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