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

Authors: Xu, Shan | Ren, Yifei | Liu, Rui | Li, Yuanjing | Hou, Tingting | Wang, Yongxiang | Wang, Xiang | Wang, Lidan | Monastero, Roberto | Du, Yifeng | Cong, Lin | Qiu, Chengxuan

Article Type: Research Article

Abstract: Background: Few community-based studies have examined occurrence and progression of subjective cognitive decline (SCD). Objective: To investigate prevalence and progression of SCD among rural-dwelling Chinese elderly people. Methods: This cohort study included 2,488 cognitively unimpaired adults (age≥65 years) who were examined at baseline (2014-2015) and followed in 2018. Demographic, epidemiological, clinical, and neuropsychological data were collected via in-person interviews and clinical examinations following a structured questionnaire. At baseline, SCD was assessed using the self-rated Ascertain Dementia 8-item Questionnaire. At follow-up, Alzheimer’s disease (AD) and vascular dementia (VaD) were clinically diagnosed following the international criteria. Data were …analyzed using logistic regression models. Results: The prevalence of SCD was 40.07%. SCD at baseline was associated with the multivariable-adjusted odds ratio (OR) of 1.51 (95% confidence interval 1.10–2.07) for incident cognitive impairment, no dementia (CIND) and 3.11 (1.64–5.93) for incident AD. Among people with SCD at baseline, the multivariable-adjusted OR of incident CIND was 0.55(0.32–0.96) for hyperlipidemia; the multivariable-adjusted OR of incident AD was 1.21 (1.14–1.30) for older age, 0.32 (0.12–0.88) for high education, 2.60 (1.11–6.08) for carrying APOE ɛ 4 allele, and 0.34 (0.13–0.86) for high social support, whereas the multivariable-adjusted OR of incident VaD was 6.30 (1.71–23.18) for obesity. Conclusion: SCD affects over 40% of rural-dwelling cognitively unimpaired older adults in China. SCD is associated with accelerated progression to CIND and AD. Older age, lack of school education, APOE ɛ 4 allele, and low social support are associated with an increased risk of progression from SCD to AD, whereas obesity is related to accelerated progression to VaD. Show more

Keywords: Alzheimer’s disease, dementia, population-based study, prevalence, risk factors, subjective cognitive decline

DOI: 10.3233/JAD-221280

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2023

Authors: Rakuša, Elena | Fink, Anne | Tamgüney, Gültekin | Heneka, Michael T. | Doblhammer, Gabriele

Article Type: Research Article

Abstract: Background: Antibiotics for systemic use may increase the risk of neurodegeneration, yet antibiotic therapy may be able to halt or mitigate an episode of neurodegenerative decline. Objective: To investigate the association of sporadic use of antibiotics and subsequent dementia risk (including Alzheimer’s disease). Methods: We used data from the largest public health insurance fund in Germany, the Allgemeine Ortskrankenkasse (AOK). Each of the 35,072 dementia cases aged 60 years and older with a new dementia diagnosis during the observation period from 2006 to 2018 was matched with two control-patients by age, sex, and time since 2006. …We ran conditional logistic regression models for dementia risk in terms of odds ratios (OR) as a function of antibiotic use for the entire antibiotic group and for each antibiotic subgroup. We controlled for comorbidities, need for long-term care, hospitalizations, and nursing home placement. Results: Antibiotic use was positively associated with dementia (OR = 1.18, 95% confidence interval (95% CI):1.14–1.22), which became negative after adjustment for comorbidities, at least one diagnosis of bacterial infection or disease, and covariates (OR = 0.93, 95% CI:0.90–0.96). Subgroups of antibiotics were also negatively associated with dementia after controlling for covariates: tetracyclines (OR = 0.94, 95% CI:0.90–0.98), beta-lactam antibacterials, penicillins (OR = 0.93, 95% CI:0.90–0.97), other beta-lactam antibacterials (OR = 0.92, 95% CI:0.88–0.95), macrolides, lincosamides, and streptogramins (OR = 0.88, 95% CI:0.85–0.92), and quinolone antibacterials (OR = 0.96, 95% CI:0.92–0.99). Conclusion: Our results suggest that there was a decreased likelihood of dementia for preceding antibiotic use. The benefits of antibiotics in reducing inflammation and thus the risk of dementia need to be carefully weighed against the increase in antibiotic resistance. Show more

Keywords: Alzheimer’s disease, antibiotics, conditional logistic regression, dementia, epidemiology, nested case-control studies

DOI: 10.3233/JAD-221153

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2023

Authors: Yahagi-Estevam, Maristella | Farias-Itao, Daniela Souza | Leite, Renata Elaine Paraizo | Rodriguez, Roberta Diehl | Pasqualucci, Carlos Augusto | Nitrini, Ricardo | Jacob-Filho, Wilson | Power, Melinda C. | Suemoto, Claudia Kimie

Article Type: Research Article

Abstract: Background: Coronary atherosclerosis assessed in vivo was associated with cognitive impairment; however, conflicting findings have been reported in autopsy samples. Objective: Our aims were to assess the association between atherosclerotic stenosis in the coronary arteries and cognitive impairment and to investigate the possibility of selection bias in an autopsy study. Methods: Coronary arteries were collected, and the largest luminal stenosis was measured. Sociodemographic, clinical, and cognitive information were reported by a reliable next-of-kin. The association was tested using logistic and linear regressions adjusted for sociodemographic and clinical variables. We restricted the sample to individuals that …were born in 1935 or earlier and stratified the analysis by cause of death to investigate the role of selection bias. Results: In 253 participants (mean age = 78.0±8.5 years old, 48% male), stenosis was not associated with cognitive impairment (OR = 0.85, 95% CI = 0.69; 1.06, p  = 0.15). In individuals who were born before 1936 in the absence of cardiovascular disease as the cause of death, greater stenosis was associated with cognitive impairment (OR = 4.02, 95% CI = 1.39; 11.6, p  = 0.01). On the other hand, this association was not present among those born in 1935 or earlier who died of cardiovascular diseases (OR = 0.83, 95% CI = 0.60; 1.16, p  = 0.28). Conclusion: We found that higher coronary stenosis was associated with cognitive impairment only in individuals born in 1935 or earlier and who had not died from cardiovascular diseases. Selection bias may be an important issue when investigating risk factors for chronic degenerative diseases in older individuals using autopsy samples. Show more

Keywords: Aging, Alzheimer’s disease, atherosclerosis, bias, cognitive impairment, dementia

DOI: 10.3233/JAD-220820

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2023

Authors: Balietti, Marta | Casoli, Tiziana | Giorgetti, Belinda | Colangeli, Roberto | Nicoletti, Cristina | Solazzi, Moreno | Pugliese, Arianna | Conti, Fiorenzo

Article Type: Research Article

Abstract: Background: Numerous mouse models of Alzheimer’s disease (AD) are available, but all suffer from certain limitations, thus prompting further attempts. To date, no one model exists with amyloidopathy in a BALB/c strain. Objective: To generate and characterize the C.B6/J-APP swe mouse, a model of AD with a mutated human gene for the amyloid-β protein precursor (AβPP) inserted in a BALB/c background. Methods: We analyzed five groups at different ages (3, 6, 9, 12, and 16–18 months) of C.B6/J-APP swe and wild-type mice (50% males and 50% …females) for the main hallmarks of AD by western blotting, amyloid-β (Aβ) ELISA, immunocytochemistry, electrophysiology, and behavioral tests. Results: The C.B6/J-APP swe mouse displays early AβPP and Aβ production, late amyloid plaques formation, high level of tau phosphorylation, synaptic deficits (reduced density and functional impairment due to a reduced post-synaptic responsiveness), neurodegeneration caused by apoptosis and necroptosis/necrosis, microgliosis, astrocytic abnormalities, and sex-related differences in explorative behavior, anxiety-like behavior, and spatial long-term and working memories. Social housing is feasible despite the intra-cage aggressiveness of male animals. Conclusion: C.B6/J-APP swe mice develop most of the distinctive features of AD and is a suitable model for the study of brain atrophy mechanisms and of the differences between males and females in the onset of cognitive/non-cognitive deficits. Show more

Keywords: Alzheimer’s disease, amyloid-β protein precursor, cognitive impairment, congenic mouse, neurodegeneration, neuroinflammation, sex-related differences, synaptic alteration

DOI: 10.3233/JAD-230195

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-24, 2023

Authors: Lin, Huamei | Pan, Tingting | Wang, Min | Ge, Jingjie | Lu, Jiaying | Ju, Zizhao | Chen, Keliang | Zhang, Huiwei | Guan, Yihui | Zhao, Qianhua | Shan, Baoci | Nie, Binbin | Zuo, Chuantao | Wu, Ping

Article Type: Research Article

Abstract: Background: Metabolic asymmetry has been observed in Alzheimer’s disease (AD), but different studies have inconsistent viewpoints. Objective: To analyze the asymmetry of cerebral glucose metabolism in AD and investigate its clinical significance and potential metabolic network abnormalities. Methods: Standardized uptake value ratios (SUVRs) were obtained from 18 F-FDG positron emission tomography (PET) images of all participants, and the asymmetry indices (AIs) were calculated according to the SUVRs. AD group was divided into left/right-dominant or bilateral symmetric hypometabolism (AD-L/AD-R or AD-BI) when more than half of the AIs of the 20 regions of interest (ROIs) were < …–2SD, >2SD, or between±1SD. Differences in clinical features among the three AD groups were compared, and the abnormal network characteristics underlying metabolic asymmetry were explored. Results: In AD group, the proportions of AD-L, AD-R, and AD-BI were 28.4%, 17.9%, and 18.5%, respectively. AD-L/AD-R groups had younger age of onset and faster rate of cognitive decline than AD-BI group (p  < 0.05). The absolute values of AIs in half of the 20 ROIs became higher at follow-up than at baseline (p  < 0.05). Compared with those in AD-BI group, metabolic connection strength of network, global efficiency, cluster coefficient, degree centrality and local efficiency were lower, but shortest path length was longer in AD-L and AD-R groups (p  < 0.05). Conclusion: Asymmetric and symmetric hypometabolism may represent different clinical subtypes of AD, which may provide a clue for future studies on the heterogeneity of AD and help to optimize the design of clinical trials. Show more

Keywords: Alzheimer’s disease, cerebral glucose hypometabolism, graph theoryn, metabolic asymmetry, metabolic connectivity, Mini-Mental State Examinatio

DOI: 10.3233/JAD-221258

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2023

Authors: Carlos, Arenn F. | Machulda, Mary M. | Rutledge, Matthew H. | Nguyen, Aivi T. | Reichard, R. Ross | Baker, Matthew C. | Rademakers, Rosa | Dickson, Dennis W. | Petersen, Ronald C. | Josephs, Keith A.

Article Type: Research Article

Abstract: Background: Increasing evidence suggests that TAR DNA-binding protein 43 (TDP-43) pathology in Alzheimer’s disease (AD), or AD-TDP, can be diffuse or limbic-predominant. Understanding whether diffuse AD-TDP has genetic, clinical, and pathological features that differ from limbic AD-TDP could have clinical and research implications. Objective: To better characterize the clinical and pathologic features of diffuse AD-TDP and differentiate it from limbic AD-TDP. Methods: 363 participants from the Mayo Clinic Study of Aging, Alzheimer’s Disease Research Center, and Neurodegenerative Research Group with autopsy confirmed AD and TDP-43 pathology were included. All underwent genetic, clinical, neuropsychologic, and neuropathologic evaluations. …AD-TDP pathology distribution was assessed using the Josephs 6-stage scale. Stages 1–3 were classified as limbic, those 4–6 as diffuse. Multivariable logistic regression was used to identify clinicopathologic features that independently predicted diffuse pathology. Results: The cohort was 61% female and old at onset (median: 76 years [IQR:70–82]) and death (median: 88 years [IQR:82–92]). Fifty-four percent were limbic and 46% diffuse. Clinically, ∼10–20% increases in odds of being diffuse associated with 5-year increments in age at onset (p  = 0.04), 1-year longer disease duration (p  = 0.02), and higher Neuropsychiatric Inventory scores p  = 0.03), while 15-s longer Trailmaking Test-B times (p  = 0.02) and higher Block Design Test scores (p  = 0.02) independently decreased the odds by  10–15%. There was evidence for association of APOE ɛ 4 allele with limbic AD-TDP and of TMEM106B rs3173615C allele with diffuse AD-TDP. Pathologically, widespread amyloid-β plaques (Thal phases: 3–5) decreased the odds of diffuse TDP-43 pathology by 80–90%, while hippocampal sclerosis increased it sixfold (p  < 0.001). Conclusion: Diffuse AD-TDP shows clinicopathologic and genetic features different from limbic AD-TDP. Show more

Keywords: Alzheimer’s disease, neuropathology, neuropsychology, TDP-43 proteinopathy

DOI: 10.3233/JAD-221094

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2023

Authors: Chu, Min | Jiang, Deming | Liu, Li | Nie, Binbin | Cui, Bo | Wang, Yihao | Rosa-Neto, Pedro | Wu, Liyong

Article Type: Research Article

Abstract: Background: The insula is the predominant brain region impaired in behavior variant frontotemporal dementia (bvFTD). However, structural and functional changes in the sub-insula in the asymptomatic stage of bvFTD are unknown. Objective: To describe structural and functional changes in insula subregions in asymptomatic carriers of the P301L mutation of the microtubule-associated protein tau (MAPT ) gene and patients with bvFTD. Methods: Six asymptomatic MAPT P301L mutation carriers and 12 MAPT negative control subjects of the same pedigree were enrolled, along with 30 patients with a clinical diagnosis of bvFTD and 30 matched controls. All …subjects underwent hybrid positron emission tomography/magnetic resonance imaging. Atlas-based parcellation using a fine-grained Brainnetome Atlas was conducted to assess gray matter (GM) volume, metabolism, and metabolic connectivity in the sub-insula (region of interest). Results: There was no significant GM atrophy or hypometabolism in insula subregions in asymptomatic MAPT P301L carriers, although decreased metabolic connectivity between vIa-middle temporal gyrus, vIa-temporal poles, dIa-middle temporal gyrus and dIa-temporal poles; and increased connectivity between vIa-orbitofrontal, vIa-dorsal lateral superior frontal gyrus, and dIa-orbitofrontal and dIa-dorsal lateral superior frontal gyrus were observed. Patients with bvFTD had significant atrophy and hypometabolism in all insula subregions and decreased metabolic connectivity in the whole brain, including vIa/dIa-middle temporal and vIa/dIa-temporal poles. The standardized uptake value ratios of vIa and dIa were negatively associated with behavioral disinhibition scale scores. Conclusion: Metabolic connectivity is altered in vIa and dIa subregions of the sub-insula in MAPT P301L mutation carriers before the occurrence of atrophy, hypometabolism, and clinical symptoms. Show more

Keywords: Behavioral variant frontotemporal dementia, 18F-FDG-PET, insula, microtubule-associated protein tau, network

DOI: 10.3233/JAD-221035

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2023

Authors: Xiang, Qingyan | Andersen, Stacy L. | Sweigart, Benjamin | Gunn, Sophia | Nygaard, Marianne | Perls, Thomas T. | Sebastiani, Paola

Article Type: Research Article

Abstract: Background: Discovering patterns of cognitive domains and characterizing how these patterns associate with other risk factors and biomarkers can improve our understanding of the determinants of cognitive aging. Objective: To discover patterns of cognitive domains using neuropsychological test results in Long Life Family Study (LLFS) and characterize how these patterns associate with aging markers. Methods: 5,086 LLFS participants were administered neuropsychological tests at enrollment. We performed a cluster analysis of six baseline neuropsychological test scores and tested the association between the identified clusters and various clinical variables, biomarkers, and polygenic risk scores using generalized estimating equations …and the Chi-square test. We used Cox regression to correlate the clusters with the hazard of various medical events. We investigated whether the cluster information could enhance the prediction of cognitive decline using Bayesian beta regression. Results: We identified 12 clusters with different cognitive signatures that represent profiles of performance across multiple neuropsychological tests. These signatures significantly correlated with 26 variables including polygenic risk scores, physical and pulmonary functions, and blood biomarkers and were associated with the hazard of mortality (p  <  0.01), cardiovascular disease (p  = 0.03), dementia (p  = 0.01), and skin cancer (p  = 0.03). Conclusion: The identified cognitive signatures capture multiple domains simultaneously and provide a holistic vision of cognitive function, showing that different patterns of cognitive function can coexist in aging individuals. Such patterns can be used for clinical intervention and primary care. Show more

Keywords: Aging, Alzheimer’s disease, cluster analysis, cognition, longevity, neuropsychology, survival

DOI: 10.3233/JAD-221025

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2023

Authors: Chen, Xiao | Li, Wanlu | Huang, Yuhui | Yang, Jiaxi | Tao, Yang | Huang, Liyan | Shen, Jiadong | Ma, Yanan | Liu, Zuyun | Xu, Xin | Xu, Xiaolin | Zong, Geng | Yuan, Changzheng

Article Type: Research Article

Abstract: Background: Cognitive role of untreated type 2 diabetes mellitus (T2DM) has been less well substantiated. Objective: We sought to explore the prospective association of T2DM and untreated T2DM with cognitive function among middle-aged and older Chinese adults. Methods: Data of 7,230 participants without baseline brain damage, mental retardation, or memory-related diseases in China Health and Retirement Longitudinal Study (CHARLS) from 2011– 2012 to 2015, were analyzed. Fasting plasma glucose and self-reported information on T2DM diagnosis and treatment were assessed. Participants were categorized into normoglycemia, impaired fasting glucose (IFG), and T2DM (including untreated and treated T2DM) groups. …Episodic memory and executive function were assessed by modified Telephone Interview for Cognitive Status every two years. We used generalized estimating equation model to examine the association of baseline T2DM status with cognitive function in succeedingyears. Results: Compared to those with normoglycemia, T2DM was associated with worse overall cognitive function after controlling for demographic variables, lifestyles, follow-up time, major clinical factors, and baseline cognitive function, although the associations were statistically non-significant (β = –0.19, 95% CI: –0.39, 0.00). However, a significant association was mainly observed for those with untreated T2DM (β = –0.26, 95% CI: –0.47, –0.04), especially in the domain of executive function (β = –0.19, 95% CI: –0.35, –0.03). In general, IFG and treated T2DM individuals had similar levels of cognitive function with normoglycemia participants. Conclusion: Our findings supported a detrimental role of untreated T2DM on cognitive function among middle-aged and older adults. Screening and early treatment for T2DM are warranted for maintaining better cognitive function in later life. Show more

Keywords: Alzheimer’s disease, cognitive function, prospective study, type 2 diabetes mellitus, untreated T2DM

DOI: 10.3233/JAD-220822

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2023

Authors: Lee, Jaegyeong | Kim, Junhyoung | Park, Ayeong | Hong, Rak-kyeun | Ko, Myungjin | Heo, Mina | Kim, Hoowon | Yeon Chung, Ji

Article Type: Research Article

Abstract: Background: Subjective cognitive decline (SCD) is a self-reported experience of declining cognitive function showing normal performance in cognitive assessments, which is a known risk factor for dementia. Recent studies highlight the importance of nonpharmacological multidomain interventions that can target multiple risk factors of dementia in older adults. Objective: This study investigated the efficacy of the Silvia program, a mobile-based multidomain intervention, to improve cognitive function and health-related outcomes of older adults with SCD. We compare its effects to a conventional paper-based multidomain program on various health indicators related to risk factors of dementia. Methods: This prospective …randomized controlled trial involved 77 older adults with SCD recruited from the Dementia Prevention and Management Center in Gwangju, South Korea during May to October 2022. Participants were randomly assigned to either the mobile- or paper-based group. Interventions were administered for 12 weeks, where pre- and post-assessments were conducted. Results: The K-RBANS total score did not show significant differences between groups. The mobile group showed better improvement in K-PRMQ scores and PSS scores than the paper group. Differences within groups showed that mobile-based interventions significantly improved K-PRMQ, STAI-X-1, PSS, and EQ-5D-5 L scores, while paper-based interventions significantly improved PSS, and EQ-5D-5 L scores. Patient adherence rate was 76.6%. Conclusion: Overall, the Silvia program was effective for improving self-reported memory failures, stress, anxiety, and health-related quality of life in older adults with SCD. However, longer periods of administration for more than 12 weeks may be needed to achieve significant improvements in cognitive function by objective measures. Show more

Keywords: Clinical trial, cognitive aging, cognitive decline, cognitive training, dementia, health promotion, healthy lifestyle, online intervention, preventive health

DOI: 10.3233/JAD-221299

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2023