheng | Zhou, Yongsheng | Wang, Zhenfu | Wang, Yuanyuan | Kong, Eryan | Wang, Xiaoning | Jia, Jianjun | Zhang, Honghong

Article Type: Research Article

Abstract: Background: Synaptic abnormalities in synaptic proteins are the initial hallmarks of Alzheimer’s disease (AD). The higher level of palmitoylation of synaptic proteins was closely associated with amyloid-β (Aβ) in AD. Cattle encephalon glycoside and ignotin (CEGI) have been shown to act as multitarget neurotrophic agents in APPswe/PS1dE9 (APP/PS1) transgenic AD mice. However, it is not clear whether CEGI can influence Aβ deposition or whether it does so by the regulation of protein palmitoylation and expression of synaptic proteins in transgenic AD mice. Objective: In this study, we investigated the roles of CEGI in modulating postsynaptic density protein 95 …(PSD-95) palmitoylation, Aβ pathologies, and expression of synaptic-associated proteins in APP/PS1 mice. Methods: Five-month-old APP/PS1 mice were treated intraperitoneally with 6.6 mL/kg of CEGI for 6 weeks. At the end of the treatment period, APP/PS1 mice were subjected to Morris water maze to test their cognitive functions. Acyl-biotinyl exchange (ABE) for PSD-95 palmitoylation, immunofluorescent staining for expression of PSD-95, N-methyl-D-aspartic acid receptor subunit 2B (NR2B), and synaptotagmin 1 (SYT1) were assessed in mouse brain sections. Results: CEGI treatment in APP/PS1 mice significantly reduced Aβ deposition, relieved memory deficits, and decreased PSD-95 palmitoylation while markedly increasing the expression of PSD-95, NR2B, and SYT1 in the frontal cortex. There was a significant correlation between Aβ expression and PSD-95 palmitoylation in APP/PS1 mice. Conclusion: Our findings demonstrate that CEGI improved AD-like neuropathology, possibly by inhibiting PSD-95 palmitoylation, improving learning memory, and enhancing expression of synaptic-associated proteins, representing a potential therapy for AD treatment. Show more

Keywords: Alzheimer’s disease, APP/PS1 transgenic mice, palmitoylation, postsynaptic density protein 95

DOI: 10.3233/JAD-220009

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2022

Authors: Welty, Starr | Thathiah, Amantha | Levine, Arthur Samuel

Article Type: Research Article

Abstract: Background: Recent studies suggest a strong association between neuronal DNA damage, elevated levels of amyloid-β (Aβ), and regions of the brain that degenerate in Alzheimer’s disease (AD). Objective: To investigate the nature of this association, we tested the hypothesis that extensive DNA damage leads to an increase in Aβ40 and Aβ42 generation. Methods: We utilized an immortalized human neuronal progenitor cell line (NPCs), ReN VM GA2. NPCs or 20 day differentiated neurons were treated with hydrogen peroxide or etoposide and allowed to recover for designated times. Sandwich ELISA was used to assess secreted Aβ40 …and Aβ42 . Western blotting, immunostaining, and neutral comet assay were used to evaluate the DNA damage response and processes indicative of AD pathology. Results: We determined that global hydrogen peroxide damage results in increased cellular Aβ40 and Aβ42 secretion 24 h after treatment in ReN GA2 NPCs. Similarly, DNA double strand break (DSB)-specific etoposide damage leads to increased Aβ40 and Aβ42 secretion 2 h and 4 h after treatment in ReN GA2 NPCs. In contrast, etoposide damage does not increase Aβ40 and Aβ42 secretion in post-mitotic ReN GA2 neurons. Conclusion: These findings provide evidence that in our model, DNA damage is associated with an increase in Aβ secretion in neuronal progenitors, which may contribute to the early stages of neuronal pathology in AD. Show more

Keywords: Alzheimer’s disease, amyloid-β , DNA repair, double strand breaks, etoposide, neurodegenerative disease, oxidative damage

DOI: 10.3233/JAD-220030

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2022

Authors: Helboe, Lone | Rosenqvist, Nina | Volbracht, Christiane | Pedersen, Lars Ø. | Pedersen, Jan T. | Christensen, Søren | Egebjerg, Jan | Christoffersen, Claus T. | Bang-Andersen, Benny | Beach, Thomas G. | Serrano, Geidy E. | Falsig, Jeppe

Article Type: Research Article

Abstract: Background: Deposits of hyperphosphorylated tau fibrils are hallmarks of a broad spectrum of tauopathies, including Alzheimer’s disease (AD). Objective: To investigate heterogeneity of tau pathology across brain extracts from a broad selection of different tauopathies and examine the binding properties of the humanized pS396-tau antibody hC10.2 and six other anti-tau antibodies. Methods: 76 individual tauopathy tissue samples were analyzed in a battery of assays: immunohistochemistry, ELISA, tau aggregation assay, western blot, [3 H]PI-2620 and [3 H]MK-6240 tau tracer binding, and aggregated seeding activity in RD_P301S HEK293T Biosensor cells. The efficiency of seven anti-tau antibodies to engage …with pathological tau species was directly compared. Results: Our data indicate that a strong correlation existed between the tau tracer binding, amount of tau aggregates, pS396-tau phosphorylation, and seeding activity. The hC10.2 antibody, which has entered clinical development, effectively engaged with its epitope across all individual cases of mid-stage and late AD, and primary tauopathies. hC10.2 was superior compared to other phospho- and total tau antibodies to prevent seeded tau aggregation in the biosensor cells. hC10.2 effectively depleted hyperphosphorylated and aggregated tau species across all tauopathy samples proportionally to the amount of tau aggregates. In AD samples, hC10.2 bound to ghost tangles which represent extracellular pathological tau species. Conclusion: S396 hyperphosphorylation is a feature of the formation of seeding-competent tau across different tauopathies and it is present both in intra- and extracellular pathological tau. hC10.2 represents an excellent candidate for a hyperphosphorylation-selective therapeutic tau antibody for the treatment of AD and primary tauopathies. Show more

Keywords: Alzheimer’s disease, human brain tissue, humanized antibody, PET tracer, seeding and spreading, tau aggregate, tauopathy, therapeutic monoclonal antibody

DOI: 10.3233/JAD-220125

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-22, 2022

Authors: Asaoka, Daisuke | Xiao, Jinzhong | Takeda, Tsutomu | Yanagisawa, Naotake | Yamazaki, Takahiro | Matsubara, Yoichiro | Sugiyama, Hideki | Endo, Noemi | Higa, Motoyuki | Kasanuki, Koji | Ichimiya, Yosuke | Koido, Shigeo | Ohno, Kazuya | Bernier, Francois | Katsumata, Noriko | Nagahara, Akihito | Arai, Heii | Ohkusa, Toshifumi | Sato, Nobuhiro

Article Type: Research Article

Abstract: Background: Probiotics have been reported to ameliorate cognitive impairment. Objective: We investigated the effect of the probiotic strain Bifidobacterium breve MCC1274 (A1) in enhancing cognition and preventing brain atrophy of older patients with mild cognitive impairment (MCI). Methods: In this RCT, 130 patients aged from 65 to 88 years old with suspected MCI received once daily either probiotic (B. breve MCC1274, 2×1010 CFU) or placebo for 24 weeks. Cognitive functions were assessed by ADAS-Jcog and MMSE tests. Participants underwent MRI to determine brain atrophy changes using Voxel-based Specific Regional Analysis System for Alzheimer’s …disease (VSRAD). Fecal samples were collected for the analysis of gut microbiota composition. Results: Analysis was performed on 115 participants as the full analysis set (probiotic 55, placebo 60). ADAS-Jcog subscale “orientation” was significantly improved compared to placebo at 24 weeks. MMSE subscales “orientation in time” and “writing” were significantly improved compared to placebo in the lower baseline MMSE (<  25) subgroup at 24 weeks. VSRAD scores worsened in the placebo group; probiotic supplementation tended to suppress the progression, in particular among those subjects with progressed brain atrophy (VOI Z-score ≥1.0). There were no marked changes in the overall composition of the gut microbiota by the probiotic supplementation. Conclusion: Improvement of cognitive function was observed on some subscales scores only likely due to the lower sensitiveness of these tests for MCI subjects. Probiotics consumption for 24 weeks suppressed brain atrophy progression, suggesting that B. breve MCC1274 helps prevent cognitive impairment of MCI subjects. Show more

Keywords: Bifidobacterium, brain atrophy, cognitive function, mild cognitive impairment, probiotics

DOI: 10.3233/JAD-220148

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-21, 2022

Authors: Wang, Wendy | Gottesman, Rebecca F. | Meyer, Michelle L. | Hughes, Timothy M. | Sullivan, Kevin J. | Wong, Dean F. | Lakshminarayan, Kamakshi | Lutsey, Pamela L.

Article Type: Short Communication

Abstract: We assessed whether carotid intima-media thickness (cIMT) is prospectively associated with amyloid-β (Aβ). 332 nondemented Atherosclerosis Risk in Communities Study participants with carotid ultrasounds (1990–1992) and PET scans (2012–2014) were studied. Participants in the highest (versus lowest) cIMT tertile had 2.17 times the odds of elevated Aβ (95%CI: 1.15–4.11), after demographic and APOE ɛ adjustments. An interaction with APOE ɛ was observed (p  = 0.02). Greater cIMT was associated with elevated Aβ independent of vascular risk factors among those with ≥1 APOE ɛ allele, but not in noncarriers. In this cohort, higher cIMT was associated with Aβ deposition …22 years later, particularly among APOE ɛ carriers. Show more

Keywords: Alzheimer’s disease, amyloid-β, carotid intima-media thickness, carotid ultrasound, florbetapir PET

DOI: 10.3233/JAD-215671

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-6, 2022

Authors: Umegaki, Hiroyuki | Suzuki, Yusuke | Komiya, Hitoshi | Watanabe, Kazuhisa | Nagae, Masaaki | Yamada, Yosuke

Article Type: Short Communication

Abstract: Quality of life (QOL) was assessed using the EQ-5D twice in 1 year in 57 older community-dwelling people (age 79.1±5.9 years) with mild cognitive impairment in a memory clinic. Screening for sarcopenia at the initial assessment revealed 40.1% of participants (23/57) were sarcopenic. QOL declined in 33.3% of participants (19/57) after around 1 year. Multiple logistic regression analysis showed that sarcopenia was associated with a decline in QOL around 1 year after initial assessment. Sarcopenia may be a risk factor for decline in QOL in older people with mild cognitive impairment.

Keywords: Appendicular muscle mass, EQ-5D, gait, grip, mild cognitive impairment, quality of life, sarcopenia

DOI: 10.3233/JAD-220123

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-5, 2022

Authors: Nakanishi, Miharu | Yamasaki, Syudo | Ando, Shuntaro | Endo, Kaori | Richards, Marcus | Hiraiwa-Hasegawa, Mariko | Kasai, Kiyoto | Nishida, Atsushi

Article Type: Research Article

Abstract: Background: Middle-aged adults may be the ideal target group for dementia-related stigma reduction interventions to encourage the utilization of services among those who may become family caregivers. Neighborhood social cohesion may diminish dementia-related stigma, particularly in terms of perceived public attitudes. The COVID-19 pandemic can further negatively impact perceived public stigma. Objective: To investigate the association between neighborhood social cohesion and dementia-related stigma during the pre- and current COVID-19 period. Methods: We employed a cross-sectional design using data from a large population-based cohort, the Tokyo Teen Cohort, in Japan. Overall, 2,469 mothers of 16-year-old adolescents self-completed …a questionnaire comprising nine dementia-related stigma questions evaluating perceived public and personal attitudes. Neighborhood social cohesion was assessed using a five-item instrument. The participants were divided into two groups according to the time of assessment: prior to the pandemic’s onset (February 2019–March 2020) and during the pandemic (April 2020–July 2021). A multiple regression analysis of stigma was performed using neighborhood social cohesion as an independent variable, and caring experience, age, educational level, and working status as covariates. Results: Personal and perceived public stigma were significantly lower in participants who perceived greater neighborhood social cohesion. However, level of personal and perceived public stigma did not differ between pre- and during the pandemic period. Conclusion: Neighborhood social cohesion may be a modifiable factor for dementia-related stigma. A localized intervention to enhance social cohesion in the neighborhood community would promote the utilization of services among those who may become family caregivers. Show more

Keywords: Asia, dementia, middle aged, mothers, social stigma

DOI: 10.3233/JAD-220043

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

Authors: Fohner, Alison E. | Sitlani, Colleen M. | Buzkova, Petra | Doyle, Margaret F. | Liu, Xiaojuan | Bis, Joshua C. | Fitzpatrick, Annette | Heckbert, Susan R. | Huber, Sally A. | Kuller, Lewis | Longstreth, William T. | Feinstein, Matthew J. | Freiberg, Matthew | Olson, Nels C. | Seshadri, Sudha | Lopez, Oscar | Odden, Michelle C. | Tracy, Russell P. | Psaty, Bruce M. | Delaney, Joseph A. | Floyd, James S.

Article Type: Short Communication

DOI: 10.3233/JAD-220091

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2022

Authors: Das, Tushar K. | Blasco-Conesa, Maria P. | Korf, Janelle | Honarpisheh, Pedram | Chapman, Matthew R. | Ganesh, Bhanu P.

Article Type: Research Article

Abstract: Background: Substantial evidence from recent research suggests an influential and underappreciated force in Alzheimer’s disease (AD) pathogenesis: the pathological signals originate from outside the brain. Pathogenic bacteria produce amyloid-like proteins “curli” that form biofilms and show functional similarities to human amyloid-β (Aβ). These proteins may contribute to neurological disease progression via signaling cascade from the gut to the brain. Objective: We propose that curli causes neuroendocrine activation from the gut to brain that promotes central Aβ pathology. Methods: PGP9.5 and TLR2 levels in response to curli in the lumen of Tg2576 AD mice were analyzed by …immunohistochemical and qRT-PCR analysis. Western blot and human 3D in vitro enteroids culture systems were also used. 16S rRNA gene sequencing was used to investigate bacterial dysbiosis. Results: We found significant increase in bacterial-amyloid curli with elevated TLR2 at the mRNA level in the pre- and symptomatic Tg-AD gut compared to littermate WT controls. This data associates with increased gram-positive bacterial colonization in the ileum of the symptomatic AD mice. We found fundamental evidence for vagus nerve activation in response to bacterial curli. Neuroendocrine marker PGP9.5 was significantly elevated in the gut epithelium of symptomatic AD mice, and this was colocalized with increased TLR2 expression. Enteroids, 3D-human ileal mini-gut monolayer in vitro model system also revealed increase levels of TLR2 upon stimulation with purified bacterial curli fibrils. Conclusion: These findings reveal the importance of pathological changes within the gut-vagus-brain signaling in response to luminal bacterial amyloid that might play a vital role in central Aβ pathogenesis seen in the AD brain. Show more

Keywords: Alzheimer’s disease, amyloid-β, bacterial amyloid, curli, dysbiosis, enteroendocrine cell, gut barrier, gut-brain axis, neuroendocrine, PGP9.5, TLR2, vagus nerve

DOI: 10.3233/JAD-220106

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2022

Authors: Duan, Lian | Qian, Xueshen | Wang, Qin | Huang, Lan | Ge, Song

Article Type: Research Article

Abstract: Background: With advancements in periodontal medicine, the relationship between periodontitis and systemic diseases has garnered increasing attention. Recently, emerging evidence has indicated that periodontitis may be involved in the pathogenesis of Alzheimer’s disease (AD). Objective: To assess the impact of experimental periodontitis on cognitive function deficits in a rat model of streptozotocin-induced AD and determine the mechanisms underlying these effects. Methods: Rats were randomly assigned to the control (C), experimental periodontitis (P), Alzheimer’s disease (AD), and experimental periodontitis with streptozotocin-induced AD (AD-P) groups. Experimental periodontitis was induced using ligation and coating with Porphyromonas gingivalis . In …the AD-P group, AD was induced by intracerebroventricular injection of streptozotocin after 6 weeks of experimental periodontitis induction. Results: Compared with the group C rats, those in group P exhibited alveolar bone resorption, learning and memory function impairment, and decreased insulin sensitivity and insulin signaling-related protein expression. Glial cell activation and cognitive impairment in streptozotocin-induced groups with significantly increased phosphorylated tau levels were more pronounced relative to the C group. The number of neurons and insulin sensitivity and insulin signaling-related protein expression in group AD-P rats were lower than those in the AD alone group, while the expressions of glial fibrillary acidic protein, tau phosphorylation, interleukin-6, and cyclooxygenase-2 were significantly increased. Conclusion: Periodontitis may be a risk factor exacerbating cognitive deficits in an AD-like neurodegenerative context, possibly by impairing the insulin signaling pathway and stimulating gliosis and neuroinflammation. Show more

Keywords: Alzheimer’s disease, insulin sensitivity, insulin signaling pathway, periodontitis, streptozotocin

DOI: 10.3233/JAD-215720

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

Authors: Mandal, Pravat K. | Dwivedi, Divya | Shukla, Deepika | Samkaria, Avantika | Roy, Rimil Guha | Arora, Yashika | Jindal, Komal

Article Type: Research Article

Abstract: Oxidative stress (OS) is a critical factor in the pathogenesis of Alzheimer’s disease (AD). Elevated OS in AD lowers the level of glutathione (GSH), a brain antioxidant. Currently, GSH is under examination in the clinical population for understanding its association with oxidative load in AD research. Significant depletion in hippocampal GSH, as observed using in vivo magnetic resonance spectroscopy (MRS), reportedly correlates with cognitive impairment in AD. Alterations in cellular-energy metabolism and increased hippocampal pH have also been reported in AD. Hence, this combined molecular interplay between hippocampal GSH and pH must be studied longitudinally for advancing AD research. …Herein, we propose a schematic model depicting the molecular events in AD pathogenesis and provide a possible link between OS, GSH depletion, and pH alterations in the hippocampus. The model would further potentiate the need for in vivo longitudinal studies to confirm the interlinked mechanism between OS, hippocampal GSH depletion, and pH increment in an AD patient brain. Show more

Keywords: cognitive dysfunction, glutathione, hippocampus, magnetic resonance spectroscopy, oxidative stress, pH

DOI: 10.3233/JAD-215729

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-6, 2022

Authors: Narukawa, Masataka | Mori, Yuko | Nishida, Riko | Takahashi, Suzuka | Saito, Takashi | Saido, Takaomi C. | Misaka, Takumi

Article Type: Short Communication

Abstract: Using an amyloid precursor protein (App ) gene knock-in (KI) mouse of Alzheimer’s disease (AD), we investigated the expression of olfactory-related genes in olfactory impairment caused by AD. We observed the change in olfactory behavior in the App -KI mice. There was no significant difference, however, in the mRNA expression levels of olfactory-related genes between the olfactory epithelia of wild-type (WT) and App -KI mice. Amyloid-β deposition was confirmed throughout the olfactory pathway in App -KI mice, but not in WT mice. These show that the change in olfactory behavior in the App -KI mice might cause by the impairment …of the olfactory pathway. Show more

Keywords: App knock-in mice, olfactory epithelium, olfactory impairment, olfactory related genes

DOI: 10.3233/JAD-220213

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2022

Authors: Leng, Fangda | Zhan, Zhenying | Sun, Yunchuang | Liu, Fang | Edison, Paul | Sun, Yongan | Wang, Zhaoxia | on behalf of Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Recently it has been proposed that microglial response has a stage-dependent effect on the progression of Alzheimer’s disease (AD). Cerebrospinal fluid (CSF) sTREM2 has emerged as a promising microglial activation marker. Objective: To test the stage-dependent role of microglia by studying the association between baseline sTREM2 and dynamic brain structural changes in AD and mild cognitive impairment (MCI) patients. Methods: 22 amyloid-β-positive (A+) and tau-positive (T+) AD and 24 A+T+MCI patients were identified from the Alzheimer’s Disease Neuroimaging Initiative. The patients had baseline CSF amyloid-β, phosphorylated-tau, and sTREM2, and were followed up for at least …one year by T1-weighted and diffusion tensor imaging scans. Gray matter volumes and white matter microstructural integrity were evaluated. Linear mixed models were applied to analyze how baseline sTREM2 may influence the rate of brain structural changes while adjusting for the effects of age, APOE4 status, and the CSF core markers. Results: In A+T+AD patients, baseline CSF sTREM2 was associated with faster mean diffusivity increase in the bilateral posterior corona radiata and right superior longitudinal fasciculus. In A+T+MCI patients, baseline CSF sTREM2 was associated slower gray matter volumetric loss in parahippocampal gyrus, left fusiform cortex, left middle temporal gyrus, and left lateral occipital cortex. Baseline CSF sTREM2 also had a protective effect against mean diffusivity increase in right inferior fronto-occipital fasciculus, left superior longitudinal fasciculus, left forceps minor, and left uncinate fasciculus. Conclusion: Microglial activation at early stage might have a protective effect against neurodegeneration, while at late stage it might facilitate AD. Future efforts on modulating microglial activation could be promising, given a carefully selected time window for intervention. Show more

Keywords: Alzheimer’s disease, diffusion tensor imaging, disease progression, microglial activation, sTREM2, voxel-based morphometry

DOI: 10.3233/JAD-220102

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

Authors: Karikari, Thomas K.

Article Type: Research Article

Abstract: The recent academic and commercial development, and regulatory approvals, of blood-based Alzheimer’s disease (AD) biomarkers are breakthrough developments of immense potential. However, clinical validation studies and therapeutic trial applications are limited almost exclusively to non-Hispanic White cohorts often including highly-educated, high-earning participants. This commentary argues that the true benefits of blood tests for AD will be realized by active inclusion of diverse groups including minoritized populations, people of socioeconomic status different from those included in existing cohorts, and residents of low- and middle-income countries. The article discusses key factors that are critical for a successful implementation of diversity programs.

Keywords: Alzheimer’s disease, amyloid-β, blood biomarker, dementia, diagnostics, low- and middle-income countries, minoritized populations, neurofilament light, phosphorylated tau

DOI: 10.3233/JAD-215730

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

Authors: Mozersky, Jessica | Roberts, J. Scott | Rumbaugh, Malia | Chhatwal, Jasmeer | Wijsman, Ellen | Galasko, Douglas | Blacker, Deborah | on behalf of AGREED

Article Type: Review Article

Abstract: In this article we address how the recent, and anticipated upcoming, FDA approvals of novel anti-amyloid medications to treat individuals with mild Alzheimer’s disease (AD) dementia could impact disclosure of biomarker results among asymptomatic research participants. Currently, research is typically the context where an asymptomatic individual may have the option to learn their amyloid biomarker status. Asymptomatic research participants who learn their amyloid status may have questions regarding the meaning of this result and the implications for accessing a potential intervention. After outlining our rationale, we provide examples of how current educational materials used in research convey messages regarding amyloid …positivity and the availability of treatments, or lack thereof. We suggest language to improve messaging, as well as strengths of current materials, in addressing these issues for research participants. Although novel medications are currently only approved for use among symptomatic individuals, their availability may have implications for disclosure among asymptomatic research participants with evidence of amyloid deposition, who may be especially interested in information on these interventions for potential prevention, or future treatment, of mild cognitive impairment or dementia due to AD. Show more

Keywords: Alzheimer’s disease, amyloid, asymptomatic disclosure, biomarkers, dementia, new medications, research ethics

DOI: 10.3233/JAD-220113

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2022

Authors: Largent, Emily A. | Bhardwaj, Twisha | Clapp, Justin T. | Sykes, Olivia Saúl | Harkins, Kristin | Grill, Joshua D.

Article Type: Research Article

Abstract: Background: Participants in Alzheimer’s disease (AD) prevention studies are generally required to enroll with a study partner; this requirement constitutes a barrier to enrollment for some otherwise interested individuals. Analysis of dyads enrolled in actual AD trials suggests that the study partner requirement shapes the population under study. Objective: To understand if individuals can identify someone to serve as their study partner and whether they would be willing to ask that individual. Methods: We conducted semi-structured interviews with cognitively unimpaired, English-speaking older adults who had previously expressed interest in AD research by signing up for a …research registry. We also interviewed their likely study partners. Audio-recorded interviews were transcribed and coded in an iterative, team-based process guided by a content analysis approach. Results: We interviewed 60 potential research participants and 17 likely study partners. Most potential participants identified one or two individuals they would be willing to ask to serve as their study partner. Interviewees saw value in the study partner role but also understood it to entail burdens that could make participation as a study partner more difficult. The role was seen as relatively more burdensome for individuals in the workforce or with family responsibilities. Calls from the researcher to discuss the importance of the role and the possibility of virtual visits were identified as potential strategies for increasing study partner availability. Conclusion: Efforts to increase recruitment, particularly representative recruitment, of participants for AD prevention studies should reduce barriers to participation by thoughtfully designing the study partner role. Show more

Keywords: Alzheimer’s disease, ethics, registries, research, research design

DOI: 10.3233/JAD-220061

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2022