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The Journal of Alzheimer’s Disease is an international multidisciplinary journal to facilitate progress in understanding the etiology, pathogenesis, epidemiology, genetics, behavior, treatment and psychology of Alzheimer’s disease.
The journal publishes research reports, reviews, short communications, book reviews, and letters-to-the-editor. The journal is dedicated to providing an open forum for original research that will expedite our fundamental understanding of Alzheimer’s disease.
Authors: Jehu, Deborah A. | Pottayil, Faheem | Dong, Yanbin | Zhu, Haidong | Sams, Richard | Young, Lufei
Article Type: Research Article
Abstract: Background: Physical activity preserves cognitive function in people without dementia, but the relationship between physical activity and cognitive domains among people living with dementia is unclear. Objective: The objective of this study was to explore the association between physical activity and cognition domains among people living with dementia. Methods: Participants living with dementia in residential care facilities (complete case analysis: n = 24/42) completed a battery of cognitive tests (global cognition : Montreal Cognitive Assessment; executive function : Trail-Making Test, Digit Span Forward Test; perception and orientation : Benton Judgement of Line Orientation Test; …language : Boston Naming Test; learning and memory : Rey Auditory Verbal Learning Test; complex attention : Digit Symbol Substitution Test). Participants wore an actigraphy monitor on their non-dominant wrist over seven days. We conducted a linear regression for total physical activity (independent variable) with race (white/black), fall risk (Morse Fall Scale), and the number of comorbidities (Functional Comorbidities Index) as covariates, and cognitive tests as variables of interest. Results: Participants were primarily male (75%), white (87.5%), and 50%had unspecified dementia (Alzheimer’s disease: 33%). Greater physical activity was associated with poorer global cognition, better executive function, and better learning and memory (p s < 0.05). Physical activity was not related to visuospatial perception, language, or complex attention. Conclusions: Physical activity may preserve executive function and learning and memory among people living with dementia. Wandering is more common in later stages of dementia, which may explain greater physical activity observed with lower global cognition. Regularly assessing physical activity may be useful in screening and monitoring cognitive changes. Show more
Keywords: Accelerometry, actigraphy, Alzheimer’s disease, cognition, cognitive domains, dementia, physical activity
DOI: 10.3233/JAD-230594
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2024
Authors: Tan, Stephanie | Kelty, Erin | Page, Amy | Etherton-Beer, Christopher | Sanfilippo, Frank | Almeida, Osvaldo P.
Article Type: Research Article
Abstract: Background: Evidence from previous observational studies suggest that infection by herpes simplex virus (HSV) and varicella zoster virus (VZV) increase the risk of dementia. Objective: To investigate if older adults exposed to HSV treatment have lower risk of dementia than the rest of the population. Methods: We used the 10% Australian Pharmaceutical Benefits Scheme (PBS) database from 2013 to 2022 to ascertain the cross-sectional, time-series and longitudinal association between exposure to HSV treatment and the dispensing of antidementia medicines. Participants were men and women aged 60 years or older. We used Anatomical Therapeutic Chemical (ATC) codes …to identify medicines dispensed for the treatment of HSV and dementia. Results: During the year 2022 6,868 (1.2%) of 559,561 of participants aged 60 years or over were dispensed antidementia agent. The odds ratio (OR) of being dispensed an antidementia agent among individuals dispensed treatment for HSV was 0.73 (99% CI = 0.56–0.95). Multilevel logistic regression for the 2013–2022 period for those dispensed HSV treatment was 0.87 (99% CI = 0.75–1.00). Split-time span series from 2013 was associated with hazard ratio of 0.98 (99% CI = 0.89–1.07) for individuals dispensed relative to those not dispensed HSV treatment. All analyses were adjusted for age, sex, and the dispensing of medicines for the treatment of diabetes, hyperlipidemia, hypertension, and ischemic heart disease. Conclusions: The dispensing of antiviral medicines for the treatment of HSV and VZV is consistently, but not conclusively, associated with decreased dispensing of antidementia medicines. This suggests that treatment of HSV and VZV infections may contribute to reduce the risk of dementia. Show more
Keywords: Keywords: Alzheimer’s disease, dementia, herpes simplex virus, varicella zoster virus
DOI: 10.3233/JAD-240391
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2024
Authors: Deng, Chengeng | Cai, Qingyuan | Zhang, Jiani | Chang, Kexin | Peng, Tiantian | Liu, Xiaoge | Cao, Feng | Yan, Xinyuan | Cheng, Junshi | Wang, Xu | Tan, Yan | Hua, Qian
Article Type: Research Article
Abstract: Background: Presenilin (PSEN, PS) is essential for γ-secretase function, and mutations can disrupt amyloid-β (Aβ) production in familial Alzheimer’s disease. Targeting γ-secretase is complex due to its broad involvement in physiological processes. Objective: Our aim was to create a novel knockin (KI) mouse model expressing PSEN1 D385A mutation and investigate the efficacy of a Geniposide and Ginsenoside Rg1 combination (NeuroProtect modified formula, NP-2) in restoring γ-secretase activity. Methods: Using gene manipulation, we established the PS1 D385A KI mouse model and confirmed the mutation, mRNA, and protein levels using Southern blotting, northern blotting, and western blotting, respectively. …In vitro γ-secretase assay was conducted to measure γ-secretase activity, while histological analyses examined neurogenesis effects. NP-2 administration evaluated its impact on γ-secretase activity. Results: The PS1 D385A KI homozygotes displayed severe cerebral hemorrhage, postnatal lethality, developmental disorders, reduced proliferation of neural progenitor cells, and disrupted γ-secretase function. The mutation abolished PS1 protein self-shearing, leading to compromised γ-secretase activity. NP-2 intervention effectively restored γ-secretase activity in the heterozygous mice. Conclusions: PS1 D385A mutant disrupted PS1 protein self-cleaving, impairing γ-secretase activity in KI mice. NP-2 restored γ-secretase function, offering potential for novel AD treatment strategies despite the challenges posed by γ-secretase’s complex role in physiological processes. Show more
Keywords: Alzheimer’s disease, amyloid-β, D385A, geniposide, ginsenoside Rg1, presenilin, γ-secretase
DOI: 10.3233/JAD-231148
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2024
Authors: Wu, Che-Yuan | Swardfager, Walter
Article Type: Article Commentary
Abstract: Pharmacoepidemiologic studies using routinely collected data allow researchers to propose drugs for repurposing trials for dementia prevention or treatment. A recent cohort study reported a 54% lower dementia risk among users of sildenafil compared to users of certain cardiovascular medications. We caution that “confounding by indication” can arise when outcomes are compared between a drug of interest and an inappropriate comparator. Here, we emphasize important considerations in selecting an active comparator. We assess the implications of substantial risk of confounding by indication in pharmacoepidemiologic studies linking phosphodiesterase-5 inhibitors to lower dementia risk.
Keywords: Alzheimer’s disease, confounding by indication, dementia, pharmacoepidemiology, phosphodiesterase-5 inhibitors
DOI: 10.3233/JAD-240520
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-3, 2024
Authors: van den Kieboom, Robin | Snaphaan, Liselore | Mark, Ruth | van Assen, Marcel | Bongers, Inge
Article Type: Research Article
Abstract: Background: Neuropsychiatric symptoms are a robust risk factor for caregiver burden in family dementia caregivers. By grouping these symptoms, clinical interpretations regarding neuropsychiatric symptoms may facilitated because different groups of symptoms may require a different approach for intervention, thereby reducing caregiver burden. Objective: As clustering of neuropsychiatric symptoms could be clinically relevant, we aimed to explore the effects of these clusters on burden in family dementia caregivers. Methods: 152 family dementia caregivers were included. Caregiver burden was measured using the Ervaren Druk door Informele Zorg (EDIZ)/Self-Perceived Pressure from Informal Care, a Dutch questionnaire. Caregivers also reported …the neuropsychiatric symptoms and functional impairments in daily activities of the people with dementia they cared for. Multiple regression analyses were used in this cross-sectional study. Results: Adjusted for functional impairments and sociodemographic variables, neuropsychiatric symptoms were associated with more caregiver burden (p < 0.001). However, this association did not differ between the three neuropsychiatric symptom clusters (p = 0.745). Conclusions: Neuropsychiatric symptoms were associated with more family caregiver burden, but no conclusive evidence was found that this association differed for the three clusters. Clustering of neuropsychiatric symptoms is, however, worth exploring further in future studies with more participants. If specific links are found, these could be targeted in clinical practice in order to prevent, reduce and/or postpone caregiver burden. Show more
Keywords: Alzheimer’s disease, behavioral and psychological symptoms of dementia, carers, community care, dementia
DOI: 10.3233/JAD-230972
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2024
Authors: Yenesew, Muluken A. | Krell-Roesch, Janina | Fekadu, Betelhem | Nigatu, Dabere | Endalamaw, Aklilu | Mekonnen, Alemtsehay | Biyadgie, Mulugeta | Wubetu, Gizachew Y. | Debiso, Alemu T. | Beyene, Kassu M. | Kelkile, Teshome S. | Enquobahrie, Daniel A. | Mersha, Tesfaye B. | Eagan, Danielle E. | Geda, Yonas E.
Article Type: Review Article
Abstract: Background: Population-based research on the prevalence and determinants of dementia, Alzheimer’s disease, and cognitive impairment is scarce in East Africa. Objective: To provide an overview of community- and population-based studies among older adults on the prevalence of dementia and cognitive impairment in East Africa, and identify research gaps. Methods: We carried out a literature search using three electronic databases (PubMed, Scopus, Google Scholar) using pertinent search terms. Results: After screening 445 publications, we identified four publications on the population-based prevalence of dementia, and three on cognitive impairment. Prevalence rates varied from 6– 23% for …dementia, and 7– 44% for cognitive impairment, among participants aged≥50–70 years. Old age and a lower education level were risk factors for dementia and cognitive impairment. Physical inactivity, lack of a ventilated kitchen, and history of central nervous system infections and chronic headache were associated with increased odds of dementia. Female sex, depression, having no spouse, increased lifetime alcohol consumption, low income, rural residence, and low family support were associated with increased odds of cognitive impairment. Potential misclassification and non-standardized data collection methods are research gaps that should be addressed in future studies. Conclusions: Establishing collaborative networks and partnering with international research institutions may enhance the capacity for conducting population-based studies on dementia and cognitive impairment in East Africa. Longitudinal studies may provide valuable insights on incidence, as well as potential risk and protective factors of dementia and cognitive impairment, and may inform the development of targeted interventions including preventive strategies in the region. Show more
Keywords: Alzheimer’s disease, cognitive impairment, dementia, East Africa, prevalence, scoping review
DOI: 10.3233/JAD-240381
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2024
Authors: Greenblatt, Charles L. | Bercovier, Herve | Klein, Benjamin Y. | Gofrit, Ofer N.
Article Type: Short Communication
Abstract: The Montreal Cognitive Assessment (MoCA) is a valuable assessment of the patient’s awareness of time and place. We show that bacille Calmette-Guerin (BCG) significantly affects MoCA testing when administered by the intravesical route. MoCA scores were lower with increasing age and higher in more formally educated individuals. Patients receiving BCG tended to maintain their MoCA scores, whereas almost half the control cases tended to show reduced scores. This benefit is supported by reduced pre-amyloid biomarkers in BCG-injected healthy volunteers and a favorable effect on neuronal dendritic development in animal models. Our results suggest that BCG has a beneficial impact on …the cognitive status of older individuals. Show more
Keywords: Alzheimer’s disease, bacille Calmette-Guerin, cognition, Montreal Cognitive Assessment, vaccines
DOI: 10.3233/JAD-240307
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-4, 2024
Authors: Machado, Mariane Gomes | Machado, Thais Helena | Caramelli, Paulo | Gonçalves Tosatti, Jessica Abdo | da Silva Carvalho, Sirley Alves | de Resende, Luciana Macedo
Article Type: Systematic Review
Abstract: Background: The assumption that hearing rehabilitation could improve quality of life and reduce dementia risk in people with hearing loss is a subject that needs further studies, especially clinical trials. It is necessary to determine the effects of hearing aid use, as part of hearing rehabilitation, among people diagnosed with dementia. Objective: To systematically review the literature to evaluate the effects of hearing aid use on cognition and quality of life of people with dementia. Methods: Protocol for this systematic review was registered (CRD42023387187). The Cochrane Central Register of Controlled Trials, Embase, MEDLINE, Scopus, CINAHL, and …Web of Science databases, as well as grey literature, including Google Scholar and ResearchGate, were systematically searched for clinical trials using MeSH terms. The PICOS principle was used to develop the inclusion criteria: population (P): adults and older adults, individuals diagnosed with dementia and hearing loss; intervention (I): rehabilitation with hearing aids; control (C): not using a hearing aid; outcome (O): cognitive and/or quality of life assessment using validated tests; study design (S): clinical trial. Results: The initial search yielded 576 studies, five of which met the inclusion criteria for qualitative analyses. Two of the included studies were randomized clinical trials, and three were crossover clinical trials, demonstrating the lack of studies on the subject. Four studies included participants with Alzheimer’s disease. Quality of life was found to improve with the use of hearing aids, and hearing rehabilitation was not shown to affect cognitive outcomes. Conclusions: Hearing aid use appears to have a positive impact on quality of life. Show more
Keywords: Alzheimer’s disease, cognition, dementia, hearing aids, hearing loss, quality of life
DOI: 10.3233/JAD-231460
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2024
Authors: Slusarenko, Alexandra | Rosenberg, Michael C. | Kazanski, Meghan E. | McKay, J. Lucas | Emmery, Laura | Kesar, Trisha M. | Hackney, Madeleine E.
Article Type: Research Article
Abstract: Background: Personalized dance-based movement therapies may improve cognitive and motor function in individuals with mild cognitive impairment (MCI), a precursor to Alzheimer’s disease. While age- and MCI-related deficits reduce individuals’ abilities to perform dance-like rhythmic movement sequences (RMS)—spatial and temporal modifications to movement—it remains unclear how individuals’ relationships to dance and music affect their ability to perform RMS. Objective: Characterize associations between RMS performance and music or dance relationships, as well as the ability to perceive rhythm and meter (rhythmic proficiency) in adults with and without MCI. Methods: We used wearable inertial sensors to evaluate the …ability of 12 young adults (YA; age = 23.9±4.2 years; 9F), 26 older adults without MCI (OA; age = 68.1±8.5 years; 16F), and 18 adults with MCI (MCI; age = 70.8±6.2 years; 10F) to accurately perform spatial, temporal, and spatiotemporal RMS. To quantify self-reported music and dance relationships and rhythmic proficiency, we developed Music (MRQ) and Dance Relationship Questionnaires (DRQ), and a rhythm assessment (RA), respectively. We correlated MRQ, DRQ, and RA scores against RMS performance for each group separately. Results: The OA and YA groups exhibited better MRQ and RA scores than the MCI group (p < 0.006). Better MRQ and RA scores were associated with better temporal RMS performance for only the YA and OA groups (r2 = 0.18–0.41; p < 0.045). DRQ scores were not associated with RMS performance in any group. Conclusions: Cognitive deficits in adults with MCI likely limit the extent to which music relationships or rhythmic proficiency improve the ability to perform temporal aspects of movements performed during dance-based therapies. Show more
Keywords: Alzheimer’s disease, dance, gait analysis, mild cognitive impairment, music, rehabilitation, rhythm, therapy
DOI: 10.3233/JAD-231453
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-20, 2024
Authors: Stricker, Nikki H. | Christianson, Teresa J. | Pudumjee, Shehroo B. | Polsinelli, Angelina J. | Lundt, Emily S. | Frank, Ryan D. | Kremers, Walter K. | Machulda, Mary M. | Fields, Julie A. | Jack Jr., Clifford R. | Knopman, David S. | Graff-Radford, Jonathan | Vemuri, Prashanthi | Mielke, Michelle M. | Petersen, Ronald C.
Article Type: Research Article
Abstract: Background: Conventional normative samples include individuals with undetected Alzheimer’s disease neuropathology, lowering test sensitivity for cognitive impairment. Objective: We developed Mayo Normative Studies (MNS) norms limited to individuals without elevated amyloid or neurodegeneration (A–N–) for Rey’s Auditory Verbal Learning Test (AVLT). We compared these MNS A–N– norms in female, male, and total samples to conventional MNS norms with varying levels of demographic adjustments. Methods: The A–N– sample included 1,059 Mayo Clinic Study of Aging cognitively unimpaired (CU) participants living in Olmsted County, MN, who are predominantly non-Hispanic White. Using a regression-based approach correcting for age, sex, …and education, we derived fully-adjusted T-score formulas for AVLT variables. We validated these A–N– norms in two independent samples of CU (n = 261) and mild cognitive impairment (MCI)/dementia participants (n = 392) > 55 years of age. Results: Variability associated with age decreased by almost half in the A–N– norm sample relative to the conventional norm sample. Fully-adjusted MNS A–N– norms showed approximately 7– 9% higher sensitivity to MCI/dementia compared to fully-adjusted MNS conventional norms for trials 1– 5 total and sum of trials. Among women, sensitivity to MCI/dementia increased with each normative data refinement. In contrast, age-adjusted conventional MNS norms showed greatest sensitivity to MCI/dementia in men. Conclusions: A–N– norms show some benefits over conventional normative approaches to MCI/dementia sensitivity, especially for women. We recommend using these MNS A–N– norms alongside MNS conventional norms. Future work is needed to determine if normative samples that are not well characterized clinically show greater benefit from biomarker-refined approaches. Show more
Keywords: Alzheimer’s disease, biomarker norms, cognitive aging, dementia, memory, mild cognitive impairment, neuropsychology, Rey’s Auditory Verbal Learning Test, robust norms, sensitivity and specificity
DOI: 10.3233/JAD-240081
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-19, 2024
Authors: Marin, Anna | Turk, Katherine W. | Schiloski, Kylie | Vives-Rodriguez, Ana | Suh, Cheongmin | Uppal, Prayerna | Dwyer, Brigid | Palumbo, Rocco | Budson, Andrew E.
Article Type: Research Article
Abstract: Background: Amyloid positron emission tomography (PET) scans provide in vivo evidence of Alzheimer’s disease (AD); however, their high cost limits their use in standard clinical care. Event related potentials (ERPs) may represent an inexpensive and non-invasive additional method for detecting AD pathology. Objective: We investigated whether ERPs, along with neuropsychological data, serve as predictors of amyloid PET status in patients with memory complaints. Methods: Veterans aged 50–100 were recruited from a memory disorders clinic. Participants underwent a neuropsychological battery and an ERP auditory oddball protocol. Twenty-eight patients had a positive amyloid PET scan, and thirty-nine …patients had a negative scan. Results: ERP-P200 target amplitude and P200 standard latency were predictors of amyloid PET status. When submitting to ROC analysis, P200 standard latency exhibited the highest specificity and sensitivity in predicting amyloid PET positivity, correctly classifying the amyloid PET status for 86% of patients. Conclusions: ERP-P200 measures are strong indicators of amyloid-β presence in patients from a memory disorder clinic. Increased P200 amplitude and decreased P200 latency in patients with a positive amyloid PET scan may be attributed to hyperactivation of perceptual bottom-up processes compensating for AD-related synaptic loss in the fronto-parietal networks. Show more
Keywords: Alzheimer’s disease, amyloid PET, biomarkers, event-related potentials
DOI: 10.3233/JAD-231038
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2024
Authors: Reive, Brady S. | Lau, Victor | Sánchez-Lafuente, Carla L. | Henri-Bhargava, Alexandre | Kalynchuk, Lisa E. | Tremblay, Marie-Ève | Caruncho, Hector J.
Article Type: Review Article
Abstract: Alzheimer’s disease (AD) accounts for most dementia cases, but we lack a complete understanding of the mechanisms responsible for the core pathology associated with the disease (e.g., amyloid plaque and neurofibrillary tangles). Inflammation has been identified as a key contributor of AD pathology, with recent evidence pointing towards Reelin dysregulation as being associated with inflammation. Here we describe Reelin signaling and outline existing research involving Reelin signaling in AD and inflammation. Research is described pertaining to the inflammatory and immunological functions of Reelin before we propose a mechanism through which inflammation renders Reelin susceptible to dysregulation resulting in the induction …and exacerbation of AD pathology. Based on this hypothesis, it is predicted that disorders of both inflammation (including peripheral inflammation and neuroinflammation) and Reelin dysregulation (including disorders associated with upregulated Reelin expression and disorders of Reelin downregulation) have elevated risk of developing AD. We conclude with a description of AD risk in various disorders involving Reelin dysregulation and inflammation. Show more
Keywords: Alzheimer’s disease, blood-brain barrier, immunity, inflammation, microglia, Reelin
DOI: 10.3233/JAD-240088
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-21, 2024
Authors: Esiaka, Darlingtina | Odo, Obinna | Luth, Elizabeth
Article Type: Research Article
Abstract: Background: Research suggests that the neighborhood in which people live can be a risk or protective factor for various health outcomes, including cognitive decline to Alzheimer’s disease. Similar to the impact of neighborhood on health outcomes, sleep difficulties have been linked to cognitive function in older adults. However, few studies have examined how neighborhood physical disorders moderate the effects of sleep on subjective cognitive decline (SCD). Objective: The study examined the moderating effect of neighborhood factors on the relationship between sleep difficulties and SCD. Methods: Data were obtained from 2,494 respondents (1,065 males and 1,429 females) …from Wave 11 of the National Health and Aging Trends (NHATS) data. Sleep difficulties were operationalized as the presence of difficulties in falling and staying asleep. Neighborhood physical disorder (e.g., vandalism, graffiti) was based on interviewer observations of respondents’ neighborhoods. SCD was operationalized as subjective reports of increasing or worse memory loss in the past 12 months and present memory rating. We utilized Linear regression to test neighborhood physical disorder as a moderator of the relationship between sleep difficulties and SCD. Results: We found a significant interaction between sleep difficulties and neighborhood physical disorder on SCD (β=0.03, SE = 0.01, 95% CI[0.00,0.51], p < 0.001). Participants who reported higher average sleep difficulties and higher levels of neighborhood physical disorder were more likely to report SCD. Conclusions: Our findings add to inform future health interventions and policy recommendations that address modifiable sources of cognitive decline and risk of Alzheimer’s disease. Show more
Keywords: ADRD risk, Alzheimer’s disease, cognitive decline, dementia, neighborhood, sleep
DOI: 10.3233/JAD-240142
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2024
Authors: von Schnehen, Andres | Hobeika, Lise | Houot, Marion | Recher, Arnaud | Puisieux, François | Huvent-Grelle, Dominique | Samson, Séverine
Article Type: Research Article
Abstract: Background: Understanding the nature and extent of sensorimotor decline in aging individuals and those with neurocognitive disorders (NCD), such as Alzheimer’s disease, is essential for designing effective music-based interventions. Our understanding of rhythmic functions remains incomplete, particularly in how aging and NCD affect sensorimotor synchronization and adaptation to tempo changes. Objective: This study aimed to investigate how aging and NCD severity impact tapping to metronomes and music, with and without tempo changes. Methods: Patients from a memory clinic participated in a tapping task, synchronizing with metronomic and musical sequences, some of which contained sudden tempo changes. …After exclusions, 51 patients were included in the final analysis. Results: Participants’ Mini-Mental State Examination scores were associated with tapping consistency. Additionally, age negatively influenced consistency when synchronizing with a musical beat, whereas consistency remained stable across age when tapping with a metronome. Conclusions: The results indicate that the initial decline of attention and working memory with age may impact perception and synchronization to a musical beat, whereas progressive NCD-related cognitive decline results in more widespread sensorimotor decline, affecting tapping irrespective of audio type. These findings underline the importance of customizing rhythm-based interventions to the needs of older adults and individuals with NCD, taking into consideration their cognitive as well as their rhythmic aptitudes. Show more
Keywords: Aging, Alzheimer’s disease, auditory perception, dementia, music, neurodegenerative diseases
DOI: 10.3233/JAD-231433
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2024
Authors: Arenson, Melanie | Bahorik, Amber | Xia, Feng | Peltz, Carrie | Cohen, Beth | Yaffe, Kristine
Article Type: Research Article
Abstract: Background: Black and Hispanic older adults have greater incidence of Alzheimer’s disease and related dementias relative to White adults, but factors underlying these disparities are not well understood, limiting the ability to address them. Objective: To determine the impact of demographics, cardiovascular disease (CVD) and risk factors, social determinants of health (SDOH), and neuropsychiatric risk factors on racial/ethnic disparities in dementia risk among Veterans. Methods: We examined a random sample of 1,579,919 older Veterans (age ≥55) without dementia who received care from the VHA from October 1, 1999 to September 30, 2021. All variables were extracted …from national VHA data. We used Cox proportional hazard regression models to examine change in variance in risk of dementia across racial/ethnic groups. Results: During follow up (mean 11.1 years), 13% of Veterans developed dementia. Relative to White Veterans, the adjusted hazard ratios (AHRs) for developing dementia in sex-adjusted models with age as timescale were 1.65 (95% CI, 1.63–1.67) for Black Veterans and 1.50 (95% CI, 1.44–1.56) for Hispanic Veterans. In the model examining CVD and risk factors, AHRs were 1.53 (95% CI, 1.50–1.55) for Black Veterans and 1.38 (95% CI, 1.33–1.44) for Hispanic Veterans. In the model examining SDOH, AHRs were 1.46 (95% CI, 1.43–1.49) for Black Veterans and 1.34 (95% CI, 1.29–1.40) for Hispanic Veterans. Conclusions: SDOH and CVD and risk factors accounted for the greatest amount of variance in racial/ethnic disparities in dementia risk. Cardiovascular disease and SDOH are strong possible targets for interventions designed to reduce these disparities. Show more
Keywords: Alzheimer’s disease, dementia, risk factors, social determinants of health, Veterans
DOI: 10.3233/JAD-240181
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2024
Authors: Fu, Jiajia | Wei, Qianqian | Chen, Xueping | Lai, Xiaohui | Shang, Huifang
Article Type: Research Article
Abstract: Background: Previous research has suggested that pathogen infections may serve as potential contributors to dementia. Objective: Consequently, the study aimed to evaluate whether pathogen exposure heightens the risk of dementia. Methods: Between 2006 and 2010, a total of 8,144 individuals from the UK Biobank had data on pathogen antibodies and were included in the baseline assessment. Cox proportional hazard models were employed for the analysis. Results: Out of the 8,144 participants, 107 eventually developed dementia, while 55 participants were diagnosed with Alzheimer’s disease (AD). Multivariate Cox regression analysis revealed that the levels of pathogen …antibody titers of EBV and C. trachomatis were associated with an increased risk of dementia/AD. The highest quartile of EBV EBNA-1 and EBV VCA p18 , and the second quartile of H. pylori VacA significantly increased the risk of dementia compared lower quartile (EBV EBNA-1 : HR = 1.938, p = 0.018; EBV VCA p18 : HR = 1.824, p = 0.040; H. pylori VacA : HR = 1.890, p = 0.033). Besides, the highest quartile of EBV VCA p18 had a higher risk of AD compared lower quartile (HR = 2.755, p = 0.029). Conclusions: The study demonstrated that exposure to EBV , H. pylori , and C. trachomatis substantially elevated the risk of dementia/AD. Despite the relatively widespread occurrence of EBV infection in the population, elevated pathogen antibody titers were still found to increase the risk of dementia/AD. Besides, since C. trachomatis and C. pneumoniae are quite homologous, this study found that trachomatis (C. trachomatis /C. pneumoniae ) may be significantly associated with the risk of AD/dementia. Show more
Keywords: Alzheimer’s disease, dementia, exposure, pathogen antibody
DOI: 10.3233/JAD-240073
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2024
Authors: Zhang, Ya-Hong | Zhao, Pu | Gao, Hui-Ling | Zhong, Man-Li | Li, Jia-Yi
Article Type: Research Article
Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative disorder caused by a complex interplay of various factors. However, a satisfactory cure for AD remains elusive. Pharmacological interventions based on drug targets are considered the most cost-effective therapeutic strategy. Therefore, it is paramount to search potential drug targets and drugs for AD. Objective: We aimed to provide novel targets and drugs for the treatment of AD employing transcriptomic data of AD and normal control brain tissues from a new perspective. Methods: Our study combined the use of a multi-layer perceptron (MLP) with differential expression analysis, variance assessment and …molecular docking to screen targets and drugs for AD. Results: We identified the seven differentially expressed genes (DEGs) with the most significant variation (ANKRD39, CPLX1, FABP3, GABBR2, GNG3, PPM1E, and WDR49) in transcriptomic data from AD brain. A newly built MLP was used to confirm the association between the seven DEGs and AD, establishing these DEGs as potential drug targets. Drug databases and molecular docking results indicated that arbaclofen, baclofen, clozapine, arbaclofen placarbil, BML-259, BRD-K72883421, and YC-1 had high affinity for GABBR2, and FABP3 bound with oleic, palmitic, and stearic acids. Arbaclofen and YC-1 activated GABAB receptor through PI3K/AKT and PKA/CREB pathways, respectively, thereby promoting neuronal anti-apoptotic effect and inhibiting p-tau and Aβ formation. Conclusions: This study provided a new strategy for the identification of targets and drugs for the treatment of AD using deep learning. Seven therapeutic targets and ten drugs were selected by using this method, providing new insight for AD treatment. Show more
Keywords: Alzheimer’s disease, drug discovery, drug target, multi-layer perceptron, transcriptome data
DOI: 10.3233/JAD-231389
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2024
Authors: Bozzay, Melanie L. | Joyce, Hannah E. | Jiang, Lan | De Vito, Alyssa N. | Emrani, Sheina | Browne, Julia | Bayer, Thomas A. | Quinn, McKenzie J. | Primack, Jennifer M. | Kelso, Catherine M. | Wu, Wen-Chih | Rudolph, James L. | McGeary, John E. | Kunicki, Zachary J.
Article Type: Research Article
Abstract: Background: Older adults with heart failure are at elevated risk of Alzheimer’s disease and related dementias (AD/ADRD). Research suggests that insomnia and depressive episodes contribute somewhat dissociable impacts on risk for AD/ADRD in this patient population, although the temporal ordering of effects is unknown. Objective: This study examined time to dementia diagnosis among patients with comorbid insomnia and/or depressive episodes in an epidemiological sample. Methods: Secondary data analyses were conducted using a cohort study of 203,819 Veterans with a primary admission diagnosis of heart failure in 129 VA Medical Centers. Results: Patients with diagnoses …of both insomnia and depressive episodes had the shortest time to a dementia diagnosis at both 1-year (Hazard ratio = 1.43, 95% CI [1.36, 1.51]) and 3-year follow-up time points (Hazard ratio = 1.40, 95% CI [1.34, 1.47]) versus patients with one or neither comorbidity. Conclusions: Individuals with both comorbidities had the shortest time to dementia onset. Screening for these comorbidities may help to identify patients at elevated risk of dementia who could benefit from enhanced monitoring or early intervention strategies for more rapid detection and management of dementia symptoms. Show more
Keywords: Alzheimer’s disease, dementia, depression, heart failure, sleep disorders, Veterans
DOI: 10.3233/JAD-240080
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2024
Authors: Bocti, Christian
Article Type: Article Commentary
Abstract: Alzheimer’s disease (AD) research has been dominated by the single-factor amyloid hypothesis in the last decades. Several other hypotheses have been proposed and increasingly attract attention considering the limited success of amyloid-based therapeutic strategies. Surprisingly, most published alternative etiological hypotheses for AD are similarly single-factor hypotheses, such as vascular, metabolic, mitochondrial, infectious, and inflammatory hypotheses, but the existence of so many different hypotheses suggests that AD is most likely a complex, multifactorial disorder. This inventory of different etiological hypotheses will hopefully help the field to move forward with explanatory models that consider the multifaceted aspects of this devastating disorder.
Keywords: Alzheimer’s disease, amyloid hypothesis, biomarkers, dementia, diagnostic criteria, etiological hypothesis, multiple etiologies, neuropathology
DOI: 10.3233/JAD-240488
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-3, 2024
Authors: Frank, Brandon | Walsh, Michael | Hurley, Landon | Groh, Jenna | Blennow, Kaj | Zetterberg, Henrik | Tripodis, Yorghos | Budson, Andrew E. | O’Connor, Maureen K. | Martin, Brett | Weller, Jason | McKee, Ann | Qiu, Wendy | Stein, Thor D. | Stern, Robert A. | Mez, Jesse | Henson, Rachel | Long, Justin | Aschenbrenner, Andrew J. | Babulal, Ganesh M. | Morris, John C. | Schindler, Suzanne | Alosco, Michael L.
Article Type: Research Article
Abstract: Background: Neuropsychiatric symptoms (NPS) can be an early manifestation of Alzheimer’s disease (AD). However, the associations among NPS, cognition, and AD biomarkers across the disease spectrum are unclear. Objective: We analyzed cross-sectional mediation pathways between cerebrospinal fluid (CSF) biomarkers of AD (Aβ1-42 , p-tau181 ), cognitive function, and NPS. Methods: Primary models included 781 participants from the National Alzheimer’s Coordinating Center (NACC) data set who had CSF analyzed for AD biomarkers using Lumipulse. NPS were assessed with the Neuropsychiatric Inventory Questionnaire (NPI-Q). We assessed cognition with the harmonized MMSE/MoCA, as well as neuropsychological tests sensitive to …AD pathology: story recall, naming, animal fluency, and Trails B. The Clinical Dementia Rating (CDR® ) scale assessed dementia severity. Mediation models were estimated with Kemeny metric covariance in a structural equation model framework, controlling for age, education, sex, and APOE ɛ 4. Results: The sample was older adults (M = 73.85, SD = 6.68; 49.9% male, 390; 27.9% dementia, 218) who were predominantly white (n = 688, 88.1%). Higher p-tau181 /Aβ1-42 ratio predicted higher NPI-Q, which was partially mediated by the MMSE/MoCA and, in a second model, story recall. No other pathway was statistically significant. Both the MMSE/MoCA and NPI-Q independently mediated the association between p-tau181 /Aβ1-42 ratio and CDR global impairment. With dementia excluded, p-tau181 /Aβ1-42 ratio was no longer associated with the NPI-Q. Conclusions: NPS may be secondary to cognitive impairment and AD pathology through direct and indirect pathways. NPS independently predict dementia severity in AD. However, AD pathology likely plays less of a role in NPS in samples without dementia. Show more
Keywords: Alzheimer’s disease, amyloid, biomarkers, cerebrospinal fluid, cognition, neuropsychiatric symptoms, p-tau
DOI: 10.3233/JAD-240125
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-19, 2024
Authors: Zhai, Weijie | Zhao, Anguo | Wei, Chunxiao | Xu, Yanjiao | Cui, Xinran | Zhang, Yan | Meng, Lingjie | Sun, Li
Article Type: Research Article
Abstract: Background: Although observational studies indicated connections between fatty acids (FAs) and Alzheimer’s disease and dementia, uncertainty persists regarding how these relationships extend to dementia with Lewy bodies (DLB). Objective: To explore the potential causal relationships between FAs and the development of DLB, thus clarifying these associations using genetic instruments to infer causality. Methods: We applied a two-sample Mendelian randomization (MR) and multivariable Mendelian randomization (MVMR) approach. Genetic data were obtained from a DLB cohort, comprising 2,591 cases and 4,027 controls of European descent. Eight FAs, including linoleic acid, docosahexaenoic acid, monounsaturated fatty acid, omega-3 fatty acid, …omega-6 fatty acid, polyunsaturated fatty acid, saturated fatty acid, and total fatty acid, were procured from a comprehensive GWAS of metabolic biomarkers of UK Biobank, conducted by Nightingale Health in 2020 (met-d), involving 114,999 individuals. Our analysis included inverse-variance weighted, MR-Egger, weighted-median, simple mode, and weighted-mode MR estimates. Cochran’s Q-statistics, MR-PRESSO, and MR-Egger intercept test were used to quantify the heterogeneity and horizontal pleiotropy of instrumental variables. Results: Only linoleic acid showed a significant genetic association with the risk of developing DLB in the univariate MR. The odds ratio for linoleic acid was 1.337 with a 95% confidence interval of 1.019–1.756 (pIVW = 0.036). Results from the MVMR showed that no FAs were associated with the incidence of DLB. Conclusions: The results did not support the hypothesis that FAs could reduce the risk of developing DLB. However, elucidating the relationship between FAs and DLB risk holds potential implications for informing dietary recommendations and therapeutic approaches in DLB. Show more
Keywords: Alzheimer’s disease, dementia, dementia with Lewy bodies, fatty acids, linoleic acid, Mendelian randomization
DOI: 10.3233/JAD-240267
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2024
Authors: Lepping, Rebecca J. | Hess, Benjamin J. | Taylor, Jasmine M. | Hanson-Abromeit, Deanna | Williams, Kristine N.
Article Type: Systematic Review
Abstract: Background: Recent research has shown beneficial results for music-based interventions (MBIs) for persons living with Alzheimer’s disease and related dementias (AD/ADRD), but reports often lack sufficient detail about the MBI methodology, which reduces replicability. A detailed checklist for best practices in how to report MBIs was created in 2011 by Robb and colleagues to remedy the lack of detail in MBI descriptions. The implementation of the checklist specifically in AD/ADRD research has not been established. Given the complexity of music and the variety of uses for research and health, specific MBI descriptions are necessary for rigorous replication and validation of …study results. Objective: This systematic mapping review utilized the “Checklist for Reporting Music-Based Interventions” to evaluate the current state of MBI descriptive specificity in AD/ADRD research. Methods: Research articles testing MBIs and reviews of MBI efficacy published between January 2015 and August 2023 were scored using the checklist and the results were summarized. Results: Forty-eight studies were screened, and reporting was inconsistent across the 11 checklist criteria. Ten out of 48 studies fully reported more than 5 of the 11 criteria. Only one of the 11 scoring criteria was at least partially reported across 47 of 48 studies. Conclusions: Thorough reporting of intervention detail for MBIs remains limited in AD/ADRD MBI research. This impedes study validation, replication, and slows the progress of research and potential application of music in practice. Greater implementation of the reporting guidelines provided by Robb and colleagues would move the field of MBI research for AD/ADRD forward more quickly and efficiently. Show more
Keywords: Alzheimer’s disease, dementia, interventions, music, reporting guidelines
DOI: 10.3233/JAD-240255
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2024
Authors: Fromm, Davida | Dalton, Sarah Grace | Brick, Alexander | Olaiya, Gbenuola | Hill, Sophia | Greenhouse, Joel | MacWhinney, Brian
Article Type: Research Article
Abstract: Background: Findings from language sample analyses can provide efficient and effective indicators of cognitive impairment in older adults. Objective: This study used newly automated core lexicon analyses of Cookie Theft picture descriptions to assess differences in typical use across three groups. Methods: Participants included adults without diagnosed cognitive impairments (Control), adults diagnosed with Alzheimer’s disease (ProbableAD), and adults diagnosed with mild cognitive impairment (MCI). Cookie Theft picture descriptions were transcribed and analyzed using CLAN. Results: Results showed that the ProbableAD group used significantly fewer core lexicon words overall than the MCI and Control groups. …For core lexicon content words (nouns, verbs), however, both the MCI and ProbableAD groups produced significantly fewer words than the Control group. The groups did not differ in their use of core lexicon function words. The ProbableAD group was also slower to produce most of the core lexicon words than the MCI and Control groups. The MCI group was slower than the Control group for only two of the core lexicon content words. All groups mentioned a core lexicon word in the top left quadrant of the picture early in the description. The ProbableAD group was then significantly slower than the other groups to mention a core lexicon word in the other quadrants. Conclusions: This standard and simple-to-administer task reveals group differences in overall core lexicon scores and the amount of time until the speaker produces the key items. Clinicians and researchers can use these tools for both early assessment and measurement of change over time. Show more
Keywords: Alzheimer’s disease, language, mild cognitive impairment, speech
DOI: 10.3233/JAD-230844
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2024
Authors: Syrjanen, Jeremy A. | Krell-Roesch, Janina | Kremers, Walter K. | Fields, Julie A. | Scharf, Eugene L. | Knopman, David S. | Petersen, Ronald C. | Vassilaki, Maria | Geda, Yonas E.
Article Type: Research Article
Abstract: Background: Studies that assess cognition prospectively and study in detail anxiety history in the participants’ medical records within the context of brain aging and Alzheimer’s disease are limited. Objective: To examine the associations of anxiety and unspecified emotional distress (UED) acquired throughout a person’s life with prospectively collected cognitive outcomes. Methods: Mayo Clinic Study of Aging participants who were cognitively unimpaired at baseline were included. Anxiety and UED data were abstracted from the medical record using the Rochester Epidemiology Project (REP) resources and were run separately as predictors in our models. The data were analyzed using …Cox proportional hazards models for the outcomes of incident mild cognitive impairment (MCI) and dementia and using linear mixed effects models for the outcomes of global and domain specific cognitive z-scores and included key covariates. Results: The study sample (n = 1,808) had a mean (standard deviation) age of 74.5 (7.3) years and 51.4% were male. Anxiety was associated with increased risk of MCI and dementia and was associated with lower baseline cognitive z-scores and accelerated decline over time in the global, memory, and attention domains. UED was associated with faster decline in all domains except visuospatial but did not show evidence of association with incident cognitive outcomes. These results varied by medication use and timing of anxiety. Conclusions: Anxiety and UED both showed inverse associations with cognition. Utilization of anxiety and UED data from across the life course, as available, from the REP system adds robustness to our results. Show more
Keywords: Alzheimer’s disease, anxiety, cognition, dementia, mild cognitive impairment, neuropsychiatric symptoms
DOI: 10.3233/JAD-240213
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2024
Authors: Chen, Xi | Walton, Karen | Brodaty, Henry | Chalton, Karen
Article Type: Review Article
Abstract: Cellular senescence, a hallmark of aging, plays an important role in age-related conditions among older adults. Targeting senescent cells and its phenotype may provide a promising strategy to delay the onset or progression of Alzheimer’s disease (AD). In this review article, we investigated efficacy and safety of nutrition senotherapy in AD, with a focus on the role of polyphenols as current and potential nutrition senotherapeutic agents, as well as relevant dietary patterns. Promising results with neuroprotective effects of senotherapeutic agents such as quercetin, resveratrol, Epigallocatechin-gallate, curcumin and fisetin were reported from preclinical studies. However, in-human trials remain limited, and findings …were inconclusive. In future, nutrition senotherapeutic agents should be studied both individually and within dietary patterns, through the perspective of cellular senescence and AD. Further studies are warranted to investigate bioavailability, dosing regimen, long term effects of nutrition senotherapy and provide better understanding of the underlying mechanisms. Collaboration between researchers needs to be established, and methodological limitations of current studies should be addressed. Show more
Keywords: Alzheimer’s disease, cellular senescence, cognition, mild cognitive impairment, nutrition senotherapeutics, senolytic agent
DOI: 10.3233/JAD-231222
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-23, 2024
Authors: Lin, Chi-Ying R. | Yonce, Shayla S. | Pacini, Nat J. | Yu, Melissa M. | Bishop, Jeffrey S. | Pavlik, Valory N. | Salas, Ramiro
Article Type: Short Communication
Abstract: The role of the cerebellum in amnestic mild cognitive impairment (aMCI), typically a prodromal stage of Alzheimer’s disease, is not fully understood. We studied the lobule-specific cerebello-cerebral connectivity in 15 cognitively normal and 16 aMCI using resting-state functional MRI. Our analysis revealed weaker connectivity between the cognitive cerebellar lobules and parietal lobe in aMCI. However, stronger connectivity was observed in the cognitive cerebellar lobules with certain brain regions, including the precuneus cortex, posterior cingulate gyrus, and caudate nucleus in participants with worse cognition. Leveraging these measurable changes in cerebello-parietal functional networks in aMCI could offer avenues for future therapeutic interventions.
Keywords: Alzheimer’s disease, cerebellum, functional MRI, mild cognitive impairment, resting state functional connectivity
DOI: 10.3233/JAD-240368
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2024
Authors: LoBue, Christian | McClintock, Shawn M. | Chiang, Hsueh-Sheng | Helphrey, Jessica | Thakkar, Vishal J. | Hart, John
Article Type: Review Article
Abstract: Multiple pharmacologic agents now have been approved in the United States and other countries as treatment to slow disease and clinical progression for Alzheimer’s disease. Given these treatments have not been proven to lessen the cognitive deficits already manifested in the Alzheimer’s Clinical Syndrome (ACS), and none are aimed for another debilitating dementia syndrome identified as primary progressive aphasia (PPA), there is an urgent need for new, safe, tolerable, and efficacious treatments to mitigate the cognitive deficits experienced in ACS and PPA. Noninvasive brain stimulation has shown promise for enhancing cognitive functioning, and there has been interest in its potential …therapeutic value in ACS and PPA. This review critically examines the evidence of five technologies in ACS and PPA: transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), transcranial random noise stimulation (tRNS), repetitive transcranial magnetic stimulation (rTMS), and noninvasive vagus nerve stimulation (nVNS). Many randomized controlled trials of tDCS and rTMS report positive treatment effects on cognition in ACS and PPA that persist out to at least 8 weeks, whereas there are few trials for tACS and none for tRNS and nVNS. However, most positive trials did not identify clinically meaningful changes, underscoring that clinical efficacy has yet to be established in ACS and PPA. Much is still to be learned about noninvasive brain stimulation in ACS and PPA, and shifting the focus to prioritize clinical significance in addition to statistical significance in trials could yield greater success in understanding its potential cognitive effects and optimal parameters. Show more
Keywords: Alzheimer’s disease, primary progressive aphasia, randomized controlled trial, semantic dementia, transcranial electrical stimulation, transcranial magnetic stimulation
DOI: 10.3233/JAD-240230
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2024
Authors: Coimbra, Judite R.M. | Resende, Rosa | Custódio, José B.A. | Salvador, Jorge A.R. | Santos, Armanda E.
Article Type: Review Article
Abstract: Disease-modifying therapies (DMT) for Alzheimer’s disease (AD) are highly longed-for. In this quest, anti-amyloid therapies take center stage supported by genetic facts that highlight an imbalance between production and clearance of amyloid-β peptide (Aβ) in AD patients. Indeed, evidence from basic research, human genetic and biomarker studies, suggests the accumulation of Aβ as a driver of AD pathogenesis and progression. The aspartic protease β-site AβPP cleaving enzyme (BACE1) is the initiator for Aβ production. Underpinning a critical role for BACE1 in AD pathophysiology are the elevated BACE1 concentration and activity observed in the brain and body fluids of AD patients. …Therefore, BACE1 is a prime drug target for reducing Aβ levels in early AD. Small-molecule BACE1 inhibitors have been extensively developed for the last 20 years. However, clinical trials with these molecules have been discontinued for futility or safety reasons. Most of the observed adverse side effects were due to other aspartic proteases cross-inhibition, including the homologue BACE2, and to mechanism-based toxicity since BACE1 has substrates with important roles for synaptic plasticity and synaptic homeostasis besides amyloid-β protein precursor (AβPP). Despite these setbacks, BACE1 persists as a well-validated therapeutic target for which a specific inhibitor with high substrate selectivity may yet to be found. In this review we provide an overview of the evolution in BACE1 inhibitors design pinpointing the molecules that reached advanced phases of clinical trials and the liabilities that precluded adequate trial effects. Finally, we ponder on the challenges that anti-amyloid therapies must overcome to achieve clinical success. Show more
Keywords: Alzheimer’s disease, amyloid-β , BACE1, BACE1 inhibitors, clinical trials, disease-modifying therapies, drug discovery
DOI: 10.3233/JAD-240146
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-26, 2024
Authors: García-Martínez, María | Pozueta-Cantudo, Ana | Lage, Carmen | Martínez-Dubarbie, Francisco | López-García, Sara | Fernández-Matarrubia, Marta | Corrales-Pardo, Andrea | Bravo, María | Cavada, Nadia C. | Anuarbe, Pedro | Infante, Jon | López-Higuera, José Miguel | Rodríguez-Cobo, Luis | Rodríguez-Rodríguez, Eloy | Butler, Christopher R. | Sánchez-Juan, Pascual
Article Type: Research Article
Abstract: Background: With the arrival of disease-modifying treatments, it is mandatory to find new cognitive markers that are sensitive to Alzheimer’s disease (AD) pathology in preclinical stages. Objective: To determine the utility of a newly developed Learning and Associative Memory face test: LAM test. This study examined the relationship between AD cerebrospinal fluid (CSF) biomarkers and performance on LAM test, and assessed its potential clinical applicability to detect subtle changes in cognitively healthy subjects at risk for AD. Methods: We studied eighty cognitively healthy volunteers from the Valdecilla cohort. 61% were women and the mean age was …67.34 years (±6.416). All participants underwent a lumbar puncture for determination of CSF biomarkers and an extensive neuropsychological assessment, including performance on learning and associative memory indices of the LAM-test after 30 min and after 1 week, and two classic word lists to assess verbal episodic memory: the Rey Auditory Verbal Learning Test (RAVLT) and the Free and Cued Selective Reminding Test (FCSRT). We analyzed cognitive performance according to amyloid status (A+ versus A–) and to ATN model (A–T–N–; A+T–N–; A+T+N–/A+T+N+). Results: Performance on the LAM-test was significantly correlated with CSF Aβ ratio. A+ participants performed worse on both learning (mean difference = 2.19, p = 0.002) and memory LAM measures than A– (mean difference = 2.19, p = 0.004). A decline in performance was observed along the Alzheimer’s continuum, with significant differences between ATN groups. Conclusions: Our findings suggest that LAM test could be a useful tool for the early detection of subjects within the AD continuum, outperforming classical memory tests. Show more
Keywords: Alzheimer’s disease, associative memory, cognitive markers, early detection, long-term forgetting, neuropsychological assessment, preclinical Alzheimer’s disease
DOI: 10.3233/JAD-240067
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2024
Authors: Zhuang, Xiaowei | Cordes, Dietmar | Bender, Andrew R. | Nandy, Rajesh | Oh, Edwin C. | Kinney, Jefferson | Caldwell, Jessica Z.K. | Cummings, Jeffrey | Miller, Justin
Article Type: Research Article
Abstract: Background: Computer-aided machine learning models are being actively developed with clinically available biomarkers to diagnose Alzheimer’s disease (AD) in living persons. Despite considerable work with cross-sectional in vivo data, many models lack validation against postmortem AD neuropathological data. Objective: Train machine learning models to classify the presence or absence of autopsy-confirmed severe AD neuropathology using clinically available features. Methods: AD neuropathological status are assessed at postmortem for participants from the National Alzheimer’s Coordinating Center (NACC). Clinically available features are utilized, including demographics, Apolipoprotein E(APOE) genotype, and cortical thicknesses derived from ante-mortem MRI scans encompassing …AD meta regions of interest (meta-ROI). Both logistic regression and random forest models are trained to identify linearly and nonlinearly separable features between participants with the presence (N = 91, age-at-MRI = 73.6±9.24, 38 women) or absence (N = 53, age-at-MRI = 68.93±19.69, 24 women) of severe AD neuropathology. The trained models are further validated in an external data set against in vivo amyloid biomarkers derived from PET imaging (amyloid-positive: N = 71, age-at-MRI = 74.17±6.37, 26 women; amyloid-negative: N = 73, age-at-MRI = 71.59±6.80, 41 women). Results: Our models achieve a cross-validation accuracy of 84.03% in classifying the presence or absence of severe AD neuropathology, and an external-validation accuracy of 70.14% in classifying in vivo amyloid positivity status. Conclusions: Our models show that clinically accessible features, including APOE genotype and cortical thinning encompassing AD meta-ROIs, are able to classify both postmortem confirmed AD neuropathological status and in vivo amyloid status with reasonable accuracies. These results suggest the potential utility of AD meta-ROIs in determining AD neuropathological status in living persons. Show more
Keywords: Alzheimer’s disease-meta-ROIs, APOE genotype, in vivo amyloid status, machine learning, severe AD neuropathology
DOI: 10.3233/JAD-231321
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-20, 2024
Authors: Puzzo, Daniela
Article Type: Article Commentary
Abstract: This commentary critically examines the long-standing emphasis on amyloid-β (Aβ)-based therapies in Alzheimer’s disease (AD), despite numerous clinical trial failures. It highlights the urgency to reassess research methodologies and challenges the initiation of anti-Aβ trials in preclinical stages of the disease without conclusive proofs of their safety and efficacy. Instead, a comprehensive approach that considers Aβ’s physiological roles and addresses AD complex nature is suggested, encouraging the idea that clinical trial failures may result from targeting the wrong mechanism. Evidence-based scientific research is needed to advance with AD treatment, moving beyond the current conception of Aβ hypothesis.
Keywords: Amyloid-β, BACE1 inhibitors, clinical trials, physiology
DOI: 10.3233/JAD-240406
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-4, 2024
Authors: Yu, Wenzhen | Zhuang, Shuting | Zhan, Mengxiong | Chen, Yong | Zhang, Jieping | Chen, Ling | Tu, Chunxiang | Zheng, Linfei | Chen, Shi
Article Type: Research Article
Abstract: Background: Ferroptosis is extremely relevant to the progression of neurodegenerative pathologies such as Alzheimer’s disease (AD). Ubiquitin-specific proteases (USP) can affect the NADPH oxidase family. Objective: Our study aimed to elucidate the potential role and molecular basis of a certain USP19 in reducing ferroptosis and mitochondrial injury in AD cells by targeting NOX4 stability. Methods: The deubiquitinase USP family gene USP19, which affects the stability of NOX4 protein, was first screened. The cell model of AD was constructed after interfering with SH-SY5Y cells by Aβ1-40 , and then SH-SY5Y cells were infected with lentiviral vectors to …knock down USP19 and overexpress NOX4, respectively. Finally, the groups were tested for cell viability, changes in cellular mitochondrial membrane potential, lipid reactive oxygen species, intracellular iron metabolism, and NOX4, Mf1, Mf2, and Drp1 protein expression. Results: 5 μmol/L Aβ1-40 intervened in SH-SY5Y cells for 24 h to construct a cell model of AD. Knockdown of USP19 decreased the expression of NOX4 protein, promoted the expression of mitochondrial fusion proteins Mnf1 and Mnf2, and inhibited the expression of the splitting protein Drp1. Furthermore, USP19 knockdown decreased mitochondrial membrane potential, SOD, MDA, intracellular iron content and increased GSH/GSSG ratio in SH-SY5Y cells. Our study revealed that NOX4 protein interacts with USP19 and knockdown of USP19 enhanced ubiquitination to maintain NOX4 protein stability. Conclusions: USP19 attenuates mitochondrial damage in SH-SY5Y cells by targeting NOX4 protein with Aβ1-40 . Show more
Keywords: Alzheimer’s disease, deubiquitinating enzyme, ferroptosis, NADPH Oxidase 4, oxidative stress
DOI: 10.3233/JAD-231193
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2024
Authors: Han, Kaiyue | Liu, Guangliang | Liu, Nan | Li, Jiangyi | Li, Jianfeng | Cui, Lihua | Cheng, Ming | Long, Junzi | Liao, Xingxing | Tang, Zhiqing | Liu, Ying | Liu, Jiajie | Chen, Jiarou | Lu, Haitao | Zhang, Hao
Article Type: Research Article
Abstract: Background: The current application effects of computerized cognitive intervention are inconsistent and limited to hospital rehabilitation settings. Objective: To investigate the effect of mobile intelligent cognitive training (MICT) on patients with post-stroke cognitive impairment (PSCI). Methods: This study was a multicenter, prospective, open-label, blinded endpoint, cluster-randomized controlled trial (RCT). 518 PSCI patients were stratified and assigned to four rehabilitation settings, and then patients were randomized into experimental and control groups in each rehabilitation setting through cluster randomization. All patients received comprehensive management for PSCI, while the experimental group additionally received MICT intervention. Treatment was 30 minutes …daily, 5 days per week, for 12 weeks. Cognitive function, activities of daily living (ADL), and quality of life (QOL) were assessed before the treatment, at weeks 6 and 12 post-treatment, and a 16-week follow-up. Results: Linear Mixed Effects Models showed patients with PSCI were better off than pre-treatment patients on each outcome measure (p < 0.05). Additionally, the improvement of these outcomes in the experimental group was significantly better than in the control group at week 6 post-treatment and 16-week follow-up (p < 0.05). The rehabilitation setting also affected the cognitive efficacy of MICT intervention in improving PSCI patients, and the degree of improvement in each outcome was found to be highest in hospital, followed by community, nursing home, and home settings. Conclusions: Long-term MICT intervention can improve cognition, ADL, and QOL in patients with PSCI, with sustained effects for at least one month. Notably, different rehabilitation settings affect the cognitive intervention efficacy of MICT on PSCI patients. However, this still needs to be further determined in future studies. Show more
Keywords: Alzheimer’s disease, cognitive impairment, mobile intelligent cognitive training, rehabilitation, stroke
DOI: 10.3233/JAD-240356
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2024
Authors: Tuena, Cosimo | Serino, Silvia | Pedroli, Elisa | Stramba-Badiale, Chiara | Goulene, Karine Marie | Stramba-Badiale, Marco | Riva, Giuseppe
Article Type: Research Article
Abstract: Background: Egocentric and allocentric spatial memory impairments affect the navigation abilities of older adults with mild cognitive impairment (MCI). Embodied cognition research hints that specific aids can be implemented into virtual reality (VR) training to enhance spatial memory. Objective: In this study, we preliminarily tested ‘ANTaging’, an embodied-based immersive VR training for egocentric and allocentric memory, compared to treatment as usual (TAU) spatial training in MCI. Methods: MCI patients were recruited for this controlled trial. A cognitive battery was administered at pre-test, after ten sessions of ANTaging or TAU intervention, and at 3-month follow-up (FU). The …primary outcomes were spatial cognition tests (Corsi supra-span, CSS; Manikin test, MT). VR egocentric and allocentric performance was also collected. Results: We found that ANTaging significantly improved MT scores at FU compared to TAU. CSS slightly improved in both groups. Concerning secondary outcomes, auditory-verbal forgetting significantly improved at post-test in the ANTaging but not TAU group and significantly declined at FU in the TAU but not in the ANTaging group. Global cognition significantly improved at FU for TAU and remained stable for ANTaging. Other tests showed no improvement or deterioration. Clinical significance showed that ANTaging is effective for CSS. Virtual egocentric and allocentric memory performance improved across ANTaging sessions. Conclusions: ANTaging holds the potential to be superior for improving spatial cognition in MCI compared to TAU. Embodied cognition research provides insights for designing effective spatial navigation rehabilitation in aging. Show more
Keywords: Alzheimer’s disease, dementia, embodied cognition, mild cognitive impairment, rehabilitation, spatial cognition, virtual reality
DOI: 10.3233/JAD-240200
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2024
Authors: Jin, He | Yang, Qiu | Chen, Guodong | Zhang, Wei | Wu, Yanchuan | Wang, Rong
Article Type: Research Article
Abstract: Background: Urinary Alzheimer-associated neuronal thread protein (AD7c-NTP) is a biomarker for the early diagnosis of Alzheimer’s disease (AD). It remains unclear whether hepatorenal function affects the urinary AD7c-NTP level. Objective: To evaluate the effects of hepatorenal function on urinary AD7c-NTP level. Methods: We enrolled 453 participants aged 60–100 years. An automated chemistry analyzer was used to determine the indicators of serum hepatorenal function. Enzyme-linked immunosorbent assay was used to measure the urinary AD7c-NTP level. Results: Spearman’s correlation analysis showed a negative correlation between urinary AD7c-NTP levels and indicators of hepatorenal function, including albumin (r … = –0.181, p < 0.001), albumin/globulin ratio (r = –0.224, p < 0.001), cholinesterase (r = –0.094, p = 0.046), total carbon dioxide (r = –0.102, p = 0.030), and glomerular filtration rate (r = –0.260, p < 0.001), as well as a positive correlation with globulin (r = 0.141, p = 0.003), aspartate transaminase (r = 0.186, p < 0.001), blood urine nitrogen (r = 0.210, p < 0.001), creatinine (r = 0.202, p < 0.001), uric acid (r = 0.229, p < 0.001), and cystatin C (r = 0.265, p < 0.001). The least absolute shrinkage and selection operator (LASSO) regression analysis and multiple linear regression model analyses showed that the statistically significant hepatorenal indicators for predicting AD7c-NTP were A/G (p = 0.007), AST (p = 0.002), BUN (p = 0.019), and UA (p = 0.003). Conclusions: The effects of hepatorenal indicators should be considered when using urinary AD7c-NTP levels in clinical settings. Show more
Keywords: Alzheimer’s disease, Alzheimer-associated neuronal thread protein, kidney, liver, hepatorenal indicator, urine
DOI: 10.3233/JAD-240148
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2024
Authors: Schwerthöffer, Dirk | Haselwarter, Tim | Grimmer, Timo
Article Type: Research Article
Abstract: Background: Obstructive sleep apnea (OSA) is associated with cognitive disorders, but little is known about prevalence of co-occurring OSA and mild cognitive impairment (MCI) as well as about co-occurring OSA and Alzheimer’s disease (AD). Pathophysiological models integrating OSA, cognitive deficits and neurodegeneration remain speculative. Findings in this area could contribute to the knowledge about pathophysiological processes in cognitive disorders and neurodegenerative processes, be helpful for the diagnosis of cognitive disorders and provide approaches for the treatment of cognitive disorders. Objective: Examining the prevalence of OSA and patterns of cognitive deficits as well as AD biomarker profiles associated with …OSA in a cohort of 104 MCI patients. Methods: Assessments used include: respiratory polygraphy, The Consortium to Establish a Registry for Alzheimer’s Disease Neuropsychological Battery (CERAD NB), Tau, phosphoTau181, amyloid-β-1–42/1–40, 18F-fluorodeoxyglucose positron emission tomography (F18-FDG-PET). Results: Prevalence of OSA of any severity: 58,7% (Apnea Hypopnea Index (AHI)≥5/h), OSA in a moderate-to-severe extent (AHI≥15/h): 25%. Only 13.1% of MCI patients with OSA reported daytime sleepiness. MCI-OSA patients showed no specific neuropsychological pattern. Presence of OSA was not associated with specific AD biomarker profiles in the whole study group besides a positive association between AD positivity in an AD biomarker sub cohort. Conclusions: OSA is highly prevalent in patients with MCI. It might often remain undiagnosed as only a small number of MCI-OSA patients report daytime sleepiness. OSA could contribute to MCI symptoms and even to AD pathology. Further research is needed to validate these findings and to investigate possible pathophysiological relationships between OSA and MCI as well as between OSA and AD. Show more
Keywords: Alzheimer’s disease, daytime sleepiness, mild cognitive impairment, obstructive sleep apnea
DOI: 10.3233/JAD-240251
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2024
Authors: Ge, Sanyu | Kitamura, Tetsuhisa | Zha, Ling | Komatsu, Masayo | Komukai, Sho | Murata, Fumiko | Maeda, Megumi | Gon, Yasufumi | Kimura, Yasuyoshi | Kiyohara, Kosuke | Sobue, Tomotaka | Fukuda, Haruhisa
Article Type: Research Article
Abstract: Background: Previous studies have shown a possible association between statin use and a decreased risk of dementia, but the association has not been sufficiently established, especially in the super-aging society of Japan. Objective: This study aimed to determine the association between statin use and the risk of dementia among Japanese participants aged> =65 years old. Methods: Data from the Longevity Improvement and Fair Evidence (LIFE) Study were utilized, including medical and long-term care (LTC) claim data from 17 municipalities between April 2014 and December 2020. A nested case-control study was conducted with one case matched to …five controls based on age, sex, municipality, and year of cohort entry. We used a conditional logistic regression model to calculate the odds ratios (ORs) and 95% confidence intervals (95% CIs). Results: This study included 57,302 cases and 283,525 controls, with 59.7% of the participants being woman. After adjusting for potential confounders, statin use was associated with a lower risk of dementia (OR, 0.70; 95% CI: 0.68–0.73) and Alzheimer’s disease (OR: 0.66; 95% CI: 0.63–0.69). Compared with non-users, the ORs of dementia were as follows: 1.42 (1.34–1.50) for 1–30 total standardized daily dose (TSDD), 0.91 (0.85–0.98) for 31–90 TSDD, 0.63 (0.58–0.69) for 91–180 TSDD, and 0.33 (0.31–0.36) for >180 TSDD in dose-analysis. Conclusions: Statin use is associated with a reduced risk of dementia and Alzheimer’s disease among older Japanese adults. A low cumulative statin dose is associated with an increased risk of dementia, whereas a high cumulative statin dose is a protective factor against dementia. Show more
Keywords: Alzheimer’s disease, dementia, Japanese older adults, LIFE study, statin
DOI: 10.3233/JAD-240113
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2024
Authors: Cassard, Lydia | Honari, Golara | Tousi, Babak
Article Type: Review Article
Abstract: This manuscript reviews the significant skin manifestations of Lewy body disease, including Parkinson’s disease and dementia with Lewy bodies, and the diagnostic utility of skin biopsy. Besides classic motor and cognitive symptoms, non-motor manifestations, particularly dermatologic disorders, can play a crucial role in disease presentation and diagnosis. This review explores the intricate relationship between the skin and Lewy body disease. Seborrheic dermatitis, autoimmune blistering diseases (bullous pemphigoid and pemphigus), rosacea, and melanoma are scrutinized for their unique associations with Parkinson’s disease, revealing potential links through shared pathophysiological mechanisms. Advances in diagnostic techniques allow the identification of promising biomarkers such as …α -synuclein in samples obtained by skin punch biopsy. Understanding the dermatologic aspects of Lewy body disease not only contributes to its holistic characterization but also holds implications for innovative diagnostic approaches. Show more
Keywords: Alzheimer’s disease, dementia with Lewy bodies, Lewy body disease, Parkinson’s disease, skin biopsy
DOI: 10.3233/JAD-240198
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2024
Authors: Portal, Benjamin | Södergren, Moa | Parés i Borrell, Teo | Giraud, Romain | Metzendorf, Nicole G. | Hultqvist, Greta | Nilsson, Per | Lindskog, Maria
Article Type: Research Article
Abstract: Background: Alzheimer’s disease (AD) is the most common neurodegenerative disease. Unfortunately, efficient and affordable treatments are still lacking for this neurodegenerative disorder, it is therefore urgent to identify new pharmacological targets. Astrocytes are playing a crucial role in the tuning of synaptic transmission and several studies have pointed out severe astrocyte reactivity in AD. Reactive astrocytes show altered physiology and function, suggesting they could have a role in the early pathophysiology of AD. Objective: We aimed to characterize early synaptic impairments in the App NL -F knock-in mouse model of AD, especially to understand the contribution …of astrocytes to early brain dysfunctions. Methods: The App NL -F mouse model carries two disease-causing mutations inserted in the amyloid precursor protein gene. This strain does not start to develop amyloid-β plaques until 9 months of age. Thanks to electrophysiology, we investigated synaptic function, at both neuronal and astrocytic levels, in 6-month-old animals and correlate the synaptic activity with emotional behavior. Results: Electrophysiological recordings in the hippocampus revealed an overall synaptic mistuning at a pre-plaque stage of the pathology, associated to an intact social memory but a stronger depressive-like behavior. Astrocytes displayed a reactive-like morphology and a higher tonic GABA current compared to control mice. Interestingly, we here show that the synaptic impairments in hippocampal slices are partially corrected by a pre-treatment with the monoamine oxidase B blocker deprenyl or the fast-acting antidepressant ketamine (5 mg/kg). Conclusions: We propose that reactive astrocytes can induce synaptic mistuning early in AD, before plaques deposition, and that these changes are associated with emotional symptoms. Show more
Keywords: Alzheimer’s disease, App knock-in mice, depression, LTP, MAO-B, synapse
DOI: 10.3233/JAD-231461
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-21, 2024
Authors: Lozupone, Madia | Dibello, Vittorio | Sardone, Rodolfo | Altamura, Mario | Bellomo, Antonello | Daniele, Antonio | Solfrizzi, Vincenzo | Resta, Emanuela | Panza, Francesco
Article Type: Editorial
Abstract: Social dysfunction is a maladaptive process of coping, problem solving, and achieving one’s goals. A new definition of apathy was cross-linked to social dysfunction, with a reduced goal-directed behavior and social interaction as a separate dimension. We hypothesized that these two neuropsychiatric symptoms may be included in the mild behavioral impairment diagnostic framework, operationalizing and standardizing late-life neuropsychiatric symptom assessment, to improve risk determination of dementia. Social dysfunction and apathy were transdiagnostic and prodromic for late-life cognitive disorders. A transdiagnostic approach could provide a useful mean for a better understanding of apathy and related conditions such as social behavior.
Keywords: Alzheimer’s disease, apathy, biopsychosocial frailty, dementia, depression, late-life cognitive disorders, mild behavioral impairment, mild cognitive impairment, social dysfunction, social withdrawal
DOI: 10.3233/JAD-240556
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-5, 2024
Authors: Taylor, Morag E. | Kerckhaert, Luuk | Close, Jacqueline C.T. | van Schooten, Kimberley S. | Lord, Stephen R.
Article Type: Research Article
Abstract: Background: Cognitive impairment (CI) may impair the ability to accurately perceive physical capacity and fall risk. Objective: We investigated perceived (measured as concern about falls) and physiological fall risk in community-dwelling older people with CI, the characteristics of the aligned and misaligned groups and the impact of misaligned perceptions on falls. Methods: Participants (n = 293) with mild-moderate CI were classified into four groups based on validated physiological and perceived fall risk assessments: 1) vigorous: low perceived and physiological fall risk; 2) anxious: high perceived and low physiological fall risk; 3) unaware: low perceived and high physiological …fall risk; and 4) aware: high perceived and physiological fall risk. Groups were compared with respect to neuropsychological and physical function, activity and quality of life measures, and prospective falls (12-months). Results: The anxious (IRR = 1.70, 95% CI = 1.02–2.84), unaware (IRR = 2.00, 95% CI = 1.22–3.26), and aware (IRR = 2.53, 95% CI = 1.67–3.84) groups had significantly higher fall rates than the vigorous group but fall rates did not significantly differ among these groups. Compared with the vigorous group: the anxious group had higher depression scores and reduced mobility and quality of life; the unaware group had poorer global cognition, executive function and mobility and lower physical activity levels; and the aware group had an increased prevalence of multiple physical and cognitive fall risk factors. Conclusions: Fall rates were increased in participants who had increased perceived and/or physiological fall risk. Contrasting fall risk patterns were evident in those who under- and over-estimated their fall risk. Understanding these characteristics will help guide fall risk assessment and prevention strategies in community-dwelling older people with CI. Show more
Keywords: Accidental falls, aged, Alzheimer’s disease, cognitive dysfunction, dementia, fear of falling, perception, risk factors
DOI: 10.3233/JAD-240489
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2024
Authors: Therrien, Sarah | Anthony, Mia | Turnbull, Adam | Lin, F. Vankee
Article Type: Research Article
Abstract: Background: Adequately evaluating risk and making decisions is vital but understudied for older adults living independently but with compromised cognition, as seen in those with mild cognitive impairment (MCI), specifically those with amnestic MCI (aMCI) which is associated with higher risk of conversion to Alzheimer’s disease. Objective: We propose to comprehensively evaluate risk-taking behaviors across domains important for everyday activities between an aMCI group and their cognitively healthy counterparts (HC). Methods: A case-control study design. Data on risk-taking behaviors via the Domain-Specific Risk-Taking Scale (DOSPERT), and candidate confounding mental health factors (i.e., neurodegeneration, depression, and fatigue) …were collected. Analyses on group difference and interaction between group and confounding factors on risk-taking behaviors were conducted. Results: The aMCI group showed a higher likelihood of risk-taking than HC (t = 4.38, df = 73, p < 0.001). Moderation analysis showed fatigue (F = 5.91, p = 0.018) and presence of depression (F = 4.52, p = 0.037), but not neurodegeneration, as significant moderators for group and DOSPERT total score, controlling for sex. In post-hoc analyses, there was a significant relationship between both fatigue (B = –7.83, SE = 3.65, t = –2.14, p = 0.036), and presence of depression (B = –20.80, SE = 9.97, t = –2.09, p = 0.041), with DOSPERT total score for HC but not for aMCI. There were no significant relationships between neurodegeneration, fatigue, or depression with any specific risk-taking domains after correction for multiple comparisons. Conclusions: Our results show differences in risk-taking behavior between older adults with and without intact cognition, and overall decision-making is affected by fatigue and depression in HC but not aMCI, together suggesting the importance of cognition in the ability to adjust risk-taking behaviors. Show more
Keywords: Alzheimer’s disease, decision making, functional status, mild cognitive impairment, risk-taking
DOI: 10.3233/JAD-231448
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2024
Authors: Elman, Jeremy A. | Schork, Nicholas J. | Rangan, Aaditya V.
Article Type: Research Article
Abstract: Background: Alzheimer’s disease (AD) exhibits considerable phenotypic heterogeneity, suggesting the potential existence of subtypes. AD is under substantial genetic influence, thus identifying systematic variation in genetic risk may provide insights into disease origins. Objective: We investigated genetic heterogeneity in AD risk through a multi-step analysis. Methods: We performed principal component analysis (PCA) on AD-associated variants in the UK Biobank (AD cases = 2,739, controls = 5,478) to assess structured genetic heterogeneity. Subsequently, a biclustering algorithm searched for distinct disease-specific genetic signatures among subsets of cases. Replication tests were conducted using the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset (AD cases = 500, controls = 470). …We categorized a separate set of ADNI individuals with mild cognitive impairment (MCI; n = 399) into genetic subtypes and examined cognitive, amyloid, and tau trajectories. Results: PCA revealed three distinct clusters (“constellations”) driven primarily by different correlation patterns in a region of strong LD surrounding the MAPT locus. Constellations contained a mixture of cases and controls, reflecting disease-relevant but not disease-specific structure. We found two disease-specific biclusters among AD cases. Pathway analysis linked bicluster-associated variants to neuron morphogenesis and outgrowth. Disease-relevant and disease-specific structure replicated in ADNI, and bicluster 2 exhibited increased cerebrospinal fluid p-tau and cognitive decline over time. Conclusions: This study unveils a hierarchical structure of AD genetic risk. Disease-relevant constellations may represent haplotype structure that does not increase risk directly but may alter the relative importance of other genetic risk factors. Biclusters may represent distinct AD genetic subtypes. This structure is replicable and relates to differential pathological accumulation and cognitive decline over time. Show more
Keywords: Alzheimer’s disease, biclustering, genetic risk, genetic subtypes, genotyping
DOI: 10.3233/JAD-231252
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2024
Authors: Mace, Ryan A. | Lyons, Christopher | Cohen, Joshua E. | Ritchie, Christine | Bartels, Stephen | Okereke, Olivia I. | Hoeppner, Bettina B. | Brewer, Judson A. | Vranceanu, Ana-Maria
Article Type: Research Article
Abstract: Background: Interventions that promote healthy lifestyles are critical for the prevention of Alzheimer’s disease and Alzheimer’s disease related dementias (AD/ADRD). However, knowledge of the best practices for implementing AD/ADRD prevention in healthcare settings remains limited. Objective: We aimed to qualitatively identify barriers and facilitators to implementing a clinical trial of a novel lifestyle intervention (My Healthy Brain ) in our medical center for older patients with subjective cognitive decline who are at-risk for AD/ADRD. Methods: We conducted focus groups with 26 healthcare professionals (e.g., physicians, psychology, nursing) from 5 clinics that treat older patients (e.g., memory …care, psychiatry). Our qualitative analysis integrated two implementation frameworks to systematically capture barriers and facilitators to AD/ADRD prevention (Consolidated Framework for Implementation Science Research) that impact implementation outcomes of acceptability, appropriateness, and feasibility (Proctor’s framework). Results: We found widespread support for an RCT of My Healthy Brain and AD/ADRD prevention. Participants identified barriers related to patients (stigma, technological skills), providers (dismissiveness of “worried well,” doubting capacity for behavior change), clinics (limited time and resources), and the larger healthcare system (underemphasis on prevention). Implementation strategies guided by Expert Recommendations for Implementing Change (ERIC) included: developing tailored materials, training staff, obtaining buy-in from leadership, addressing stigmatized language and practices, identifying “champions,” and integrating with workflows and resources. Conclusions: The results will inform our recruitment, enrollment, and retention procedures to implement the first randomized clinical trial of My Healthy Brain . Our study provides a blueprint for addressing multi-level barriers to the implementation of AD/ADRD prevention for older patients in medical settings. Show more
Keywords: Alzheimer’s disease, brain health, dementia, implementation, prevention, qualitative
DOI: 10.3233/JAD-240365
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-23, 2024
Authors: Amaral-Carvalho, Viviane | Bento Lima-Silva, Thais | Inácio Mariano, Luciano | Cruz de Souza, Leonardo | Cerqueira Guimarães, Henrique | Santoro Bahia, Valéria | Nitrini, Ricardo | Tonidandel Barbosa, Maira | Sanches Yassuda, Mônica | Caramelli, Paulo
Article Type: Research Article
Abstract: Background: The Addenbrooke’s Cognitive Examination-Revised (ACE-R) is an accessible cognitive tool that supports the early detection of mild cognitive impairment (MCI), Alzheimer’s disease (AD), and behavioral variant frontotemporal dementia (bvFTD). Objective: To investigate the diagnostic efficacy of the ACE-R in MCI, AD, and bvFTD through the identification of novel coefficients for differentiation between these diseases. Methods: We assessed 387 individuals: 102 mild AD, 37 mild bvFTD, 87 with amnestic MCI patients, and 161 cognitively unimpaired controls. The Mokken scaling technique facilitated the extraction out of the 26 ACE-R items that exhibited a common latent trait, thereby …generating the Mokken scales for the AD group and the MCI group. Subsequently, we performed logistic regression, integrating each Mokken scales with sociodemographic factors, to differentiate between AD and bvFTD, as well as between AD or MCI and control groups. Ultimately, the Receiver Operating Characteristic curve analysis was employed to assess the efficacy of the coefficient’s discrimination. Results: The AD-specific Mokken scale (AD-MokACE-R) versus bvFTD exhibited an Area Under the Curve (AUC) of 0.922 (88% sensitivity and specificity). The AD-MokACE-R versus controls achieved an AUC of 0.968 (93% sensitivity, 94% specificity). The MCI-specific scale (MCI-MokACE-R) versus controls demonstrated an AUC of 0.859 (78% sensitivity, 79% specificity). Conclusions: The ACE-R’s capacity is enhanced through statistical methods and demographic integration, allowing for accurate differentiation between AD and bvFTD, as well as between MCI and controls. This new method not only reinforces its clinical value in early diagnosis but also surpasses traditional approaches noted in prior studies. Show more
Keywords: Aging, Alzheimer’s disease, cognition, dementia, frontotemporal dementia, mild cognitive impairment, neuropsychological tests
DOI: 10.3233/JAD-240554
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2024
Authors: Sommerlad, Andrew | Grothe, Jessica | Umeda, Sumiyo | Ikeda, Manabu | Kanemoto, Hideki | Livingston, Gill | Luppa, Melanie | Rankin, Katherine P. | Riedel-Heller, Steffi G. | Röhr, Susanne | Suzuki, Maki | Huntley, Jonathan
Article Type: Research Article
Abstract: Background: People with dementia commonly have impaired social functioning and may not recognize this. This lack of awareness may result in worse outcomes for the person and their family carers. Objective: We aimed to characterize awareness of social functioning in dementia and describe its association with dementia severity. Methods: Multi-center cross-sectional study of people aged >65 years with dementia and family informants recruited from Germany, Japan and the United Kingdom. We used the Social Functioning in Dementia (SF-DEM) scale, assessing “spending time with other people” (domain 1), “communicating with other people” (domain 2), and “sensitivity to …other people” (domain 3), and calculated lack of awareness into social functioning as the discrepancy between patient and informant ratings. Results: 108 participants with dementia (50.9% women), mean age = 78.9 years, and mean MMSE score = 22.7. Patient and informant domain 1 ratings did not differ, but patient-rating was higher than carers for domain 2 (11.2 versus 10.1; p = 0.003) and domain 3 (9.7 versus 8.1; p < 0.001). Sixty people with dementia overestimated their overall social functioning, 30 underestimated, and 18 gave ratings congruent with their informant. Performance on the MMSE and its sub-domains was not associated with SF-DEM discrepancy score. Conclusions: We found that awareness of social functioning in dementia was a multidimensional concept, which varies according to subdomains of social functioning. Clinicians should help family members understand and adapt by explaining their relative with dementia’s lack of awareness about aspects of their social functioning. Show more
Keywords: Alzheimer’s disease, awareness, dementia, insight, metacognition, social functioning
DOI: 10.3233/JAD-240311
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2024
Authors: Rice, Paige E. | Thumuluri, Deepthi | Barnstaple, Rebecca | Fanning, Jason | Laurita-Spanglet, Jessie | Soriano, Christina T. | Hugenschmidt, Christina E.
Article Type: Review Article
Abstract: Background: Dance combines cultural and aesthetic elements with behaviors important for brain health, including physical activity, social engagement, and cognitive challenge. Therefore, dance could positively impact public health given the rapidly aging population, increasing incidence of Alzheimer’s disease and related dementias, and lack of uptake of exercise in many older adults. Despite a high volume of literature, existing literature does not support evidence-based guidelines for dance to support healthy aging. Objective: To conduct a scoping review of the dance intervention literature in older adults and provide information to facilitate a more consistent approach among scientists in designing dance …interventions for older adults that stimulate physical and neurocognitive health adaptations. Methods: Study characteristics (sample size, population, study design, outcomes, intervention details) were ascertained from 112 separate studies of dance reported in 127 papers that reported outcomes important for brain health (cardiorespiratory fitness, balance and mobility, cognition, mood, and quality of life). Results: High heterogeneity across studies was evident. Class frequency ranged from < 1 to 5 classes per week, class length from 30–120 minutes, and intervention duration from 2 weeks to 18 months. Studies often did not randomize participants, had small (< 30) sample sizes, and used varied comparator conditions. Over 50 tests of cognition, 40 dance forms, and 30 tests of mobility were identified. Conclusions: Based on these results, important future directions are establishing common data elements, developing intervention mapping and mechanistic modeling, and testing dosing parameters to strengthen and focus trial design of future studies and generate evidence-based guidelines for dance. Show more
Keywords: Aging, Alzheimer’s disease, cardiorespiratory fitness, cognition, health, physical fitness, physical function performance
DOI: 10.3233/JAD-230741
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-38, 2024
Authors: Fan, Meixiang | Li, Qingfeng | Yang, Tingting | Yang, Yinghua | Chen, Zhihua | Xuan, Guo | Ruan, Ye | Sun, Shuangyuan | Wang, Meng | Chen, Xiaoli | Huang, Yanyan | Yang, Zhi | Wang, Ying
Article Type: Research Article
Abstract: Background: Previous trials have indicated that multimodal training could improve cognitive functions and moods in individuals with mild cognitive impairment (MCI). However, evidence was mainly obtained from studies in high-income countries. Objective: This trial aims to investigate the efficacy, safety, and potential mechanism of a multimodal intervention on cognitive function in individuals with MCI living in a community. Methods: In this single-blind, randomized controlled trial, 120 participants with MCI were randomly assigned to either the intervention group or the control group. The intervention group received the multimodal intervention, while the control group received regular health education. …Neuropsychological tests and magnetic resonance imaging (MRI) were conducted at baseline and after the 12-week intervention. Results: Fifty-nine and fifty-seven participants respectively in the intervention and control groups completed the trial. The intervention group shown improvements in primary outcome, Mini-Mental State Exam (MMSE) total score (mean difference –0.96, 95% CI [–1.58, –0.34], p = 0.003), and secondary outcomes: MMSE recall (–0.39, 95% CI [–0.71, –0.07], p = 0.019), MMSE language (–0.26, 95% CI [–0.44, –0.07], p = 0.007), Auditory Verbal Learning Test instantaneous memory (–3.30, 95% CI [–5.70, –0.89], p = 0.008), Digit Symbol Substitution Test total score (–2.91, 95% CI [–5.67, –0.15], p = 0.039), digit span forwards (–1.25, 95% CI [–1.93, –0.56], p < 0.001), and Digit Span Test (–1.33, 95% CI [–2.33, –0.34], p = 0.009) compared to the control group. Improvements were observed in structural and functional connectivity related to language, concentration, executive function, memory, and recall functioning via MRI in the intervention group. Conclusions: The multimodal intervention improved cognitive function in individuals with MCI in cognitive performance and neuroimaging. Show more
Keywords: Alzheimer’s disease, behavior therapy, clinical trial, cognitive dysfunction
DOI: 10.3233/JAD-231370
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2024
Authors: Brar, Manjot | Mc Ardle, Ríona | Hagan, Alexander | Al-Oraibi, Amani | Hanjari, Matilda | Stephan, Blossom | Brayne, Carol | Lafortune, Louise | Bains, Manpreet | Qureshi, Nadeem | Robinson, Louise
Article Type: Systematic Review
Abstract: Background: Increased understanding of dementia risk-reduction and early detection of Alzheimer’s disease and related disorders has spurred interest in the identification of risks for dementia, underlying putative biologies, or dementia itself. Implementation of such approaches require acceptability to the public. Research prior to 2012 indicated limited acceptability for population dementia screening. The changing landscape of dementia prevention research may influence recent perceptions. Additionally, perspectives from underserved populations, such as ethnic minorities and low socio-economic groups, are lacking. Objective: In this systematic review, we sought published studies since 2012 on attitudes and preferences of people with dementia, carers and …the general public from ethnic minorities and low socio-economic groups regarding dementia screening. Methods: This review was preregistered on PROSPERO (CRD42023384115) and followed PRISMA guidelines. Key search terms were entered into five databases. Articles were included if they focused on population or risk screening for dementia via primary/community care-based assessments, and which included majority ethnic minority or low socio-economic groups or discretely considered these groups in data analysis. Data were synthesized narratively. Results: Seven studies reported perspectives of ethnic minorities regarding dementia screening; one study included people from low socio-economic groups. Results indicated that participants from ethnic minorities were willing to undergo dementia screening. Predictors of willingness included belief in benefits, desire to boost diversity, and to implement lifestyle changes. Unwillingness was associated with anxiety regarding results. Conclusions: Although there seems to be high acceptability for screening in the studied groups, more research is necessary to explore the practical considerations for screening such as cultural and economic barriers, trust, and post-screening actions. Show more
Keywords: Alzheimer’s disease, attitudes, dementia, ethnic minorities, low socioeconomic status, preferences, screening
DOI: 10.3233/JAD-240315
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2024
Authors: Gonzales, Mitzi M. | Kojis, Daniel | Spartano, Nicole L. | Thibault, Emma G. | DeCarli, Charles S. | El Fakhri, Georges | Johnson, Keith A. | Beiser, Alexa S. | Seshadri, Sudha
Article Type: Research Article
Abstract: Background: Higher midlife physical activity engagement has been associated with lower dementia risk in late life. However, the underlying mechanisms contributing to the protective effect remain unclear. Objective: The goal of the current study was to evaluate the associations of physical activity with cerebral amyloid-β (Aβ) and tau in a predominately middle-aged community-based cohort, as well as to explore whether the associations differ by sex or age. Methods: Participants from the Framingham Heart Study underwent 11 C-Pittsburgh Compound B amyloid and 18 F-Flortaucipir tau positron emission tomography (PET) imaging. Total physical activity levels were evaluated by …self-report using the Physical Activity Index (PAI). Cross-sectional associations between total PAI with regional Aβ and tau PET retention were evaluated using linear regression models adjusted for demographic and cardiovascular risk factors. Interactions with sex and age group were examined and stratified analyses were performed when significant. FDR-correction for multiple comparisons was applied. Results: The sample included 354 participants (mean age 53±8 years, 51% female). Higher total PAI scores were associated with lower entorhinal cortex tau PET binding (β (SE) = –0.021(0.008), p = 0.049). There were significant interactions with sex. In men alone, total PAI inversely associated with entorhinal cortex (β (SE) = –0.035(0.009), p = 0.001), inferior temporal (β (SE) = –0.029(0.010), p = 0.012), and rhinal cortex tau(β (SE) = –0.033(0.010), p = 0.002). Conclusions: The results suggest that higher midlife physical activity engagement may confer resistance to tau pathology. However, the effects may vary based on sex, highlighting the importance of better understanding and tailoring lifestyle interventions to address sex disparities. Show more
Keywords: Alzheimer’s disease, amyloid-β, midlife, PET imaging, physical activity, tau
DOI: 10.3233/JAD-240322
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2024
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