Journal of Alzheimer's Disease - Volume 100, issue 3

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. 100, no. 3, pp. 843-862, 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. 100, no. 3, pp. 863-878, 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. 100, no. 3, pp. 879-897, 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. 100, no. 3, pp. 899-909, 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. 100, no. 3, pp. 911-921, 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. 100, no. 3, pp. 923-934, 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. 100, no. 3, pp. 935-943, 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. 100, no. 3, pp. 945-959, 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. 100, no. 3, pp. 961-972, 2024

Authors: Leng, Fangda | Hinz, Rainer | Gentleman, Steve | Dani, Melanie | Brooks, David J. | Edison, Paul

Article Type: Research Article

Abstract: Background: Neuroinflammation in Alzheimer’s disease is known as an important process in the disease, yet how microglial activation affects disease progression remains unclear. Objective: The current study aims to interrogate the predictive value of neuroinflammation biomarker (11 C-PBR28 PET), together with A/T/N imaging markers on disease deterioration in a cognitively impaired patient cohort. Methods: The study included 6 AD and 27 MCI patients, who had MRI, 11 C-PBR28, 18 F-flutemetamol (amyloid marker), 18 F-AV1451 (tau marker) PET scans, and were followed up with multiple neuropsychological assessments for at least one year (1.6 and 2.8 years on …average for AD and MCI). The predictive values of imaging biomarkers on baseline and longitudinal cognition were interrogated using linear regression to identify the biomarkers that could explain disease progression. Results: Linear mixed models found the average intercepts (baseline) MMSE were 23.5 for AD and 28.2 for MCI patients, and the slope of MMSE (annual change) were –0.74 for AD and –0.52 for MCI patients. White matter microstructural integrity was predictive of baseline cognition, while PET markers of amyloid, tau and neuroinflammation were predictive of longitudinal cognitive decline. Both amyloid and neuroinflammation PET markers were predictors independent of each other. And a sub-group analysis showed the predictive effect of neuroinflammation on cognitive decline is independent of amyloid and tau. Conclusions: Our study highlights the prognostic value of disease specific markers (amyloid, tau and neuroinflammation) in clinically diagnosed AD and MCI patients and suggests that the effects of these molecular markers are mediated by structural damage to the brain. Show more

Keywords: Alzheimer’s disease, 11C-PBR28, mild cognitive impairment, neuroinflammation, positron emission tomography

DOI: 10.3233/JAD-230442

Citation: Journal of Alzheimer's Disease, vol. 100, no. 3, pp. 973-986, 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. 100, no. 3, pp. 987-998, 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. 100, no. 3, pp. 999-1015, 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. 100, no. 3, pp. 1017-1037, 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. 100, no. 3, pp. 1039-1053, 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. 100, no. 3, pp. 1055-1073, 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. 100, no. 3, pp. 1075-1082, 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. 100, no. 3, pp. 1083-1097, 2024