Journal of Alzheimer's Disease - Volume 95, issue 1

Authors: Olmos-Villaseñor, Rocio | Sepulveda-Silva, Consuelo | Julio-Ramos, Teresa | Fuentes-Lopez, Eduardo | Toloza-Ramirez, David | Santibañez, Rodrigo A. | Copland, David A. | Mendez-Orellana, Carolina

Article Type: Systematic Review

Abstract: Background: Semantic and Phonological fluency (SF and PF) are routinely evaluated in patients with Alzheimer’s disease (AD). There are disagreements in the literature regarding which fluency task is more affected while developing AD. Most studies focus on SF assessment, given its connection with the temporoparietal amnesic system. PF is less reported, it is related to working memory, which is also impaired in probable and diagnosed AD. Differentiating between performance on these tasks might be informative in early AD diagnosis, providing an accurate linguistic profile. Objective: Compare SF and PF performance in healthy volunteers, volunteers with probable AD, and …patients with AD diagnosis, considering the heterogeneity of age, gender, and educational level variables. Methods: A total of 8 studies were included for meta-analysis, reaching a sample size of 1,270 individuals (568 patients diagnosed with AD, 340 with probable AD diagnosis, and 362 healthy volunteers). Results: The three groups consistently performed better on SF than PF. When progressing to a diagnosis of AD, we observed a significant difference in SF and PF performance across our 3 groups of interest (p  = 0.04). The age variable explained a proportion of this difference in task performance across the groups, and as age increases, both tasks equally worsen. Conclusion: The performance of SF and PF might play a differential role in early AD diagnosis. These tasks rely on partially different neural bases of language processing. They are thus worth exploring independently in diagnosing normal aging and its transition to pathological stages, including probable and diagnosed AD. Show more

Keywords: Alzheimer’s disease, phonemic fluency, semantic fluency, verbal fluency

DOI: 10.3233/JAD-221272

Citation: Journal of Alzheimer's Disease, vol. 95, no. 1, pp. 1-12, 2023

Authors: Nadeau, Patricia A. | Jobin, Benoît | Boller, Benjamin

Article Type: Systematic Review

Abstract: Background: Improved health care for people with Down syndrome (DS) has resulted in an increase in their life expectancy therefore increasing comorbidities associated with age-related problems in this population, the most frequent being Alzheimer’s disease (AD). To date, several cognitive tests have been developed to evaluate cognitive changes related to the development of mild cognitive impairment (MCI) and AD in people with DS. Objective: Identify and evaluate available cognitive tests for the diagnosis of MCI and AD in people with DS. Methods: A systematic search of the Pubmed and PsycInfo databases was performed …to identify articles published from January 1, 2000 and July 1, 2022. Keysearch terms were DS, AD or MCI, cognition, and assessment. Relevant studies assessing the diagnostic accuracy of cognitive tests for AD or MCI with standard clinical evaluation were extracted. Risk of bias was assessed using the QUADAS 2. Results: We identified 15 batteries, 2 intelligence scales, 14 memory tests, 11 executive, functioning tests, 11 motor and visuospatial functioning tests, 5 language tests, 3 attention tests, and 2 orientation tests. Analysis showed that the CAMCOG-DS present a fair to excellent diagnostic accuracy for detecting AD in patients with DS. However, for the diagnosis of MCI, this battery showed poor to good diagnostic accuracy. Conclusion: The findings highlight important limitations of the current assessment available for the screening of mild cognitive impairment and AD in patients with DS and support the need for more clinical trials to ensure better screening for this highly at-risk population. Show more

Keywords: Alzheimer’s disease, cognition, Down syndrome, mild cognitive impairment

DOI: 10.3233/JAD-220991

Citation: Journal of Alzheimer's Disease, vol. 95, no. 1, pp. 13-51, 2023

Authors: Nowrangi, Milap A. | Outen, John D. | Kim, John | Avramopoulos, Dimitrios | Lyketsos, Constantine G. | Rosenberg, Paul B.

Article Type: Systematic Review

Abstract: Background: Despite the burden on patients and caregivers, there are no approved therapies for the neuropsychiatric symptoms of Alzheimer’s disease (NPS-AD). This is likely due to an incomplete understanding of the underlying mechanisms. Objective: To review the neurobiological mechanisms of NPS-AD, including depression, psychosis, and agitation. Methods: Understanding that genetic encoding gives rise to the function of neural circuits specific to behavior, we review the genetics and neuroimaging literature to better understand the biological underpinnings of depression, psychosis, and agitation. Results: We found that mechanisms involving monoaminergic biosynthesis and function are likely key elements …of NPS-AD and while current treatment approaches are in line with this, the lack of effectiveness may be due to contributions from additional mechanisms including neurodegenerative, vascular, inflammatory, and immunologic pathways. Conclusion: Within an anatomic-genetic framework, development of novel effective biological targets may engage targets within these pathways but will require a better understanding of the heterogeneity in NPS-AD. Show more

Keywords: Agitation, Alzheimer’s disease, apathy, behavior, dementia, depression, genetics, neuroimaging, neuropsychiatric

DOI: 10.3233/JAD-221247

Citation: Journal of Alzheimer's Disease, vol. 95, no. 1, pp. 53-68, 2023

Authors: Sutin, Angelina R. | Aschwanden, Damaris | Luchetti, Martina | Stephan, Yannick | Terracciano, Antonio

Article Type: Short Communication

Abstract: Subjective memory is useful to detect cognitive deficits not apparent on objective tests. This research evaluates whether memory rated by an interviewer predicts incident dementia. Health and Retirement Study participants without cognitive impairment at baseline whose memory was rated by the interviewer were analyzed (N  = 12,749). Worse interviewer-rated memory was associated with higher risk of incident dementia over 15 years (HR = 1.40, 95% CI = 1.27–1.54). The association was evident even among participants in the top quartile of objective memory performance (HR = 1.71, 95% CI = 1.26–2.32). Interviewer-rated memory may be a low-cost supplement to neuropsychological evaluation to predict dementia risk beyond self-reports and objective cognitive …testing. Show more

Keywords: Alzheimer’s disease, early indicator, incident dementia, interviewer ratings, observer ratings, subjective memory

DOI: 10.3233/JAD-230417

Citation: Journal of Alzheimer's Disease, vol. 95, no. 1, pp. 69-74, 2023

Authors: Cheng, Cheng | Yang, Cui | Jia, Congcong | Wang, Qingshan

Article Type: Article Commentary

Abstract: Alzheimer’s disease (AD) is a complex, heterogeneous, and progressive neurodegenerative dementia. Although the majority of AD research has primarily focused on disease-associated alterations of the cortex and hippocampus in the cerebrum, emerging evidence has highlighted the cerebellum’s involvement in sleep, cognition, and AD. In this commentary, we discuss a recently published article in Alzheimer ’s and Dementia , which examines changes in cerebellar electrophysiology, sleep-wake cycles, and neuropathology in APPswe /PS1Δ E9 mice. We also explore the potential role of the cerebellum in AD, offering a fresh perspective on the study of cerebellar involvement in the disease.

Keywords: Alzheimer’s disease, cerebellum, electroencephalogram, neuropathology, sleep disturbances

DOI: 10.3233/JAD-230381

Citation: Journal of Alzheimer's Disease, vol. 95, no. 1, pp. 75-78, 2023

Authors: Chen, Randi | Morris, Brian J. | Donlon, Timothy A. | Ross, G. Webster | Kallianpur, Kalpana J. | Allsopp, Richard C. | Nakagawa, Kazuma | Willcox, Bradley J. | Masaki, Kamal H.

Article Type: Research Article

Abstract: Background: It is well established that mid-life hypertension increases risk of dementia, whereas the association of late-life hypertension with dementia is unclear. Objective: To determine whether FOXO3 longevity-associated genotype influences the association between late-life hypertension and incident dementia. Methods: Subjects were 2,688 American men of Japanese ancestry (baseline age: 77.0±4.1 years, range 71–93 years) from the Kuakini Honolulu Heart Program. Status was known for FOXO3 rs2802292 genotype, hypertension, and diagnosis of incident dementia to 2012. Association of FOXO3 genotype with late-life hypertension and incident dementia, vascular dementia (VaD) and Alzheimer’s disease (AD) was …assessed using Cox proportional hazards models. Results: During 21 years of follow-up, 725 men were diagnosed with all-cause dementia, 513 with AD, and 104 with VaD. A multivariable Cox model, adjusting for age, education, APOE ɛ 4, and cardiovascular risk factors, showed late-life hypertension increased VaD risk only (HR = 1.71, 95% CI = 1.08–2.71, p  = 0.022). We found no significant protective effect of FOXO3 longevity genotype on any type of dementia at the population level. However, in a full Cox model adjusting for age, education, APOE ɛ 4, and other cardiovascular risk factors, there was a significant interaction effect of late-life hypertension and FOXO3 longevity genotype on incident AD (β = –0.52, p  = 0.0061). In men with FOXO3 rs2802292 longevity genotype (TG /GG ), late-life hypertension showed protection against AD (HR = 0.72; 95% CI = 0.55–0.95, p  = 0.021). The non-longevity genotype (TT ) (HR = 1.16; 95% CI = 0.90–1.51, p  = 0.25) had no protective effect. Conclusion: This longitudinal study found late-life hypertension was associated with lower incident AD in subjects with FOXO3 genotype. Show more

Keywords: Alzheimer’s disease, FOXO3, genetics, hypertension, longitudinal study, vascular dementia

DOI: 10.3233/JAD-230350

Citation: Journal of Alzheimer's Disease, vol. 95, no. 1, pp. 79-91, 2023

Authors: Stallard, Eric | Kociolek, Anton | Jin, Zhezhen | Ryu, Hyunnam | Lee, Seonjoo | Cosentino, Stephanie | Zhu, Carolyn | Gu, Yian | Fernandez, Kayri | Hernandez, Michelle | Kinosian, Bruce | Stern, Yaakov

Article Type: Research Article

Abstract: Background: The major aims of the three Predictors Studies have been to further our understanding of Alzheimer’s disease (AD) progression sufficiently to predict the length of time from disease onset to major disease outcomes in individual patients with AD. Objectives: To validate a longitudinal Grade of Membership (L-GoM) prediction algorithm developed using clinic-based, mainly white patients from the Predictors 2 Study in a statistically representative community-based sample of Hispanic (N = 211) and non-Hispanic (N = 62) older adults (with 60 males and 213 females) from the Predictors 3 Study and extend the algorithm to mild cognitive impairment (MCI). Methods: …The L-GoM model was applied to data collected at the initial Predictors 3 visit for 150 subjects with AD and 123 with MCI. Participants were followed annually for up to seven years. Observed rates of survival and need for full-time care (FTC) were compared to those predicted by the algorithm. Results: Initial MCI/AD severity in Predictors 3 was substantially higher than among clinic-based AD patients enrolled at the specialized Alzheimer’s centers in Predictors 2. The observed survival and need for FTC followed the L-GoM model trajectories in individuals with MCI or AD, except for N = 32 subjects who were initially diagnosed with AD but reverted to a non-AD diagnosis on follow-up. Conclusion: These findings indicate that the L-GoM model is applicable to community-dwelling, multiethnic older adults with AD. They extend the use of the model to the prediction of outcomes for MCI. They also justify release of our L-GoM calculator at this time. Show more

Keywords: Alzheimer’s disease, custodial care, dementia progression, life tables, mild cognitive impairment, mortality determinants, patient-specific modeling, prognostic factors, survival, validation

DOI: 10.3233/JAD-220811

Citation: Journal of Alzheimer's Disease, vol. 95, no. 1, pp. 93-117, 2023

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

Article Type: Research Article

Abstract: Background: TMA-93 examines relational binding using images. Biomarker validation has demonstrated that it is discriminative for diagnosing early AD. The effect of cognitive reserve on TMA-93 performance remains unexplored and could improve the interpretative framework for using the test. Objective: To study the effect of cognitive reserve on TMA-93 performance and to provide new norms for the test that include its measurement. Methods: Cognitively unimpaired people aged 55 and over were systematically recruited for this cross-sectional normative study in southern Spain. Age, sex, and scores on the Cognitive Reserve Questionnaire (CRQ; maximum score: 25 points) were …collected, and the TMA-93 was administered (maximum score: 30 points). Percentile-based reference data that captured combinations of socio-demographics variables with significant effect on TMA-93 performance were calculated. Results: 902 participants (62.5% female; age: median = 68, IQR = 61–75, range = 55–90) were included. CRQ total scores were globally low (median = 8, IQR = 5–13, range = 0–24). Cognitive reserve, including modifiable items as reading activity and intellectual gaming activity, and age mainly supported the TMA-93 total score variance. Sex seemed to have some influence in the elderly. TMA-93 total scores medians began to drop from 70–75 years old. Higher total score on the CRQ and, possibly, female sex determined a gentler slope. New norms based on these variables showed wide variations in scores for the 5th and 10th percentiles. Conclusion: Visual relational binding ability depends on cognitive reserve, including modifiable items. The age-related binding deficit is buffered by higher cognitive reserve and, at older ages, by female sex. Show more

Keywords: Alzheimer’s disease, cognitive reserve, memory, neuropsychological tests.

DOI: 10.3233/JAD-221110

Citation: Journal of Alzheimer's Disease, vol. 95, no. 1, pp. 119-129, 2023

Authors: Inoriza, José M. | Carreras, Marc | Coderch, Jordi | Turro-Garriga, Oriol | Sáez, Marc | Garre-Olmo, Josep

Article Type: Research Article

Abstract: Background: The large number of dementia cases produces a great pressure on health and social care services, which requires efficient planning to meet the needs of patients through infrastructure, equipment, and financial, technical, and personal resources adjusted to their demands. Dementia analysis requires studies with a very precise patient characterization of both the disease and comorbidities present, and long-term follow-up of patients in clinical aspects and patterns of resource utilization and costs generated. Objective: To describe and quantify direct healthcare expenditure and its evolution from three years before and up to ten years after the diagnosis of dementia, …compared to a matched group without dementia. Methods: Retrospective cohort design with follow-up from 6 to 14 years. We studied 996 people with dementia (PwD) and 2,998 controls matched for age, sex, and comorbidity. This paper adopts the provider’s perspective as the perspective of analysis and refers to the costs actually incurred in providing the services. Aggregate costs and components per patient per year were calculated and modelled. Results: Total health expenditure increases in PwD from the year of diagnosis and in each of the following 7 years, but not thereafter. Health status and mortality are factors explaining the evolution of direct costs. Dementia alone is not a statistically significant factor in explaining differences between groups. Conclusion: The incremental direct cost of dementia may not be as high or as long as studies with relatively short follow-up suggest. Dementia would have an impact on increasing disease burden and mortality. Show more

Keywords: Alzheimer’s disease, dementia, health care expenditure, health management organization, real world data, social care expenditure

DOI: 10.3233/JAD-221220

Citation: Journal of Alzheimer's Disease, vol. 95, no. 1, pp. 131-147, 2023

Authors: Kilpatrick, Lisa A. | Siddarth, Prabha | Krause-Sorio, Beatrix | Milillo, Michaela M. | Aguilar-Faustino, Yesenia | Ercoli, Linda | Narr, Katherine L. | Khalsa, Dharma S. | Lavretsky, Helen

Article Type: Research Article

Abstract: Background: Yoga may be an ideal early intervention for those with modifiable risk factors for Alzheimer’s disease (AD) development. Objective: To examine the effects of Kundalini yoga (KY) training versus memory enhancement training (MET) on the resting-state connectivity of hippocampal subregions in women with subjective memory decline and cardiovascular risk factors for AD. Methods: Participants comprised women with subjective memory decline and cardiovascular risk factors who participated in a parent randomized controlled trial (NCT03503669) of 12-weeks of KY versus MET and completed pre- and post-intervention resting-state magnetic resonance imaging scans (yoga: n  = 11, age = 61.45±6.58 years; MET: …n  = 11, age = 64.55±6.41 years). Group differences in parcellated (Cole-anticevic atlas) hippocampal connectivity changes (post- minus pre-intervention) were evaluated by partial least squares analysis, controlling for age. Correlations between hippocampal connectivity and perceived stress and frequency of forgetting (assessed by questionnaires) were also evaluated. Results: A left anterior hippocampal subregion assigned to the default mode network (DMN) in the Cole-anticevic atlas showed greater increases in connectivity with largely ventral visual stream regions with KY than with MET (p  < 0.001), which showed associations with lower stress (p  < 0.05). Several posterior hippocampal subregions assigned to sensory-based networks in the Cole-anticevic atlas showed greater increases in connectivity with regions largely in the DMN and frontoparietal network with MET than with KY (p  < 0.001), which showed associations with lower frequency of forgetting (p  < 0.05). Conclusion: KY training may better target stress-related hippocampal connectivity, whereas MET may better target hippocampal sensory-integration supporting better memory reliability, in women with subjective memory decline and cardiovascular risk factors. Show more

Keywords: Alzheimer’s disease, cardiovascular, hippocampus, memory, resting-state, yoga

DOI: 10.3233/JAD-221159

Citation: Journal of Alzheimer's Disease, vol. 95, no. 1, pp. 149-159, 2023

Authors: Yu, Yueyi | Xia, Xinyi | Meng, Xiaosheng | Li, Dan | Qin, Qi

Article Type: Research Article

Abstract: Background: Increasing evidence illustrates the value of plasma biomarkers of Alzheimer’s disease (AD) to screen for and identify dementia with Lewy bodies (DLB). However, confirmatory studies are needed to demonstrate the feasibility of these markers. Objective: To determine the feasibility of plasma tau phosphorylated at threonine 181 (p-tau181) and amyloid-β42 (Aβ42 ) as potential biomarkers to differentiate AD and DLB. Methods: We evaluated plasma samples from patients with DLB (n  = 47) and AD (n  = 55) and healthy controls (HCs, n  = 30), using ELISAs to measure p-tau181 and Aβ42 . Additionally, we examined neuropsychological assessment scores …for participants. The plasma biomarkers were investigated for correlation with neuropsychological assessments and discriminant ability to identify DLB. Results: Plasma p-tau181 was significantly lower in DLB than in AD and HCs. Plasma Aβ42 was significantly higher in DLB than in AD but lower in DLB than in HCs. We found good correlations between plasma Aβ42 and neuropsychological scores in the whole cohort, while p-tau181 was associated with cognitive status in DLB. In the distinction between DLB and HCs, plasma p-tau181 and Aβ42 showed similar accuracy, while Aβ42 showed better accuracy than p-tau181 in discriminating DLB and AD. Conclusion: In a single-center clinical cohort, we confirmed the high diagnostic value of plasma p-tau181 and Aβ42 for distinguishing patients with DLB from HCs. Plasma Aβ42 improved the differential diagnosis of DLB from AD. Show more

Keywords: Alzheimer’s disease, biomarkers, cognitive assessment, Lewy body dementia

DOI: 10.3233/JAD-230085

Citation: Journal of Alzheimer's Disease, vol. 95, no. 1, pp. 161-169, 2023

Authors: Zhou, Chaomin | Zhan, Lin | He, Pinghong | Yuan, Jing | Zha, Yan

Article Type: Research Article

Abstract: Background: Cognitive impairment (CI) is highly prevalent in patients undergoing hemodialysis. Whether fluid overload with malnutrition as assessed by the ratio of extracellular water to intracellular water (ECW/ICW) is associated with CI in patients on maintenance hemodialysis (MHD) has yet to be studied. Objective: This study aimed to investigate the association between ECW/ICW and CI in patients with MHD. Methods: We conducted a multicenter, cross-sectional study that enrolled 3,025 adult patients with MHD. Cognitive function was assessed through the Mini-Mental State Examination. The ECW/ICW was derived from a portable body composition monitor and analyzed by quartiles. …Results: 23.04% of participants had CI in our study. The prevalence of CI tended to increase as the quartiles of the ECW/ICW ratio increased. Unadjusted analysis showed that participants in quartile 4 were 3.02 times more likely to have a CI compared to those in quartile 1. After adjusting for age, sex, education, smoking status, body mass index, dialysis vintage, history of hypertension, and history of stroke, the adjusted OR (95% CI) for the highest quartile of ECW/ICW ratio was 1.36 (1.01, 1.83) for CI compared with the lowest quartile. Interestingly, the association between ECW/ICW ratio and CI persisted across all subgroups stratified by age, gender, history of diabetes, and stroke. (p for interaction > 0.05 for all). Conclusion: An increased ECW/ICW ratio is associated with higher odds of cognitive impairment in patients undergoing hemodialysis. Show more

Keywords: Alzheimer’s disease, cognitive impairment, extracellular water to intracellular water ratio, fluid overload, maintenance hemodialysis

DOI: 10.3233/JAD-230196

Citation: Journal of Alzheimer's Disease, vol. 95, no. 1, pp. 171-179, 2023

Authors: Ruiz-Adame, Manuel | Ibañez, Agustín | Mollayeva, Tatyana | Trépel, Dominic

Article Type: Research Article

Abstract: Background: People with high levels of neuroticism are greater users of health services. Similarly, people with dementia have a higher risk of hospitalization and medical visits. As a result, dementia and a high level of neuroticism increase healthcare use (HCU). However, how these joint factors impact the HCU at the population level is unknown. Similarly, no previous study has assessed the degree of generalization of such impacts, considering relevant variables including age, gender, socioeconomic, and country-level variability. Objective: To examine how neuroticism and dementia interact in the HCU. Methods: A cross-sectional study was performed on a …sample of 76,561 people (2.4% with dementia) from 27 European countries and Israel. Data were analyzed with six steps multilevel non-binomial regression modeling, a statistical method that accounts for correlation in the data taken within the same participant. Results: Both dementia (Incidence Rate Ratio (IRR): 1.537; α= 0.000) and neuroticism (IRR: 1.122; α= 0.000) increased the HCU. The effect of having dementia and the level of neuroticism increased the HCU: around 53.67% for the case of having dementia, and 12.05% for each increment in the level of neuroticism. Conversely, high levels of neuroticism in dementia decreased HCU (IRR: 0.962; α= 0.073). These results remained robust when controlling for age, gender, socioeconomic, and country-levels effects. Conclusion: Contrary to previous findings, neuroticism trait in people with dementia decreases the HCU across sociodemographic, socioeconomic, and country heterogeneity. These results, which take into account this personality trait among people with dementia, are relevant for the planning of health and social services. Show more

Keywords: Alzheimer’s disease, dementia, health care use, health economics, neuroticism, personality traits

DOI: 10.3233/JAD-230265

Citation: Journal of Alzheimer's Disease, vol. 95, no. 1, pp. 181-193, 2023

Authors: Kohler, Iliana V. | Kämpfen, Fabrice | Bandawe, Chiwoza | Kohler, Hans-Peter

Article Type: Research Article

Abstract: Background: Cognition and its age-related changes remain vastly understudied in low-income countries (LICs), despite evidence suggesting that cognitive decline among aging low-income populations is a rapidly increasing disease burden often occurring at younger ages as compared to high-income countries (HICs). Objective: We examine patterns of cognition among men and women, 45 + years old, living in rural Malawi. We analyze how key socioeconomic characteristics predict levels of cognition and its changes as individuals get older. Methods: Utilizing the Mature Adults Cohort of the Malawi Longitudinal Study of Families and Health (MLSFH-MAC) collected during 2012–2017, we estimate standard regression …models to analyze predictors of the age- and sex-specific levels and longitudinal changes in cognition. Cognition is assessed with a screening instrument that is adapted to this low-literacy context and measures different domains such as language, attention, or executive functioning. Results: Women have lower levels of cognition than men, a pattern in stark contrast to findings in HICs. Schooling and socioeconomic status increase the probability of having consistently high performance during the cognitive assessment. Cognitive decline accelerates with age and is detectable already at mid-adult ages (45–55 years). Despite lower levels of cognitive function observed among women, the pace of decline with age is similar for both genders. Conclusion: Women are particularly affected by poor cognition in this context. The study emphasizes the importance of prioritizing cognitive health and research on cognition among older individuals in sub-Saharan Africa LICs, to which relatively little health care resources continue to be allocated. Show more

Keywords: Age- and sex-specific patterns, Alzheimer’s disease, cognition, gender differences, longitudinal changes, low-income countries, Sub-Saharan Africa

DOI: 10.3233/JAD-230271

Citation: Journal of Alzheimer's Disease, vol. 95, no. 1, pp. 195-212, 2023

Authors: Hartley, Sigan L. | Fleming, Victoria | Schworer, Emily K. | Peven, Jamie | Handen, Benjamin L. | Krinsky-McHale, Sharon | Hom, Christy | Lee, Laisze | Tudorascu, Dana L. | Laymon, Charles | Minhas, Davneet | Luo, Weiquan | Cohen, Annie | Zaman, Shahid | Ances, Beau M. | Mapstone, Mark | Head, Elizabeth | Lai, Florence | Rosas, H. Diana | Klunk, William | Christian, Bradley

Article Type: Research Article

Abstract: Background: Trisomy 21 causes Down syndrome (DS) and is a recognized cause of early-onset Alzheimer’s disease (AD). Objective: The current study sought to determine if premorbid intellectual disability level (ID) was associated with variability in age-trajectories of AD biomarkers and cognitive impairments. General linear mixed models compared the age-trajectory of the AD biomarkers PET Aβ and tau and cognitive decline across premorbid ID levels (mild, moderate, and severe/profound), in models controlling trisomy type, APOE status, biological sex, and site. Methods: Analyses involved adults with DS from the Alzheimer’s Biomarkers Consortium-Down Syndrome. Participants completed measures of …memory, mental status, and visuospatial ability. Premorbid ID level was based on IQ or mental age scores prior to dementia concerns. PET was acquired using [11 C] PiB for Aβ, and [18 F] AV-1451 for tau. Results: Cognitive data was available for 361 participants with a mean age of 45.22 (SD = 9.92) and PET biomarker data was available for 154 participants. There was not a significant effect of premorbid ID level by age on cognitive outcomes. There was not a significant effect of premorbid ID by age on PET Aβ or on tau PET. There was not a significant difference in age at time of study visit of those with mild cognitive impairment-DS or dementia by premorbid ID level. Conclusion: Findings provide robust evidence of a similar time course in AD trajectory across premorbid ID levels, laying the groundwork for the inclusion of individuals with DS with a variety of IQ levels in clinical AD trials. Show more

Keywords: Alzheimer’s disease, amyloid, cognitive, dementia, Down syndrome, imaging, intellectual, memory, tau

DOI: 10.3233/JAD-230200

Citation: Journal of Alzheimer's Disease, vol. 95, no. 1, pp. 213-225, 2023

Authors: Huang, Lin | Li, Yatian | Wu, Jingnan | Chen, Nan | Xia, Huanhuan | Guo, Qihao

Article Type: Research Article

Abstract: Background: A rapid digital instrument is needed to facilitate community-based screening of mild cognitive impairment (MCI) and Alzheimer’s disease (AD) in China. Objective: We developed a voice recognition-based cognitive assessment (Shanghai Cognitive Screening, SCS) on mobile devices and evaluated its diagnostic performance. Methods: Participants (N = 251) including healthy controls (N = 98), subjective cognitive decline (SCD, N = 42), MCI (N = 80), and mild AD (N = 31) were recruited from the memory clinic at Shanghai Sixth People’s Hospital. The SCS is fully self-administered, takes about six minutes and measures the function of visual memory, language, and executive function. Participants were instructed to complete …SCS tests, gold-standard neuropsychological tests and standardized structural 3T brain MRI. Results: The Cronbach’s alpha was 0.910 of the overall scale, indicating high internal consistency. The SCS total score had an AUC of 0.921 to detect AD (sensitivity = 0.903, specificity = 0.945, positive predictive value = 0.700, negative predictive value = 0.986, likelihood ratio = 16.42, number needed for screening utility = 0.639), and an AUC of 0.838 to detect MCI (sensitivity = 0.793, specificity = 0.671, positive predictive value = 0.657, negative predictive value = 0.803, likelihood ratio = 2.41, number needed for screening utility = 0.944). The subtests demonstrated moderate to high correlations with the gold-standard tests from their respective cognitive domains. The SCS total score and its memory scores all correlated positively with relative volumes of the whole hippocampus and almost all subregions, after controlling for age, sex, and education. Conclusion: The SCS has good diagnostic accuracy for detecting MCI and AD dementia and has the potential to facilitate large-scale screening in the general community. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, episodic memory, neuropsychology

DOI: 10.3233/JAD-230277

Citation: Journal of Alzheimer's Disease, vol. 95, no. 1, pp. 227-236, 2023

Authors: López-Martos, David | Brugulat-Serrat, Anna | Cañas-Martínez, Alba | Canals-Gispert, Lidia | Marne, Paula | Gramunt, Nina | Suárez-Calvet, Marc | Milà-Alomà, Marta | Minguillon, Carolina | Fauria, Karine | Zetterberg, Henrik | Blennow, Kaj | Gispert, Juan Domingo | Molinuevo, José Luis | Grau-Rivera, Oriol | Sánchez-Benavides, Gonzalo

Article Type: Research Article

Abstract: Background: Conventional neuropsychological norms likely include cognitively unimpaired (CU) individuals with preclinical Alzheimer’s disease (AD) pathology (amyloid-β, tau, and neurodegeneration) since they are based on cohorts without AD biomarkers data. Due to this limitation, population-based norms would lack sensitivity for detecting subtle cognitive decline due to AD, the transitional stage between healthy cognition and mild cognitive impairment. We have recently published norms for memory tests in individuals with normal cerebrospinal fluid (CSF) AD biomarker levels. Objective: The aim of the present study was to provide further AD biomarker-based cognitive references covering attentional, executive function, linguistic, and visual processing …tests. Methods: We analyzed 248 CU individuals aged between 50–70 years old with normal CSF Aβ, p-tau, and neurodegeneration (t-tau) biomarker levels. The tests included were the Trail Making Test (TMT), Semantic Fluency Test, Digit and Symbol Span, Coding, Matrix Reasoning, Judgement of Line Orientation and Visual Puzzles. Normative data were developed based on regression models adjusted for age, education, and sex when needed. We present equations to calculate z-scores, the corresponding normative percentile tables, and online calculators. Results: Age, education, and sex were associated with performance in all tests, except education for the TMT-A, and sex for the TMT-B, Coding, and Semantic Fluency. Cut-offs derived from the current biomarker-based reference data were higher and more sensitive than standard norms. Conclusion: We developed reference data obtained from individuals with evidence of non-pathologic AD biomarker levels that may improve the objective characterization of subtle cognitive decline in preclinical AD. Show more

Keywords: Alzheimer’s disease, biomarkers, cognition, normative data, preclinical

DOI: 10.3233/JAD-230290

Citation: Journal of Alzheimer's Disease, vol. 95, no. 1, pp. 237-249, 2023

Authors: Ikeda, Manabu | Mori, Etsuro | Orimo, Satoshi | Yamada, Tomomi | Konishi, Osamu

Article Type: Research Article

Abstract: Background: In patients with dementia with Lewy bodies (DLB), it is unknown whether adjunct zonisamide is as effective and safe as increasing levodopa dose when levodopa has inadequate efficacy on parkinsonism. Objective: To compare adjunct zonisamide 25 mg/day versus an increased levodopa dose (increased by 100 mg/day) in patients with DLB treated with levodopa ≤300 mg/day for parkinsonism. Methods: The DUEL study was a multicenter, randomized, controlled, open-label, parallel-group, interventional, non-inferiority trial. During the observation period, levodopa was administered at ≤300 mg/day for 4 weeks. Subsequently, patients were randomized to receive adjunct zonisamide 25 mg/day or levodopa increased by 100 mg/day. …Results: Respective adjusted mean changes in MDS-UPDRS Part III total score at 16 and 24 weeks (primary endpoint) were –6.3 and –4.4 in the zonisamide add-on and –0.8 and 2.0 in the levodopa increase groups. The adjusted mean difference at 24 weeks was –6.4 (95% confidence interval [CI] –13.5, 0.7); the upper limit of the 95% CI (0.7) was lower than the non-inferiority margin (3.0). No significant between-group differences were observed in total scores of the MDS-UPDRS Part II, Eating Questionnaire, EuroQol-5 dimension-5 level, Zarit Caregiver Burden Interview, or other secondary endpoints. No notable between-group differences were observed in adverse event incidences. Conclusion: Adjunct zonisamide 25 mg/day may yield moderate improvement in motor symptoms in patients with DLB when the levodopa effect is insufficient, but it could not be verified that the zonisamide 25 mg/day was as effective as levodopa 100 mg/day because levodopa showed no sufficient efficacy as assumed. Show more

Keywords: Alzheimer’s disease, dementia with Lewy bodies, levodopa, Lewy body disease, parkinsonism, randomized controlled trial, zonisamide

DOI: 10.3233/JAD-230335

Citation: Journal of Alzheimer's Disease, vol. 95, no. 1, pp. 251-264, 2023

Authors: Mc Ardle, Ríona | Hamilton, Calum | Del Din, Silvia | Kingston, Andrew | Robinson, Louise | Galna, Brook | Thomas, Alan J. | Rochester, Lynn

Article Type: Research Article

Abstract: Background: Promoting physical activity, such as habitual walking behaviors, in people with cognitive impairment may support their ability to remain independent with a good quality of life for longer. However, people with cognitive impairment participate in less physical activity compared to cognitively unimpaired older adults. The local area in which people live may significantly impact abilities to participate in physical activity. For example, people who live in more deprived areas may have less safe and walkable routes. Objective: To examine this further, this study aimed to explore associations between local area deprivation and physical activity in people with …cognitive impairment and cognitively unimpaired older adults (controls). Methods: 87 participants with cognitive impairment (mild cognitive impairment or dementia) and 27 older adult controls from the North East of England were included in this analysis. Participants wore a tri-axial wearable accelerometer (AX3, Axivity) on their lower backs continuously for seven days. The primary physical activity outcome was daily step count. Individuals’ neighborhoods were linked to UK government area deprivation statistics. Hierarchical Bayesian models assessed the association between local area deprivation and daily step count in people with cognitive impairment and controls. Results: Key findings indicated that there was no association between local area deprivation and daily step count in people with cognitive impairment, but higher deprivation was associated with lower daily steps for controls. Conclusion: These findings suggest that cognitive impairment may be associated with lower participation in physical activity which supersedes the influence of local area deprivation observed in normal aging. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, dementia, digital technology, exercise, home environment, walking, wearable electronic devices

DOI: 10.3233/JAD-230358

Citation: Journal of Alzheimer's Disease, vol. 95, no. 1, pp. 265-273, 2023

Authors: Lee, Annie J. | Sanchez, Didi | Reyes-Dumeyer, Dolly | Brickman, Adam M. | Lantigua, Rafael A. | Vardarajan, Badri N. | Mayeux, Richard

Article Type: Research Article

Abstract: Background: Queries for the presence of cardiovascular and cerebrovascular risk factors are typically assessed through self-report. However, the reliability and validity of self-reported cardiovascular and cerebrovascular risk factors remain inconsistent in aging research. Objective: To determine the reliability and validity of the most frequently self-reported vascular risk factors: hypertension, diabetes, and heart disease. Methods: 1,870 individuals aged 65 years or older among African Americans, Caribbean Hispanics, and white non-Hispanic individuals were recruited as part of a community study of aging and dementia. We assessed the reliability, validity, sensitivity, specificity, and percent agreement of self-reported hypertension, diabetes, …and heart disease, in comparison with direct measures of blood pressure, hemoglobin A1c (HbA1c), and medication use. The analyses were subsequently stratified by age, sex, education, and ethnic group. Results: Reliability of self-reported hypertension, diabetes, and heart disease was excellent. Agreement between self-reports and clinical measures was moderate for hypertension (kappa: 0.58), good for diabetes (kappa: 0.76–0.79), and moderate for heart disease (kappa: 0.45) differing slightly by age, sex, education, and ethnic group. Sensitivity and specificity for hypertension was 88.6% –78.1%, for diabetes was 87.7% –92.0% (HbA1c ≥6.5%) or 92.7% –92.8% (HbA1c ≥7%), and for heart disease was 85.8% –75.5%. Percent agreement of self-reported was 87.0% for hypertension, 91.6% –92.6% for diabetes, and 77.4% for heart disease. Conclusion: Ascertainment of self-reported histories of hypertension, diabetes, and heart disease are reliable and valid compared to direct measurements or medication use. Show more

Keywords: Alzheimer’s disease, diabetes, heart disease, hypertension, reliability and validity, vascular risk factors

DOI: 10.3233/JAD-230374

Citation: Journal of Alzheimer's Disease, vol. 95, no. 1, pp. 275-285, 2023

Authors: Li, Jixuan | Zeng, Qingze | Luo, Xiao | Li, Kaicheng | Liu, Xiaocao | Hong, Luwei | Zhang, Xinyi | Zhong, Siyan | Qiu, Tiantian | Liu, Zhirong | Chen, Yanxing | Huang, Peiyu | Zhang, Minming

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is accompanied with impaired neurovascular coupling. However, its early alteration remains elusive along the AD continuum. Objective: This study aimed to investigate the early disruption of neurovascular coupling in cognitively normal (CN) and mild cognitive impairment (MCI) elderly and its association with cognition and AD pathologies. Methods: We included 43 amyloid-β-negative CN participants and 38 amyloid-β-positive individuals (18 CN and 20 MCI) from the Alzheimer’s Disease Neuroimaging Initiative dataset. Regional homogeneity (ReHo) map was used to represent neuronal activity and cerebral blood flow (CBF) map was used to represent cerebral blood perfusion. …Neurovascular coupling was assessed by CBF/ReHo ratio at the voxel level. Analyses of covariance to detect the between-group differences and to further investigate the relations between CBF/ReHo ratio and AD biomarkers or cognition. In addition, the correlation of cerebral small vessel disease (SVD) burden and neurovascular coupling was assessed as well. Results: Related to amyloid-β-negative CN group, amyloid-β-positive groups showed decreased CBF/ReHo ratio mainly in the left medial and inferior temporal gyrus. Furthermore, lower CBF/ReHo ratio was associated with a lower Mini-Mental State Examination score as well as higher AD pathological burden. No association between CBF/ReHo ratio and SVD burden was observed. Conclusion: AD pathology is a major correlate of the disturbed neurovascular coupling along the AD continuum, independent of SVD pathology. The CBF/ReHo ratio may be an index for detecting neurovascular coupling abnormalities, which could be used for early diagnosis in the future. Show more

Keywords: Alzheimer’s disease, arterial spin labeling, functional magnetic resonance imaging, neurovascular coupling, positron emission tomography

DOI: 10.3233/JAD-230503

Citation: Journal of Alzheimer's Disease, vol. 95, no. 1, pp. 287-298, 2023

Authors: Yabuuchi, Kenichi | Kimura, Noriyuki | Masuda, Teruaki | Matsubara, Etsuro

Article Type: Research Article

Abstract: Background: The differences in positron emission tomography (PET) imaging among older adults with mild cognitive impairment (MCI), according to the recruitment source, remain unclear. Objective: To investigate the differences in brain amyloid deposition and cortical glucose metabolism according to recruitment source among older adults with MCI. Methods: Participants in the clinic-based MCI cohort, who were referred to Oita University Hospital for cognitive decline, consisted of 90 adults with MCI. The community-based MCI cohort, which participated in a prospective cohort study, consisted of 118 adults with MCI. Participants underwent cognitive function evaluation, 11 C-Pittsburgh compound B (PiB)-PET, …and 18 F-fluorodeoxyglucose (FDG)-PET. The prevalence of amyloid positivity and mean PiB and FDG uptake values were compared between the cohorts. Moreover, a voxel-by-voxel group study was performed to determine the areas with significant differences between the clinic- and community-based MCI cohorts. Results: The prevalence of amyloid positivity and mean PiB uptake value in the clinic-based MCI cohort were significantly higher than those in the community-based MCI cohort (p  < 0.001 and p  < 0.001, respectively). The mean FDG uptake value in the clinic-based MCI cohort was significantly lower than that in the community-based MCI cohort (p  < 0.001). SPM 8 analysis showed significantly increased PiB uptake in the precuneus and parietotemporal lobe and significantly decreased FDG uptake in the posterior cingulate in the clinic-based MCI cohort compared to the community-based MCI cohort. Conclusion: The prevalence and severity of amyloid pathology in older adults with MCI varied depending on the recruitment source. Show more

Keywords: Alzheimer’s disease, brain amyloid deposition, clinic-based cohort, community-based cohort, cortical glucose metabolism, mild cognitive impairment

DOI: 10.3233/JAD-230550

Citation: Journal of Alzheimer's Disease, vol. 95, no. 1, pp. 299-306, 2023

Authors: White, Lon R. | Corrada, Maria M. | Kawas, Claudia H. | Cholerton, Brenna A. | Edland, Steve E. | Flanagan, Margaret E. | Montine, Thomas J.

Article Type: Research Article

Abstract: Background: Decedents with late-life dementia are often found at autopsy to have vascular pathology, cortical Lewy bodies, hippocampal sclerosis, and/or TDP-43 encephalopathy alone or with concurrent Alzheimer’s disease (AD) lesions. Nonetheless, it is commonly believed that AD neuropathologic changes (NC) are the dominant or exclusive drivers of late-life dementia. Objective: Assess associations of end-of-life cognitive impairment with any one or any combination of five distinct NC. Assess impairment prevalence among subjects having natural resistance to each type of NC. Methods: Brains from 1,040 autopsied participants of the Honolulu-Asia Study, the Nun Study, and the 90 + Study were …examined for NC of AD, Lewy body dementia, microvascular brain injury, hippocampal sclerosis, and limbic predominate TDP-43 encephalopathy. Associations with impairment were assessed for each NC and for NC polymorbidity (variable combinations of 2-5 concurrent NC). Results: Among 387 autopsied decedents with severe cognitive impairment, 20.4% had only AD lesions (ADNC), 25.3% had ADNC plus 1 other NC, 11.1% had ADNC plus 2 or more other NC, 28.7% had no ADNC but 1-4 other NC, and 14.5% had no/negligible NC. Combinations of any two, three, or four NC were highly frequent among the impaired. Natural resistance to ADNC or any other single NC had a modest impact on overall cohort impairment levels. Conclusion: Polymorbidity involving 1-5 types of concurrent NC is a dominant neuropathologic feature of AD and related dementias. This represents a daunting challenge to future prevention and could explain failures of prior preventive intervention trials and of efforts to identify risk factors. Show more

Keywords: Alzheimer’s disease, Alzheimer’s disease and related dementias, autopsy, co-morbidity, dementia, neuropathology, polymorbidity, prevention

DOI: 10.3233/JAD-230331

Citation: Journal of Alzheimer's Disease, vol. 95, no. 1, pp. 307-316, 2023

Authors: Vicente, Mariane C. | Paneghini, Julia L. | Stabile, Angelita M. | Amorim, Mateus | Anibal Silva, Conceição E. | Patrone, Luis Gustavo A. | Cunha, Thiago M. | Bícego, Kênia C. | Almeida, Maria C. | Carrettiero, Daniel C. | Gargaglioni, Luciane H.

Article Type: Research Article

Abstract: Background: Neuroinflammation in Alzheimer’s disease (AD) can occur due to excessive activation of microglia in response to the accumulation of amyloid-β peptide (Aβ). Previously, we demonstrated an increased expression of this peptide in the locus coeruleus (LC) in a sporadic model for AD (streptozotocin, STZ; 2 mg/kg, ICV). We hypothesized that the STZ-AD model exhibits neuroinflammation, and treatment with an inhibitor of microglia (minocycline) can reverse the cognitive, respiratory, sleep, and molecular disorders of this model. Objective: To evaluate the effect of minocycline treatment in STZ model disorders. Methods: We treated control and STZ-treated …rats for five days with minocycline (30 mg/kg, IP) and evaluated cognitive performance, chemoreflex response to hypercapnia and hypoxia, and total sleep time. Additionally, quantification of Aβ, microglia analyses, and relative expression of cytokines in the LC were performed. Results: Minocycline treatment improved learning and memory, which was concomitant with a decrease in microglial cell density and re-establishment of morphological changes induced by STZ in the LC region. Minocycline did not reverse the STZ-induced increase in CO2 sensitivity during wakefulness. However, it restored the daytime sleep-wake cycle in STZ-treated animals to the same levels as those observed in control animals. In the LC, levels of A and expression of Il10 , Il1b , and Mcp1 mRNA remained unaffected by minocycline, but we found a strong trend of minocycline effect on Tnf- α. Conclusion: Our findings suggest that minocycline effectively reduces microglial recruitment and the inflammatory morphological profile in the LC, while it recovers cognitive performance and restores the sleep-wake pattern impaired by STZ. Show more

Keywords: Alzheimer’s disease, locus coeruleus, microglia, minocycline, streptozotocin

DOI: 10.3233/JAD-230151

Citation: Journal of Alzheimer's Disease, vol. 95, no. 1, pp. 317-337, 2023

Authors: Lin, Yijia | Hu, Tingjun | Cheng, Lizhen | Chen, Yixin | Li, Wei | Guo, Qihao | Miao, Ya

Article Type: Research Article

Abstract: Background: A connection between plasma levels of haptoglobin (Hp) and Alzheimer’s disease (AD) has been shown in several observational studies. It is debatable, nonetheless, how the two are related causally. Objective: To establish the causal relationship between Hp and AD using a two-sample Mendelian randomization (MR) study. Methods: From the extensive genome-wide association studies and FinnGen dataset, summaries and statistics pertaining to AD were gathered. We investigated the possibility of a causal link between Hp and AD using a two-sample MR study. Inverse variance weighting was used as the primary analytical technique, and it was supported …by the joint application of complementary analyses and fixed effects meta-analysis to combine results from various sources. Results: Genetically determined Hp was causally associated with AD [odds ratio (OR), 1.05; 95% confidence interval (CI), 1.02 to 1.09; p  = 8.96×10–4 ]; Inverse variance-weighted estimates coming from different data sources were combined in a meta-analysis with consistent findings (OR, 1.03; 95% CI, 1.01 to 1.05; p  = 2.00×10–3 ). The outcomes of the inverse MR analysis showed that AD had no appreciable causal impact on Hp. Conclusion: The present MR analysis shows that higher plasma Hp leads to an increased risk of AD. Strategies for plasma Hp testing may open up new doors for the early diagnosis and prevention of AD. Show more

Keywords: Alzheimer’s disease, causality, haptoglobins, Mendelian randomization analysis

DOI: 10.3233/JAD-230159

Citation: Journal of Alzheimer's Disease, vol. 95, no. 1, pp. 339-348, 2023

Authors: Leitão, André D.G. | Spencer, Brian | Sarsoza, Floyd | Ngolab, Jennifer | Amalraj, Jessica | Masliah, Eliezer | Wu, Chengbiao | Rissman, Robert A.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) cases are often characterized by the pathological accumulation of α-synuclein (α-syn) in addition to amyloid-β (Aβ) and tau hallmarks. The role of α-syn has been extensively studied in synucleinopathy disorders, but less so in AD. Recent studies have shown that α-syn may also play a role in AD and its downregulation may be protective against the toxic effects of Aβ accumulation. Objective: We hypothesized that selectively knocking down α-syn via RNA interference improves the neuropathological and biochemical findings in AD mice. Methods: Here we used amyloid precursor protein transgenic …(APP-Tg) mice to model AD and explore pathologic and behavioral phenotypes with knockdown of α-syn using RNA interference. We selectively reduced α-syn levels by stereotaxic bilateral injection of either LV-shRNA α-syn or LV-shRNA-luc (control) into the hippocampus of AD mice. Results: We found that downregulation of α-syn results in significant reduction in the number of Aβ plaques. In addition, mice treated with LV-shRNA α-syn had amelioration of abnormal microglial activation (Iba1) and astrocytosis (GFAP) phenotypes in AD mice. Conclusion: Our data suggests a novel link between Aβ and α-syn pathology as well as a new therapeutic angle for targeting AD. Show more

Keywords: Alzheimer’s disease, alpha-synuclein, amyloid-β , biomarkers, lentivirus

DOI: 10.3233/JAD-230232

Citation: Journal of Alzheimer's Disease, vol. 95, no. 1, pp. 349-361, 2023