Journal of Alzheimer's Disease - Volume 92, issue 2

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

Article Type: Article Commentary

Abstract: One of the main players in apoptosis during Alzheimer’s disease progression are different members of caspase family of proteases. The most well-known member of this family is caspase-3, in which alterations of its levels have been detected in samples from Alzheimer’s disease patients. There are numerous intracellular factors involved in regulation of cellular apoptosis through regulation of caspase-3 activity, the most important of which is the PI3K/AKT signaling pathway. This commentary tries to highlight the probable relations between PI3K/AKT signaling pathway and caspase-3 in Alzheimer’s disease.

Keywords: Alzheimer’s disease, apoptosis, caspase-3, PI3K/AKT

DOI: 10.3233/JAD-221157

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 391-393, 2023

Authors: Panyard, Daniel J. | Deming, Yuetiva K. | Darst, Burcu F. | Van Hulle, Carol A. | Zetterberg, Henrik | Blennow, Kaj | Kollmorgen, Gwendlyn | Suridjan, Ivonne | Carlsson, Cynthia M. | Johnson, Sterling C. | Asthana, Sanjay | Engelman, Corinne D. | Lu, Qiongshi

Article Type: Research Article

Abstract: Background: Our understanding of the pathophysiology underlying Alzheimer’s disease (AD) has benefited from genomic analyses, including those that leverage polygenic risk score (PRS) models of disease. The use of functional annotation has been able to improve the power of genomic models. Objective: We sought to leverage genomic functional annotations to build tissue-specific AD PRS models and study their relationship with AD and its biomarkers. Methods: We built 13 tissue-specific AD PRS and studied the scores’ relationships with AD diagnosis, cerebrospinal fluid (CSF) amyloid, CSF tau, and other CSF biomarkers in two longitudinal cohort studies of AD. …Results: The AD PRS model that was most predictive of AD diagnosis (even without APOE ) was the liver AD PRS: n  = 1,115; odds ratio = 2.15 (1.67–2.78), p  = 3.62×10–9 . The liver AD PRS was also statistically significantly associated with cerebrospinal fluid biomarker evidence of amyloid-β (Aβ42 :Aβ40 ratio, p  = 3.53×10–6 ) and the phosphorylated tau:amyloid-β ratio (p  = 1.45×10–5 ). Conclusion: These findings provide further evidence of the role of the liver-functional genome in AD and the benefits of incorporating functional annotation into genomic research. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid biomarkers, functional annotation, liver, polygenic risk score

DOI: 10.3233/JAD-220599

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 395-409, 2023

Authors: Tandon, Raghav | Levey, Allan I. | Lah, James J. | Seyfried, Nicholas T. | Mitchell, Cassie S.

Article Type: Research Article

Abstract: Background: The complex and not yet fully understood etiology of Alzheimer’s disease (AD) shows important proteopathic signs which are unlikely to be linked to a single protein. However, protein subsets from deep proteomic datasets can be useful in stratifying patient risk, identifying stage dependent disease markers, and suggesting possible disease mechanisms. Objective: The objective was to identify protein subsets that best classify subjects into control, asymptomatic Alzheimer’s disease (AsymAD), and AD. Methods: Data comprised 6 cohorts; 620 subjects; 3,334 proteins. Brain tissue-derived predictive protein subsets for classifying AD, AsymAD, or control were identified and validated with …label-free quantification and machine learning. Results: A 29-protein subset accurately classified AD (AUC = 0.94). However, an 88-protein subset best predicted AsymAD (AUC = 0.92) or Control (AUC = 0.92) from AD (AUC = 0.98). AD versus Control: APP, DHX15, NRXN1, PBXIP1, RABEP1, STOM, and VGF. AD versus AsymAD: ALDH1A1, BDH2, C4A, FABP7, GABBR2, GNAI3, PBXIP1, and PRKAR1B. AsymAD versus Control: APP, C4A, DMXL1, EXOC2, PITPNB, RABEP1, and VGF. Additional predictors: DNAJA3, PTBP2, SLC30A9, VAT1L, CROCC, PNP, SNCB, ENPP6, HAPLN2, PSMD4, and CMAS. Conclusion: Biomarkers were dynamically separable across disease stages. Predictive proteins were significantly enriched to sugar metabolism. Show more

Keywords: Alzheimer’s disease, biomarkers, machine learning, metabolism, proteomics, recursive feature elimination

DOI: 10.3233/JAD-220683

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 411-424, 2023

Authors: Beydoun, Hind A. | Beydoun, May A. | Maldonado, Ana I. | Fanelli-Kuczmarski, Marie T. | Weiss, Jordan | Evans, Michele K. | Zonderman, Alan B.

Article Type: Research Article

Abstract: Background: Cross-sectional studies have linked cognition to allostatic load (AL) which reflects multisystem dysregulation from life course exposure to stressors. Objective: To examine baseline and changes in AL and their relationships with 11 cognitive function test scores, while exploring health disparities according to sex and race. Methods: Longitudinal [Visit 1 (2004–2009) and Visit 2 (2009–2013)] data were analyzed from 2,223 Healthy Aging in Neighborhoods of Diversity across the Life Span participants. We calculated AL total score using cardiovascular, metabolic, and inflammatory risk indicators, and applied group-based trajectory modeling to define AL change. Results: Overall …and stratum-specific relationships were evaluated using mixed-effects linear regression models that controlled for socio-demographic, lifestyle, and health characteristics. Baseline AL was significantly associated with higher log-transformed Part A Trail Making Test score [Loge (TRAILS A)] (β = 0.020, p  = 0.004) and increasing AL was associated with higher Benton Visual Retention Test score [BVRT] (β = 0.35, p  = 0.002) at baseline, in models that controlled for age, sex, race, poverty status, education, literacy, smoking, drug use, the 2010 healthy eating index and body mass index. Baseline AL and AL change were not related to change in cognitive function between visits. There were no statistically significant interaction effects by sex or race in fully-adjusted models. Conclusion: At baseline, AL was associated with worse attention or executive functioning. Increasing AL was associated with worse non-verbal memory or visuo-constructional abilities at baseline. AL was not related to change in cognitive function over time, and relationships did not vary by sex or race. Show more

Keywords: Adults, allostatic load, cognitive function, health disparities, longitudinal study

DOI: 10.3233/JAD-220888

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 425-443, 2023

Authors: Teoh, Nicole Shu Ning | Gyanwali, Bibek | Lai, Mitchell K.P. | Chai, Yuek Ling | Chong, Joyce R. | Chong, Eddie Jun Yi | Chen, Christopher | Tan, Chuen Seng | Hilal, Saima

Article Type: Research Article

Abstract: Background: Neuroinflammation has been postulated to play an important role in cognitive impairment, cognitive decline, and dementia. Inflammatory biomarkers such as interleukin-6 (IL-6) and IL-8 are found to be associated with the neuro-inflammatory process and worse cognitive function. However, it is unknown whether these interleukins are associated with long-term cognitive function. Objective: To investigate the association of baseline IL-6 and IL-8 with cognitive function at baseline as well as its association with cognitive decline over five-year follow-up. Methods: 387 patients were recruited from an ongoing memory clinic-based study who underwent comprehensive physical, medical, neuropsychological and blood …assessments together with brain MRI. IL-6 and IL-8 were measured using LUMINEX assays. The National Institute of Neurological Disorders and Stroke-Canadian Stroke Network neuropsychological battery was used to assess cognitive decline across multiple domains. Results: Among the 387 (mean age = 72.9 years and 53.7% males) participants, 322 had at least two follow-up assessments and were included in the longitudinal analysis. Negative linear trend associations were found between tertiles of IL-8 with baseline global cognition (p-trend< 0.001), attention (p-trend = 0.005), executive function (p-trend< 0.001), and visuospatial function (p-trend = 0.002) domains. No association was found between baseline IL-8 and cognitive decline. IL-6 was not associated with both baseline and follow-up cognition. Conclusion: IL-8 was associated with worse cognition especially in attention, executive function, and visuospatial function, suggesting the role of neuroinflammation in cognitive impairment. Hence, blood inflammatory biomarkers may be useful indicators in identifying patients at risk of cognitive impairment and warrant consideration for inclusion in treatment trials. Show more

Keywords: Blood biomarker, cognitive decline, inflammation mediators, interleukin-6, interleukin-8, memory clinic

DOI: 10.3233/JAD-220971

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 445-455, 2023

Authors: Zhu, Carolyn W. | Gu, Yian | Kociolek, Anton J. | Fernandez, Kayri K. | Cosentino, Stephanie | Stern, Yaakov

Article Type: Research Article

Abstract: Background: Little is known regarding healthcare expenditures for patients with dementia with Lewy bodies (DLB) during the end of life. Objective: This study estimated Medicare expenditures during the last 5 years of life in a decedent sample of patients who were clinically diagnosed with Alzheimer’s disease (AD) or DLB and had autopsy confirmed diagnosis. Methods: The study included 58 participants clinically diagnosed with mild dementia at study entry (AD: n  = 44, DLB: n  = 14) and also had autopsy-confirmed diagnoses of pure AD (n  = 32), mixed AD+Lewy body (LB) (n  = 5), or pure LB (n  = 11). Total …Medicare expenditures were compared by clinical and pathology confirmed diagnosis, adjusting for sex, age at death, and patient’s cognition, function, comorbidities, and psychiatric and extrapyramidal symptoms. Results: When pathology diagnoses were not considered, predicted annualized total Medicare expenditures during the last 5 years of life were similar between clinically diagnosed AD ($7,465±1,098) and DLB ($7,783±1,803). When clinical diagnoses were not considered, predicted expenditures were substantially higher in patients with pathology confirmed mixed AD+LB ($12,005±2,455) than either pure AD ($6,173±941) or pure LB ($4,629±1,968) cases. Considering clinical and pathology diagnosis together, expenditures for patients with clinical DLB and pathology mixed AD+LB ($23,592±3,679) dwarfed other groups. Conclusion: Medicare expenditures during the last 5 years of life were substantially higher in patients with mixed AD+LB pathology compared to those with pure-AD and pure-LB pathologies, particularly in those clinically diagnosed with DLB. Results highlight the importance of having both clinical and pathology diagnoses in examining healthcare costs. Show more

Keywords: Alzheimer’s disease, clinical diagnosis, cost of care, dementia with Lewy bodies, Medicare claims, pathology confirmed diagnosis

DOI: 10.3233/JAD-221021

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 457-466, 2023

Authors: van den Berg, Emma | Nilsson, Johanna | Kersten, Iris | Brinkmalm, Gunnar | de Kort, Anna M. | Klijn, Catharina J.M. | Schreuder, Floris H.B.M. | Jäkel, Lieke | Gobom, Johan | Portelius, Erik | Zetterberg, Henrik | Brinkmalm, Ann | Blennow, Kaj | Kuiperij, H. Bea | Verbeek, Marcel M.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA) share pathogenic pathways related to amyloid-β deposition. Whereas AD is known to affect synaptic function, such an association for CAA remains yet unknown. Objective: We therefore aimed to investigate synaptic dysfunction in CAA. Methods: Multiple reaction monitoring mass spectrometry was used to quantify cerebrospinal fluid (CSF) concentrations of 15 synaptic proteins in CAA and AD patients, and age- and sex-matched cognitively unimpaired controls. Results: We included 25 patients with CAA, 49 patients with AD, and 25 controls. Only neuronal pentraxin-2 levels were decreased in …the CSF of CAA patients compared with controls (p  = 0.04). CSF concentrations of 12 other synaptic proteins were all increased in AD compared with CAA or controls (all p ≤0.01) and were unchanged between CAA and controls. Synaptic protein concentrations in the subgroup of CAA patients positive for AD biomarkers (CAA/ATN+; n  = 6) were similar to AD patients, while levels in CAA/ATN- (n  = 19) were comparable with those in controls. A regression model including all synaptic proteins differentiated CAA from AD at high accuracy levels (area under the curve 0.987). Conclusion: In contrast to AD, synaptic CSF biomarkers were found to be largely unchanged in CAA. Moreover, concomitant AD pathology in CAA is associated with abnormal synaptic protein levels. Impaired synaptic function in AD was confirmed in this independent cohort. Our findings support an apparent differential involvement of synaptic dysfunction in CAA and AD and may reflect distinct pathological mechanisms. Show more

Keywords: Alzheimer’s disease, biomarkers, cerebral amyloid angiopathy, cerebrospinal fluid, synaptic pathology

DOI: 10.3233/JAD-220977

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 467-475, 2023

Authors: Ren, Jun-Rong | Wang, Zhen | Cheng, Yuan | He, Chen-Yang | Jian, Jie-Ming | Fan, Dong-Yu | Shen, Ying-Ying | Chen, Dong-Wan | Li, Hui-Yun | Yi, Xu | Zeng, Gui-Hua | Tan, Cheng-Rong | Shi, An-Yu | Chen, Li-Yong | Mao, Qing-Xiang | Wang, Yan-Jiang | Wang, Jun

Article Type: Research Article

Abstract: Background: The kidney-brain crosstalk has been involved in Alzheimer’s disease (AD) with the mechanism remaining unclear. The anti-aging factor Klotho was reported to attenuate both kidney injury and AD pathologies. Objective: To investigate whether plasma Klotho participated in kidney-brain crosstalk in AD. Methods: We enrolled 33 PiB-PET-positive AD patients and 33 amyloid-β (Aβ)-negative age- and sex-matched cognitively normal (CN) controls from the Chongqing Ageing & Dementia Study (CADS). The levels of plasma Klotho, Aβ, and tau in the cerebrospinal fluid (CSF) were measured by enzyme-linked immunosorbent assay. Results: We found higher plasma Klotho and …lower estimated glomerular filtration rate (eGFR) levels in AD patients compared with CN. The eGFR was positively associated with Aβ42 , Aβ40 levels in CSF and negatively associated with CSF T-tau levels. Plasma Klotho levels were both negatively correlated with CSF Aβ42 and eGFR. Mediation analysis showed that plasma Klotho mediated 24.96% of the association between eGFR and CSF Aβ42 . Conclusion: Renal function impacts brain Aβ metabolism via the kidney-brain crosstalk, in which the plasma Klotho may be involved as a mediator. Targeting Klotho to regulate the kidney-brain crosstalk provides potential therapeutic approaches for AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, estimated glomerular filtration rate, kidney-brain crosstalk, Klotho

DOI: 10.3233/JAD-221107

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 477-485, 2023

Authors: Ono, Rei | Sakurai, Takashi | Sugimoto, Taiki | Uchida, Kazuaki | Nakagawa, Takeshi | Noguchi, Taiji | Komatsu, Ayane | Arai, Hidenori | Saito, Tami

Article Type: Research Article

Abstract: Background: Prognosis-related information regarding dementia needs to be updated, as changes in medical and long-term care environments for patients with dementia in recent decades may be improving the prognosis of the disease. Objective: We aimed to investigate the mortality, cause of death, and prognostic factors by types of dementia in a Japanese clinic-based cohort. Methods: The National Center for Geriatrics and Gerontology-Life Stories of People with Dementia consists of clinical records and prognostic data of patients who visited the Memory Clinic in Japan. Patients who attended the clinic between July 2010 and September 2018, or their …close relatives, were asked about death information via a postal survey. A cohort of 3,229 patients (mean age, 76.9; female, 1,953) was classified into six groups: normal cognition (NC), mild cognitive impairment (MCI), Alzheimer’s disease (AD), vascular dementia, dementia with Lewy bodies (DLB), and frontotemporal lobar degeneration. A Cox proportional hazards model was employed to compare the mortality of each type of dementia, MCI, and NC. Results: Patients with all types of dementia and MCI had higher mortality rates than those with NC (hazard risks: 2.61–5.20). The most common cause of death was pneumonia, followed by cancer. In the MCI, AD, and DLB groups, older age, male sex, and low cognitive function were common prognostic factors but not presence of apolipoprotein E ɛ4 allele. Conclusion: Our findings suggest important differences in the mortality risk and cause of death among patients with dementia, which will be useful in advanced care planning and policymaking. Show more

Keywords: Alzheimer’s disease, cause of death, frontotemporal lobar degeneration, Lewy bodies, mild cognitive impairment, mortality, prognostic factor, vascular dementia

DOI: 10.3233/JAD-221290

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 487-498, 2023

Authors: Kikuchi, Hiroyuki | Takahashi, Miki | Komatsu, Hiroaki | Axelsen, Paul H.

Article Type: Research Article

Abstract: Background: The extraction and quantification of amyloid-β (Aβ) peptides in brain tissue commonly uses formic acid (FA) to disaggregate Aβ fibrils. However, it is not clear whether FA can disaggregate post-translationally modified Aβ peptides, or whether it induces artifact by covalent modification during disaggregation. Of particular interest are Aβ peptides that have been covalently modified by 4-hydroxy-2-nonenal (HNE), an oxidative lipid degradation product produced in the vicinity of amyloid plaques that dramatically accelerates the aggregation of Aβ peptides. Objective: Test the ability of FA to disaggregate Aβ peptides modified by HNE and to induce covalent artifacts. …Methods: Quantitative liquid-chromatography-tandem-mass spectrometry of monomeric Aβ peptides and identify covalently modified forms. Results: FA disaggregated ordinary Aβ fibrils but also induced the time-dependent formylation of at least 2 residue side chains in Aβ peptides, as well as oxidation of its methionine side chain. FA was unable to disaggregate Aβ peptides that had been covalently modified by HNE. Conclusion: The inability of FA to disaggregate Aβ peptides modified by HNE prevents FA-based approaches from quantifying a pool of HNE-modified Aβ peptides in brain tissue that may have pathological significance. Show more

Keywords: Ascorbate, copper, deuterium-stabilized fatty acids, liposomes, mass spectrometry, mouse, oxidative stress, polyunsaturated

DOI: 10.3233/JAD-220940

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 499-511, 2023

Authors: Stocks, Jane | Heywood, Ashley | Popuri, Karteek | Beg, Mirza Faisal | Rosen, Howie | Wang, Lei

Article Type: Research Article

Abstract: Background: The A/T/N framework allows for the assessment of pathology-specific markers of MRI-derived structural atrophy and hypometabolism on 18 FDG-PET. However, how these measures relate to each other locally and distantly across pathology-defined A/T/N groups is currently unclear. Objective: To determine the regions of association between atrophy and hypometabolism in A/T/N groups both within and across time points. Methods: We examined multivariate multimodal neuroimaging relationships between MRI and 18 FDG-PET among suspected non-Alzheimer’s disease pathology (SNAP) (A–T/N+; n  = 14), Amyloid Only (A+T–N–; n  = 24) and Probable AD (A+T+N+; n  = 77) groups. Sparse canonical correlation analyses were …employed to model spatially disjointed regions of association between MRI and 18 FDG-PET data. These relationships were assessed at three combinations of time points –cross-sectionally, between baseline visits and between month 12 (M-12) follow-up visits, as well as longitudinally between baseline and M-12 follow-up. Results: In the SNAP group, spatially overlapping relationships between atrophy and hypometabolism were apparent in the bilateral temporal lobes when both modalities were assessed at the M-12 timepoint. Amyloid-Only subjects showed spatially discordant distributed atrophy-hypometabolism relationships at all time points assessed. In Probable AD subjects, local correlations were evident in the bilateral temporal lobes when both modalities were assessed at baseline and at M-12. Across groups, hypometabolism at baseline correlated with non-local, or distant, atrophy at M-12. Conclusion: These results support the view that local concordance of atrophy and hypometabolism is the result of a tau-mediated process driving neurodegeneration. Show more

Keywords: Alzheimer’s disease, amyloid, cerebrospinal fluid, magnetic resonance imaging, multimodal imaging, neuroimaging, positron emission tomography, suspected non-Alzheimer’s disease pathology, tau

DOI: 10.3233/JAD-220975

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 513-527, 2023

Authors: Makri, M. | Christakidou, A. | Tsolaki, M.

Article Type: Research Article

Abstract: Background: People with mild cognitive impairment (MCI) need to prevent the further decline of their cognitive functions, and one way to do so is by learning a foreign language. Objective: This study describes the development of a protocol for a novel, non-pharmacological intervention for people with MCI that seeks to prevent or reduce cognitive decline by teaching English through songs. Methods: The development of this protocol follows a mixed-methodology approach, consisting of three stages: 1) development of the protocol of the intervention, 2) a randomized controlled trial study with two arms over six …months that includes an intervention group and a control group, and 3) the evaluation of the protocol by trainers. In the second stage, we recruited a total of 128 people with MCI from the five participating countries of this study (Greece, Spain, Croatia, Slovenia, and Italy). This educational program will assess three main outcomes after 6 months of the English Lessons with the Use of Songs for People with Mild Cognitive Impairment (E.L.So.M.C.I.) workshops. Results: Our primary outcome will hopefully be an improvement in general cognition in the intervention group compared to the control group from baseline to 6 months follow-up. Secondary outcomes include a decrease in participants’ anxiety and depression and an improvement in their quality of life. Development of English language skills is the last outcome. Show more

Keywords: Anxiety, cognition, depression, learning English, mild cognitive impairment, non-pharmacological intervention, prevention, randomized controlled trial, songs for learning English

DOI: 10.3233/JAD-220184

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 529-546, 2023

Authors: Petti, Ulla | Baker, Simon | Korhonen, Anna | Robin, Jessica

Article Type: Research Article

Abstract: Background: Language impairment in Alzheimer’s disease (AD) has been widely studied but due to limited data availability, relatively few studies have focused on the longitudinal change in language in the individuals who later develop AD. Significant differences in speech have previously been found by comparing the press conference transcripts of President Bush and President Reagan, who was later diagnosed with AD. Objective: In the current study, we explored whether the patterns previously established in the single AD-healthy control (HC) participant pair apply to a larger group of individuals who later receive AD diagnosis. Methods: We replicated …previous methods on two larger corpora of longitudinal spontaneous speech samples of public figures, consisting of 10 and 9 AD-HC participant pairs. As we failed to find generalizable patterns of language change using previous methodology, we proposed alternative methods for data analysis, investigating the benefits of using different language features and their change with age, and compiling the single features into aggregate scores. Results: The single features that showed the strongest results were moving average type:token ratio (MATTR) and pronoun-related features. The aggregate scores performed better than the single features, with lexical diversity capturing a similar change in two-thirds of the participants. Conclusion: Capturing universal patterns of language change prior to AD can be challenging, but the decline in lexical diversity and changes in MATTR and pronoun-related features act as promising measures that reflect the cognitive changes in many participants. Show more

Keywords: Alzheimer’s disease, biomarker, cognitive dysfunction, dementia, early diagnosis, language, medical informatics, natural language processing, speech

DOI: 10.3233/JAD-220847

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 547-564, 2023

Authors: Lee, Seunghoon | Jeong, Hyunsuk | Koh, Im-Seok | Suh, Jeewon | Cho, HyunSung | Kim, YongBok | Cho, EunJung | Chang, Jhin Goo | Hong, Minha | Lee, Su Young

Article Type: Research Article

Abstract: Background: Providing correct information about dementia and people living with dementia and improving the attitude toward the disease have important implications in overcoming prejudice and negative perceptions and strengthening the social support system. However, studies are limited about which aspects of dementia knowledge affect attitudes toward it and the influence of such knowledge on particular aspects of such attitudes. Objective: This study examined which part of dementia knowledge affects attitudes toward dementia and, furthermore, the influence of such knowledge on two aspects of attitudes in the general population. Methods: A population-based cross-sectional survey of 1,200 participants …aged 20 years or older was adopted. A landline and wireless telephone survey was conducted from October 12 to October 22, 2021. The survey data included self-report questions about dementia knowledge, dementia attitudes, demographics, and family information. Multiple linear regression analysis was performed. Results: Dementia knowledge was positively associated with global dementia attitudes. In terms of the relationship between the two dimensions of dementia attitudes and knowledge, the latter displayed a significant positive association with accepting attitudes (β = 0.121, p  < 0.001) but not with affective attitudes (β = 0.064, p  = 0.084). Among dementia knowledge, dementia symptom/diagnosis and policy categories were positively associated with accepting attitudes (β = 0.198, p  = 0.006; β = 0.357, p  < 0.001). Conclusion: Our study suggests that people with more dementia knowledge have more accepting attitudes toward dementia. It may be effective to continue education on dementia to improve the public accepting attitudes. However, to improve negative emotional attitudes toward dementia, various approaches beyond education may be needed. Show more

Keywords: Attitude, dementia, knowledge, population

DOI: 10.3233/JAD-220736

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 565-572, 2023

Authors: Tan, Yi Jayne | Siow, Isabel | Saffari, Seyed Ehsan | Ting, Simon K.S. | Li, Zeng | Kandiah, Nagaendran | Tan, Louis C.S. | Tan, Eng King | Ng, Adeline S.L.

Article Type: Research Article

Abstract: Background: Suppressor of tumorgenicity 2 (ST2) is highly expressed in brain tissue and is a receptor for interleukin 33 (IL-33). ST2 exists in two forms, a transmembrane receptor (ST2L) and a soluble decoy receptor (sST2). IL-33 binds to ST2L, triggering downstream signaling pathways involved in amyloid plaque clearance. Conversely, sST2 binds competitively to IL-33, attenuating its neuroprotective effects. High sST2 levels have been reported in mild cognitive impairment (MCI) and Alzheimer’s disease (AD), suggesting that the IL-33/ST2 signaling pathway may be implicated in neurodegenerative diseases. Objective: To investigate plasma sST2 levels in controls and patients with MCI, AD, …frontotemporal dementia (FTD), and Parkinson’s disease (PD). Methods: Plasma sST2 levels were measured using ELISA in 397 subjects (91 HC, 46 MCI, 38 AD, 28 FTD, and 194 PD). Cerebrospinal fluid (CSF) levels of sST2 were measured in 22 subjects. Relationship between sST2 and clinical outcomes were analyzed. Results: Plasma sST2 levels were increased across all disease groups compared to controls, with highest levels seen in FTD followed by AD and PD. Dementia patients with higher sST2 had lower cross-sectional cognitive scores in Frontal Assessment Battery and Digit Span Backward. At baseline, PD-MCI patients had higher sST2, associated with worse attention. In the longitudinal PD cohort, higher sST2 significantly associated with decline in global cognition and visuospatial domains. Plasma sST2 levels correlated with CSF sST2 levels. Conclusion: Plasma sST2 is raised across neurodegenerative diseases and is associated with poorer cognition. Higher baseline sST2 is a potential biomarker of disease severity in neurodegeneration. Show more

Keywords: Cognition, dementia, neurodegeneration, Parkinson’s disease, ST2

DOI: 10.3233/JAD-221072

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 573-580, 2023

Authors: Zhao, Yong-Li | Ou, Ya-Nan | Ma, Ya-Hui | Tan, Lan | Yu, Jin-Tai

Article Type: Research Article

Abstract: Background: Subjective cognitive decline (SCD) is considered as a preclinical hallmark of Alzheimer’s disease (AD). However, the characteristics of SCD associated with amyloid pathology remain unclear. Objective: We aimed to explore the associations between SCD characteristics with amyloid pathology. Methods: Using logistic regression analyses, we analyzed the associations between cerebrospinal fluid (CSF) amyloid pathology with AD risk factors, SCD-specific characteristics (onset of SCD within the last five years, age at onset ≥60 years, feelings of worse performance, informant confirmation of complaints, worries, other domains of cognition complaints), as well as subthreshold depressive and anxiety symptoms among …individuals with SCD. Results: A total of 535 SCD individuals with available CSF Aβ42 information from the Chinese Alzheimer’s Biomarker and LifestylE (CABLE) study (mean age of 63.5 years, range 40 to 88 years; 47.10% female) were enrolled. The characteristics of informant confirmation of complaints (OR, 95% CI = 2.00, 1.19–3.36), subthreshold depressive symptoms (OR, 95% CI = 2.31, 1.05–5.09), and subthreshold anxiety symptoms (OR, 95% CI = 2.22, 1.09–4.51) were found to be significantly associated with pathological amyloid in multivariate analyses when adjusting for age, sex, education, and APOE ɛ4. Besides, age and females were observed risks for amyloid pathology in subscale analyses. Nonetheless, we did not find any associations of other SCD-specific characteristics with amyloid pathology in this study. Conclusion: Our study suggested that informant confirmed complaints and subthreshold psychiatric symptoms might be critical for discriminating AD-related SCD from non-AD related SCD. Show more

Keywords: Alzheimer’s disease, amyloid, cerebrospinal fluid, subjective cognitive decline

DOI: 10.3233/JAD-221154

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 581-590, 2023

Authors: Gabrielli, Alexander P. | Weidling, Ian | Ranjan, Amol | Wang, Xiaowan | Novikova, Lesya | Chowdhury, Subir Roy | Menta, Blaise | Berkowicz, Alexandra | Wilkins, Heather M. | Peterson, Kenneth R. | Swerdlow, Russell H.

Article Type: Research Article

Abstract: Background: Mitochondria can trigger Alzheimer’s disease (AD)-associated molecular phenomena, but how mitochondria impact apolipoprotein E (APOE ; apoE) is not well known. Objective: Consider whether and how mitochondrial biology influences APOE and apoE biology. Methods: We measured APOE expression in human SH-SY5Y neuronal cells with different forms of mitochondrial dysfunction including total, chronic mitochondrial DNA (mtDNA) depletion (ρ0 cells); acute, partial mtDNA depletion; and toxin-induced mitochondrial dysfunction. We further assessed intracellular and secreted apoE protein levels in the ρ0 cells and interrogated the impact of transcription factors and stress signaling pathways known to influence …APOE expression. Results: SH-SY5Y ρ0 cells exhibited a 65-fold increase in APOE mRNA, an 8-fold increase in secreted apoE protein, and increased intracellular apoE protein. Other models of primary mitochondrial dysfunction including partial mtDNA-depletion, toxin-induced respiratory chain inhibition, and chemical-induced manipulations of the mitochondrial membrane potential similarly increased SH-SY5Y cell APOE mRNA. We explored potential mediators and found in the ρ0 cells knock-down of the C/EBPα and NFE2L2 (Nrf2) transcription factors reduced APOE mRNA. The activity of two mitogen-activated protein kinases, JNK and ERK, also strongly influenced ρ0 cell APOE mRNA levels. Conclusion: Primary mitochondrial dysfunction either directly or indirectly activates APOE expression in a neuronal cell model by altering transcription factors and stress signaling pathways. These studies demonstrate mitochondrial biology can influence the biology of the APOE gene and apoE protein, which are implicated in AD. Show more

Keywords: Alzheimer’s disease, APOE , apolipoprotein E, mitochondria, mitochondrial DNA

DOI: 10.3233/JAD-221177

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 591-604, 2023

Authors: Gyllenhammar, Måns | Rennie, Anna | Padilla, Daniel Ferreira | Wallert, John | Rydström, Anders | Wahlund, Lars-Olof | Eriksdotter, Maria | Westman, Eric | Ekman, Urban

Article Type: Research Article

Abstract: Background: Cognitive reserve (CR) is hypothesized to partially explain the discrepancy between Alzheimer’s disease related brain pathology and cognitive performance. Educational attainment is often used as a proxy for CR. Objective: To examine the association of years of education and the relationship between atrophy in the medial temporal lobe and episodic memory, in a cross-sectional ecological multi-center memory clinic cohort. Methods: Included patients (n  = 702) had undergone memory clinic examination and were diagnosed with subjective cognitive impairment (n  = 99), mild cognitive impairment (n  = 471), or dementia (n  = 132). Total years of education were used as a …moderating variable and neuropathology was operationalized as visual ratings of medial temporal lobe atrophy (MTA) on magnetic resonance imaging and computer tomography images. Weighted least squares regression and multiple regression were used to analyze moderation and the effect of education separately by diagnostic group. A composite score of two episodic memory tests constituted the dependent variable. Results: After controlling for age and gender the interaction term between MTA and years of education was significant indicating moderation. In particular, the regression model showed that at low levels of MTA, high education individuals had better episodic memory performance. However, at higher MTA levels, high education individuals had the lowest episodic memory performance. Education had a significant positive effect on episodic memory in SCI and MCI, but not dementia. Conclusion: These results extend the findings of education moderating the effect of MTA on cognition to a naturalistic memory clinic setting. Implications of the findings for theories on CR are discussed. Show more

Keywords: Cognitive aging, cognitive impairments, cognitive neuroscience, cognitive reserve, magnetic resonance imaging, neuropsychology

DOI: 10.3233/JAD-220741

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 605-614, 2023

Authors: Chatterjee, Pratishtha | Doré, Vincent | Pedrini, Steve | Krishnadas, Natasha | Thota, Rohith | Bourgeat, Pierrick | Ikonomovic, Milos D. | Rainey-Smith, Stephanie R. | Burnham, Samantha C. | Fowler, Christopher | Taddei, Kevin | Mulligan, Rachel | Ames, David | Masters, Colin L. | Fripp, Jürgen | Rowe, Christopher C. | Martins, Ralph N. | Villemagne, Victor L.

Article Type: Research Article

Abstract: Background: Astrocyte reactivity is an early event along the Alzheimer’s disease (AD) continuum. Plasma glial fibrillary acidic protein (GFAP), posited to reflect astrocyte reactivity, is elevated across the AD continuum from preclinical to dementia stages. Monoamine oxidase-B (MAO-B) is also elevated in reactive astrocytes observed using 18 F-SMBT-1 PET in AD. Objective: The objective of this study was to evaluate the association between the abovementioned astrocyte reactivity biomarkers. Methods: Plasma GFAP and Aβ were measured using the Simoa® platform in participants who underwent brain 18 F-SMBT-1 and Aβ–PET imaging, comprising 54 healthy control (13 Aβ–PET+ …and 41 Aβ–PET–), 11 mild cognitively impaired (3 Aβ–PET+ and 8 Aβ–PET–) and 6 probable AD (5 Aβ–PET+ and 1 Aβ–PET–) individuals. Linear regressions were used to assess associations of interest. Results: Plasma GFAP was associated with 18 F-SMBT-1 signal in brain regions prone to early Aβ deposition in AD, such as the supramarginal gyrus (SG), posterior cingulate (PC), lateral temporal (LT) and lateral occipital cortex (LO). After adjusting for age, sex, APOE ɛ4 genotype, and soluble Aβ (plasma Aβ42/40 ratio), plasma GFAP was associated with 18 F-SMBT-1 signal in the SG, PC, LT, LO, and superior parietal cortex (SP). On adjusting for age, sex, APOE ɛ4 genotype and insoluble Aβ (Aβ–PET), plasma GFAP was associated with 18 F-SMBT-1 signal in the SG. Conclusion: There is an association between plasma GFAP and regional 18 F-SMBT-1 PET, and this association appears to be dependent on brain Aβ load. Show more

Keywords: Astrocyte reactivity, biomarkers, 18F-SMBT-1, glial fibrillary acidic protein, monoamine oxidase B, positron emission tomography

DOI: 10.3233/JAD-220908

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 615-628, 2023

Authors: Atef, Roaa Zayed | Michalowsky, Bernhard | Raedke, Anika | Platen, Moritz | Mohr, Wiebke | Mühlichen, Franka | Thyrian, Jochen René | Hoffmann, Wolfgang

Article Type: Research Article

Abstract: Background: Hearing loss is common in people with dementia (PwD) and a modifiable risk factor for cognitive decline. Recent studies revealed that hearing loss could cause social isolation and depression, which is associated with health-related quality of life (HRQoL). However, there is a lack of knowledge about the impact of the utilization of hearing aids on these outcomes. Objective: To assess whether hearing aids use might be positively associated with the progression of cognitive function, depression, and HRQoL among PwD. Methods: We analyzed two-year follow-up data from 258 PwD (≥70 years, living at home). Cognitive decline …was measured with Mini-Mental Status Examination (MMSE), depression using Geriatric Depression Scale (GDS), and HRQoL with Quality of Life in Alzheimer’s Disease Scale (QoL-AD). The impact of hearing aid utilization on the progression of outcomes was assessed using multivariate regression models. Results: 123 patients had hearing loss (47.7%), from which n  = 54 (43.9%) used hearing aids. Patients with hearing loss were older and had a lower HRQoL than those without hearing loss. Use of hearing aids in patients with hearing loss was associated with a lower increase in depressive symptoms (b = –0.74, CI95 –1.48 ––0.01, p  = 0.047) over time as compared to those not using hearing aids. There was no effect on PwD’s cognition, and the association with higher HRQoL was significant after one, but not consistently over two years. Conclusion: Early detection and intervention of presbycusis using hearing aids might improve mental health and HRQoL in dementia. Show more

Keywords: Cognitive decline, dementia, depression, health-related quality of life, hearing aids, hearing loss

DOI: 10.3233/JAD-220938

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 629-638, 2023

Authors: Royall, Donald R. | Palmer, Raymond F.

Article Type: Research Article

Abstract: Background: We have explored dementia’s blood-based protein biomarkers in the Texas Alzheimer’s Research and Care Consortium (TARCC) study. Among them are adipokines, i.e., proteins secreted by adipose tissue some of which have been associated with cognitive impairment. Objective: To associate adipokines with dementia severity and replicate their association across cohorts and biofluids (serum /plasma). Methods: We used eight rationally chosen blood-based protein biomarkers as indicators of a latent variable, i.e., “Adipokines”. We then associated that construct with dementia severity as measured by the latent dementia-specific phenotype “δ” in structural equation models (SEM). Significant factor loadings and …Adipokines’ association with δ were replicated across biofluids in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Results: Eight adipokine proteins loaded significantly on the Adipokines construct. Adipokines measured in plasma (ADNI) or serum (TARCC) explained 24 and 70% of δ’s variance, respectively. An Adipokine composite score, derived from the latent variables, rose significantly across clinical diagnoses and achieved high areas under the receiver operating characteristic curve (ROC/AUC) for discrimination of Alzheimer’s disease from normal controls (NC) or cases of mild cognitive impairment (MCI) and between NC and MCI. Conclusion: These results again suggest that SEM can be used to create latent biomarker classifiers that replicate across samples and biofluids, and that a substantial fraction of dementia’s variance is attributable to peripheral blood-based protein levels via the patterns codified in those latent constructs. Show more

Keywords: Adipokines, adiponectin, Alzheimer’s disease, Alzheimer’s Disease Neuroimaging Initiative, cognition, dementia, g, intelligence, leptin, resistin, Texas Alzheimer’s Research and Care Consortium

DOI: 10.3233/JAD-221052

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 639-652, 2023

Authors: Agger, Mikkel Pejstrup | Danielsen, Else Rubæk | Carstensen, Marcus Schultz | Nguyen, N. Mai | Horning, Maibritt | Henney, Mark Alexander | Jensen, Christopher Boe Ravn | Baandrup, Anders Ohlhues | Kjær, Troels Wesenberg | Madsen, Kristoffer Hougaard | Miskowiak, Kamilla | Petersen, Paul Michael | Høgh, Peter

Article Type: Research Article

Abstract: Background: Recent studies suggested induction of 40 Hz neural activity as a potential treatment for Alzheimer’s disease (AD). However, prolonged exposure to flickering light raises adherence and safety concerns, encouraging investigation of tolerable light stimulation protocols. Objective: To investigate the safety, feasibility, and exploratory measures of efficacy. Methods: This two-stage randomized placebo-controlled double-blinded clinical trial, recruited first cognitive healthy participants (n  = 3/2 active/placebo), and subsequently patients with mild-to-moderate AD (n  = 5/6, active/placebo). Participants were randomized 1:1 to receive either active intervention with 40 Hz Invisible Spectral Flicker (ISF) or placebo intervention with color and intensity matched non-flickering white …light. Results: Few and mild adverse events were observed. Adherence was above 86.1% of intended treatment days, with participants remaining in front of the device for >51.3 min (60 max) and directed gaze >34.9 min. Secondary outcomes of cognition indicate a tendency towards improvement in the active group compared to placebo (mean: –2.6/1.5, SD: 6.58/6.53, active/placebo) at week 6. Changes in hippocampal and ventricular volume also showed no tendency of improvement in the active group at week 6 compared to placebo. At week 12, a potential delayed effect of the intervention was seen on the volume of the hippocampus in the active group compared to placebo (mean: 0.34/–2.03, SD: 3.26/1.18, active/placebo), and the ventricular volume active group (mean: –0.36/2.50, SD: 1.89/2.05, active/placebo), compared to placebo. Conclusion: Treatment with 40 Hz ISF offers no significant safety or adherence concerns. Potential impact on secondary outcomes must be tested in larger scale clinical trials. Show more

Keywords: 40 Hz, Alzheimer’s disease, gamma entrainment, invisible spectral flicker, light-based neurostimulation

DOI: 10.3233/JAD-221238

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 653-665, 2023

Authors: Sun, Huimin | Liu, Min | Liu, Jue

Article Type: Research Article

Abstract: Background: Dementia is a critical global public health problem. Previous cohort studies have found that influenza vaccination can decrease the risk of dementia. Objective: This meta-analysis aimed to systematically examine the relationship between influenza vaccination and dementia risk. Methods: We searched PubMed, Embase, Web of Science, ScienceDirect, medRxiv, and bioRxiv for studies investigating dementia risk based on influenza vaccination status, up to September 14, 2022. Relative risks (RRs) and 95% confidence intervals (95% CIs) were pooled in the meta-analysis. Subgroup analyses and sensitivity analyses were conducted as well. Results: Of the 4,087 articles initially …reviewed, 6 cohort studies were included in the final meta-analysis, and all eligible studies were at low risk of bias. There were 2,087,195 participants without dementia at baseline (mean age: 61.8–75.5 years, 57.05% males), and 149,804 (7.18%) cases of dementia occurred during 4.00–13.00 years of follow-up. Pooled analysis of adjusted RRs found that influenza vaccination could reduce dementia risk by 31% (RR = 0.69, 95% CI: 0.57–0.83). Subgroup analyses showed that in the study with a mean age of 75–80 years or 75%–100% males, the association was generally weakened compared with studies with a mean age of 60–75 years or 25%–50% males. The results were stable in the sensitivity analyses, and no publication bias was observed. Conclusion: Influenza vaccination in older adults was markedly associated with a decreased risk of dementia. More mechanistic studies and epidemiological studies are needed to clarify the association between influenza vaccination and decreased dementia risk. Show more

Keywords: Alzheimer’s disease, dementia, influenza, meta-analysis, vaccination

DOI: 10.3233/JAD-221036

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 667-678, 2023

Authors: Andersson, John | Sundström, Anna | Nordin, Maria | Segersson, David | Forsberg, Bertil | Adolfsson, Rolf | Oudin, Anna

Article Type: Research Article

Abstract: Background: Growing evidence show that long term exposure to air pollution increases the risk of dementia. Objective: The aim of this study was to investigate associations between PM2.5 exposure and dementia in a low exposure area, and to investigate the role of olfaction and the APOE ɛ4 allele in these associations. Methods: Data were drawn from the Betula project, a longitudinal study on aging, memory, and dementia in Sweden. Odor identification ability was assessed using the Scandinavian Odor Identification Test (SOIT). Annual mean PM2.5 concentrations were obtained from a dispersion-model and matched at …the participants’ residential address. Proportional hazard regression was used to calculate hazard ratios. Results: Of 1,846 participants, 348 developed dementia during the 21-year follow-up period. The average annual mean PM2.5 exposure at baseline was 6.77μg/m3 , which is 1.77μg/m3 above the WHO definition of clean air. In a fully adjusted model (adjusted for age, sex, APOE , SOIT, cardiovascular diseases and risk factors, and education) each 1μg/m3 difference in annual mean PM2.5 -concentration was associated with a hazard ratio of 1.23 for dementia (95% CI: 1.01–1.50). Analyses stratified by APOE status (ɛ4 carriers versus non-carriers), and odor identification ability (high versus low), showed associations only for ɛ4 carriers, and for low performance on odor identification ability. Conclusion: PM2.5 was associated with an increased risk of dementia in this low pollution setting. The associations between PM2.5 and dementia seemed stronger in APOE carriers and those with below average odor identification ability. Show more

Keywords: Alzheimer’s disease, Apolipoprotein E, olfaction, particulate matter, vascular dementia

DOI: 10.3233/JAD-220469

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 679-689, 2023

Authors: Tang, Mingyu | Su, Ning | Zhang, Dingding | Dai, Yi | Yao, Ming | Zhou, Lixin | Cui, Liying | Zhang, Shuyang | Zhu, Yicheng | Ni, Jun

Article Type: Research Article

Abstract: Background: Apolipoprotein E (APOE) is closely related to Alzheimer’s disease and other age-related diseases. In recent years, several studies have shown an interaction of APOE by age on brain volume. However, validation in larger cohorts is required. Objective: We explored the age-related effect of APOE on brain volumes in a community-dwelling cohort. Methods: Inhabitants in Shunyi District in Beijing aged≥35 years were invited to join this study from 2013 to 2016. The baseline assessments, APOE genotyping and brain magnetic resonance imaging were performed. Neuroimaging small vessel disease characteristics and brain volumes (global …measures, cerebral lobes, hippocampus, brainstem, and subcortical nuclei) were acquired. The general linear model was used to analyze the interaction of APOE genotypes by age on brain volumes, and the age of 60 years was chosen as a cut-off value for stratification analysis. Results: A total of 1,105 subjects were enrolled in the final analysis with a mean age of 56.18 (9.30) years, and 37.7% were men. APOE ɛ 3/ɛ 3 carriers account for 71.8%, ɛ 2 (+) 14.0%, and ɛ 4 (+) 14.2%. Compared with APOE ɛ 3/ɛ 3, a significant protective effect for APOE ɛ 4 (+) on brain parenchyma fraction (β  =  0.450, p  = 0.048) was observed in subjects aged≤60 years; in participants aged > 60 years, a negative effect for APOE ɛ 4 (+) on hippocampus (β  =  1.087, p  = 0.021) was found. Conclusion: Our study reveals that APOE ɛ 4 has differential effects on cerebral structures in different stages of lifespan, suggesting its complicated biological function and underlying antagonistic pleiotropy. Show more

Keywords: Age stratification, antagonistic pleiotropy, APOE ɛ4, brain structure, interaction

DOI: 10.3233/JAD-220834

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 691-700, 2023

Authors: Mann, Frank D. | Clouston, Sean A.P. | Cuevas, Adolfo | Waszczuk, Monika A. | Kuan, Pei-Fen | Carr, Melissa A. | Docherty, Anna R. | Shabalin, Andrea A. | Gandy, Sam E. | Luft, Benjamin J.

Article Type: Research Article

Abstract: Background: There is a high incidence of cognitive impairment among World Trade Center (WTC) responders, comorbid with post-traumatic stress disorder (PTSD). Yet, it remains unknown whether genetic liability for Alzheimer’s disease, PTSD, educational attainment, or for a combination of these phenotypes, is associated with cognitive impairment in this high-risk population. Similarly, whether the effects of genetic liability are comparable to PTSD and indicators of exposure severity remains unknown. Objective: In a study of 3,997 WTC responders, polygenic scores for Alzheimer’s disease, PTSD, and educational attainment were used to test whether genome-wide risk for one or more …of these phenotypes is associated with cognitive impairment, controlling for population stratification, while simultaneously estimating the effects of demographic factors and indicators of 9/11 exposure severity, including symptoms of PTSD. Results: Polygenic scores for Alzheimer’s disease and educational attainment were significantly associated with an increase and decrease, respectively, in the hazard rate of mild cognitive impairment. The polygenic score for Alzheimer’s disease was marginally associated with an increase in the hazard rate of severe cognitive impairment, but only age, exposure severity, and symptoms of PTSD were statistically significant predictors. Conclusion: These results add to the emerging evidence that many WTC responders are suffering from mild cognitive impairments that resemble symptoms of Alzheimer’s disease, as genetic liability for Alzheimer’s disease predicted incidence of mild cognitive impairment. However, compared to polygenic scores, effect sizes were larger for PTSD and the type of work that responders completed during rescue and recovery efforts. Show more

Keywords: Alzheimer’s disease, educational attainment, mild cognitive impairment, polygenic score, post-traumatic stress disorder

DOI: 10.3233/JAD-220892

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 701-712, 2023

Authors: Wang, Zebin | Zeng, Shan | Jing, Yan | Mao, Wenjuan | Li, Hongyan

Article Type: Research Article

Abstract: Background: Sarm1 (Sterile alpha and TIR motif-containing 1) is a key protein that regulates neurodegenerative pathologies. Alzheimer’s disease (AD) is highly associated with neurodegenerative lesions and biorhythmic disturbances. Objective: This study aims to decipher the role of Sarm1 in AD-induced circadian rhythm disturbances and AD progression. Methods: Open field and water maze tests were used to assess the cognitive function of mice. Thioflavin-S staining was used to assess amyloid-β (Aβ) plaque deposition in the hippocampus and cortex. Rhythmic waveform of home cage activity and temperature was recorded to evaluate circadian rhythm. Expression of clock molecules including …Bmal1 and Per2 in the hippocampus were analyzed using western blot and real-time PCR. Further, HT22 cells with Sam1 knockout were treated with Aβ31–35 treatment to initiate circadian rhythm disorder in the cellular level to assess the changes in Bmal1 and Per2. Results: Our data suggested that Sarm1 deficiency rescued cognitive disorder, decreased Aβ plaque deposition in the hippocampus and cortex, inhibited astrocyte activation, improved circadian rhythm, altered clock molecule expression in the cortex and hippocampus in APP/PS1 mice. Conclusion: Sarm1 attenuates circadian rhythm disturbances and reduces AD progression. These data support the potential use of Sarm1 as a therapeutic target to improve circadian rhythm to impede AD progression. Show more

Keywords: Alzheimer’s disease, circadian rhythm, sarm1

DOI: 10.3233/JAD-221027

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 713-722, 2023

Article Type: Correction

DOI: 10.3233/JAD-229021

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 723-723, 2023

Authors: Abdelhamid, Mona | Zhou, Chunyu | Ohno, Kazuya | Kuhara, Tetsuya | Taslima, Ferdous | Abdullah, Mohammad | Jung, Cha-Gyun | Michikawa, Makoto

Article Type: Correction

DOI: 10.3233/JAD-229022

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 725-725, 2023

Authors: Figueiredo, Cláudia P. | Bicca, Maíra A. | Latini, Alexandra | Prediger, Rui Daniel S. | Medeiros, Rodrigo | Calixto, João B.

Article Type: Correction

DOI: 10.3233/JAD-229023

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 727-728, 2023