Journal of Alzheimer's Disease - Volume 100, issue 2

Authors: Toya, Shunji | Hashimoto, Mamoru | Manabe, Yuta | Yamakage, Hajime | Ikeda, Manabu

Article Type: Research Article

Abstract: Background: Quality of life (QOL) and treatment needs of patients with dementia with Lewy bodies (DLB) and their caregivers are important factors to consider when developing treatment strategies. Objective: To investigate factors associated with QOL in patients with DLB, and to examine factors associated with activities of daily living (ADL) if ADL was associated with QOL. Methods: We previously conducted a questionnaire survey study to investigate the treatment needs of patients with DLB and their caregivers. This pre-specified additional analysis evaluated the Physical Component Score (PCS) and Mental Component Score (MCS) of the Short Form-8 for …QOL, and the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part II total score for ADL. Results: In total, 231 patient– caregiver pairs and 38 physicians were included. Multivariable analysis of QOL showed that the MDS-UPDRS Part II total score (standard regression coefficient [β], – 0.432) was associated with the PCS, and presence of depression (β, – 0.330) was associated with the MCS. The severity of postural instability/gait disorder (PIGD) (β, 0.337) and rigidity (β, 0.266), presence of hallucinations (β, 0.165), male sex (β, 0.157), and use of “short stay” or “small-scale, multifunctional home care” (β, 0.156) were associated with worsened ADL. Conclusions: In patients with DLB, QOL was negatively impacted by severity of ADL disability and depression, and ADL was negatively impacted by severity of PIGD and rigidity, hallucinations, male sex, and use of “short stay” or “small-scale, multifunctional home care.” Show more

Keywords: Activities of daily living, Alzheimer’s disease, cross-sectional studies, dementia, depression, hallucinations, Lewy body, parkinsonism, quality of life

DOI: 10.3233/JAD-231302

Citation: Journal of Alzheimer's Disease, vol. 100, no. 2, pp. 525-538, 2024

Authors: Howard, Erica | Moody, Jena N. | Prieto, Sarah | Hayes, Jasmeet P.

Article Type: Research Article

Abstract: Background: Traumatic brain injury (TBI) may confer risk for Alzheimer’s disease (AD) through amyloid-β (Aβ) overproduction. However, the relationship between TBI and Aβ levels in cerebrospinal fluid (CSF) remains unclear. Objective: To explore whether Aβ overproduction is implicated in the relationship between TBI and AD, we compared CSF levels of Aβ in individuals with a TBI history versus controls (CTRLs) and related CSF Aβ levels to cognitive markers associated with preclinical AD. Methods: Participants were 112 non-impaired Veterans (TBI = 56, CTRL = 56) from the Alzheimer’s Disease Neuroimaging Initiative-Department of Defense database with available cognitive data (Boston Naming Test …[BNT], Rey Auditory Verbal Learning Test [AVLT]) and CSF measures of Aβ42 , Aβ40 , and Aβ38 . Mediation models explored relationships between TBI history and BNT scores with Aβ peptides as mediators. Results: The TBI group had higher CSF Aβ40 (t  = –2.43, p  = 0.017) and Aβ38 (t  = –2.10, p  = 0.038) levels than the CTRL group, but groups did not differ in CSF Aβ42 levels or Aβ42 /Aβ40 ratios (p  > 0.05). Both Aβ peptides negatively correlated with BNT (Aβ40 : rho = –0.20, p  = 0.032; Aβ38 : rho = –0.19, p  = 0.048) but not AVLT (p  > 0.05). Aβ40 had a significant indirect effect on the relationship between TBI and BNT performance (β= –0.16, 95% CI [–0.393, –0.004], P M  = 0.54). Conclusions: TBI may increase AD risk and cognitive vulnerability through Aβ overproduction. Biomarker models incorporating multiple Aβ peptides may help identify AD risk among those with TBI. Show more

Keywords: Alzheimer’s disease, amyloid plaques, cognitive decline, neuropsychology, traumatic brain injury

DOI: 10.3233/JAD-240254

Citation: Journal of Alzheimer's Disease, vol. 100, no. 2, pp. 539-550, 2024

Authors: Deng, Senli | He, Ruikun | Yue, Zhongbao | Li, Benchao | Li, Fengping | Xiao, Qing | Wang, Xiaoge | Li, Yuanyuan | Chen, Ruilin | Rong, Shuang

Article Type: Research Article

Abstract: Background: The current research on advanced glycosylation end products (AGEs) and cognitive function is limited. Objective: We aimed to investigate the relationship between multiple plasma AGEs and cognitive function and mild cognitive impairment (MCI). Methods: Baseline data from The Lifestyle and Healthy Aging of Chinese Square Dancer Study was used in this cross-sectional study. Ultra-high-performance liquid chromatography tandem mass spectrometry was used to determine plasma levels of carboxymethyl lysine (CML), carboxyethyl lysine (CEL), and methyl imidazolinone (MG-H1). Four cognitive tests were used to obtain the four cognitive domain scores and the composite z scores. The Petersen …criteria were used to diagnose MCI. The data were analyzed by multivariable linear and logistic regression models. Results: This study included 1,018 participants (median age 61.0 years, 87.3% female). After multivariate adjustment, the βs of the highest quartile of CML and CEL compared to the lowest quartile were –0.28 (–0.38, –0.17) and –0.13 (–0.23, –0.03), respectively, for the composite z score. For the four cognitive domains, CML was negatively correlated with memory, attention, and executive function, and CEL was negatively associated with memory and language function. In addition, higher CML was associated with a higher odds of MCI. MG-H1 was not associated with cognitive function. Conclusions: High plasma AGE levels were correlated with poorer cognitive function, particularly CML and CEL, higher levels of CML were also associated with higher odds of MCI. To clarify the effects of different AGEs on cognitive function and the underlying mechanisms, further longitudinal and experimental studies are needed. Show more

Keywords: Advanced glycation end products, Alzheimer’s disease, carboxyethyl lysine, carboxymethyl lysine, cognitive function, mild cognitive impairment

DOI: 10.3233/JAD-240296

Citation: Journal of Alzheimer's Disease, vol. 100, no. 2, pp. 551-562, 2024

Authors: Chandler, Julie M. | Ye, Wenyu | Mi, Xiaojuan | Doty, Erin G. | Johnston, Joseph A.

Article Type: Research Article

Abstract: Background: Impact of Alzheimer’s disease (AD) progression on patient health-related quality of life (HRQoL), caregiver time, and societal costs is not well characterized in early AD. Objective: To assess the association of change in cognition with HRQoL, caregiver time, and societal costs over 36 months, and estimate the impact of slowing disease progression on these outcomes. Methods: This post-hoc analysis included patients with amyloid-positive mild cognitive impairment (MCI) and mild AD dementia (MILD AD) from the 36-month GERAS-US study. Disease progression was assessed using the Mini-Mental State Examination score. Change in outcomes associated with slowing …AD progression was estimated using coefficients from generalized linear models. Results: At baseline, 300 patients had MCI and 317 had MILD AD. Observed natural progression over 36 months was associated with: 5.1 point decline in the Bath Assessment of Subjective Quality of Life in Dementia (BASQID) score (for HRQoL), increase in 1,050 hours of total caregiver time, and $8,504 total societal costs for MCI; 6.6 point decline in the BASQID score, increase in 1,929 hours of total caregiver time, and $12,795 total societal costs for MILD AD per person. Slowing AD progression by 30% could result in per person savings in HRQoL decline, total caregiver time, and total societal costs: for MCI: 1.5 points, 315 hours, and $2,638; for MILD AD: 2.0 points, 579 hours, and $3,974. Conclusions: Slowing AD progression over 36 months could slow decline in HRQoL and save caregiver time and societal cost in patients with MCI and MILD AD. Show more

Keywords: Alzheimer’s disease, amyloid, burden of illness, cost of illness, dementia, economic burden, healthcare costs, health-related quality of life, mild cognitive impairment, PET scan

DOI: 10.3233/JAD-231166

Citation: Journal of Alzheimer's Disease, vol. 100, no. 2, pp. 563-578, 2024

Authors: Caballero, H. Sebastian | McFall, G. Peggy | Gee, Myrlene | MacDonald, Stuart | Phillips, Natalie A. | Fogarty, Jennifer | Montero-Odasso, Manuel | Camicioli, Richard | Dixon, Roger A.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) and Lewy body disease (LBD) are characterized by early and gradual worsening perturbations in speeded cognitive responses. Objective: Using simple and choice reaction time tasks, we compared two indicators of cognitive speed within and across the AD and LBD spectra: mean rate (average reaction time across trials) and inconsistency (within person variability). Methods: The AD spectrum cohorts included subjective cognitive impairment (SCI, n  = 28), mild cognitive impairment (MCI, n  = 121), and AD (n  = 45) participants. The LBD spectrum included Parkinson’s disease (PD, n  = 32), mild cognitive impairment in PD (PD-MCI, n  = 21), …and LBD (n  = 18) participants. A cognitively unimpaired (CU, n  = 39) cohort served as common benchmark. We conducted multivariate analyses of variance and discrimination analyses. Results: Within the AD spectrum, the AD cohort was slower and more inconsistent than the CU, SCI, and MCI cohorts. The MCI cohort was slower than the CU cohort. Within the LBD spectrum, the LBD cohort was slower and more inconsistent than the CU, PD, and PD-MCI cohorts. The PD-MCI cohort was slower than the CU and PD cohorts. In cross-spectra (corresponding cohort) comparisons, the LBD cohort was slower and more inconsistent than the AD cohort. The PD-MCI cohort was slower than the MCI cohort. Discrimination analyses clarified the group difference patterns. Conclusions: For both speed tasks, mean rate and inconsistency demonstrated similar sensitivity to spectra-related comparisons. Both dementia cohorts were slower and more inconsistent than each of their respective non-dementia cohorts. Show more

Keywords: Alzheimer’s disease, Canadian consortium on neurodegeneration in aging (CCNA), cognitive speed, COMPASS-ND study, inconsistency, Lewy body disease, mean rate, reaction time

DOI: 10.3233/JAD-240210

Citation: Journal of Alzheimer's Disease, vol. 100, no. 2, pp. 579-601, 2024

Authors: He, Qiang | Wang, Wenjing | Xiong, Yang | Tao, Chuanyuan | Ma, Lu | You, Chao

Article Type: Research Article

Abstract: Background: The identification of biomarkers for different dementias in plasma and cerebrospinal fluid (CSF) has made substantial progress. However, they are observational studies, and there remains a lack of research on dementias with low incidence rates. Objective: We performed a comprehensive Mendelian randomization to identify potential biomarkers for different dementia type. Methods: The summary-level datasets encompassed 734 plasma and 154 cerebrospinal fluid proteins sourced from recently published genome-wide association studies (GWAS). Summary statistics for different dementias, including any dementia (refering to any type of dementia symptoms, 218,792 samples), Alzheimer’s disease (AD, 63,926 samples), vascular dementia (212,389 …samples), frontotemporal dementia (3,024 samples), dementia with Lewy bodies (DLB, 6,618 samples), and dementia in Parkinson’s disease (216,895 samples), were collected from large GWAS. The primary method is inverse variance weighting, with additional sensitivity analyses conducted to ensure the robustness of the findings. Results: The molecules released into CSF, namely APOE2 for any dementia, APOE2 and Siglec-3 for AD, APOE2 for vascular dementia, and APOE2 for DLB, might be potential biomarkers. CD33 for AD and SNCA for DLB in plasma could be promising biomarkers. Conclusions: This is the first study to integrate plasma and CSF proteins to identify potential biomarkers for different dementias. Show more

Keywords: Alzheimer’s disease, association, biomarkers, cerebrospinal fluid, dementia, plasma, proteins

DOI: 10.3233/JAD-240260

Citation: Journal of Alzheimer's Disease, vol. 100, no. 2, pp. 603-611, 2024

Authors: Desai, Shivum | Chen, Ivy Y. | Hom, Christy | Doran, Eric | Nguyen, Dana D. | Benca, Ruth M. | Lott, Ira T. | Mander, Bryce A.

Article Type: Research Article

Abstract: Background: While obstructive sleep apnea (OSA) and insomnia symptoms in neurotypical populations are associated with Alzheimer’s disease (AD), their association with dementia in adults with Down syndrome (DS) remains less clear, even though these symptoms are prevalent and treatable in DS. Understanding their associations with AD-related dementia status, cognitive impairment, and functional deterioration may lead to interventions to slow decline or disease progression in adults with DS. Objective: To characterize differences in OSA and insomnia symptom expression by dementia status, and to determine which sleep factors support dementia diagnosis. Methods: Multimodal consensus conference was used to …determine dementia status in 52 adults with DS (52.2 ± 6.4 years, 21 women). Cognitive impairment, adaptive behavior skills, and symptoms of OSA and insomnia were quantified using validated assessments for adults with DS and their primary informants. Results: A sex by dementia status interaction demonstrated that older women with DS and dementia had more severe terminal insomnia but not OSA symptoms relative to older women with DS who were cognitively stable (CS). Greater insomnia symptom severity was associated with greater functional impairments in social and self-care domains adjusting for age, sex, premorbid intellectual impairment, and dementia status. Conclusions: Insomnia symptoms are more severe in women with DS with dementia than in women with DS and no dementia, and regardless of dementia status or sex, more severe insomnia symptoms are associated with greater impairment in activities of daily living. These findings underscore the potential importance of early insomnia symptom evaluation and treatment in women with DS at risk of developing AD. Show more

Keywords: Activities of daily living, Alzheimer’s disease, dementia, disorders of excessive somnolence, Down syndrome, sleep, sleep apnea syndromes, sleep initiation and maintenance disorders

DOI: 10.3233/JAD-220750

Citation: Journal of Alzheimer's Disease, vol. 100, no. 2, pp. 613-629, 2024

Authors: Kaur, Daman Preet | Bucholc, Magda | Finn, David P. | Todd, Stephen | Wong-Lin, Kong Fatt | McClean, Paula L.

Article Type: Research Article

Abstract: Background: The Clinical Dementia Rating Scale Sum of Boxes (CDRSOB) score is known to be highly indicative of cognitive-functional status and is regularly employed for clinical and research purposes. Objective: Our aim is to determine whether CDRSOB is consistent with clinical diagnosis in evaluating drug class associations with risk of progression to mild cognitive impairment (MCI) and dementia. Methods: We employed weighted Cox regression analysis on longitudinal NACC data, to identify drug classes associated with disease progression risk, using clinical diagnosis and CDRSOB as the outcome. Results: Aspirin (antiplatelet/NSAID), angiotensin II inhibitors (antihypertensive), and …Parkinson’s disease medications were significantly associated with reduced risk of progression to MCI/dementia and Alzheimer’s disease medications were associated with increased MCI-to-Dementia progression risk with both clinical diagnosis and CDRSOB as the outcome. However, certain drug classes/subcategories, like anxiolytics, antiadrenergics, calcium (Ca2+ ) channel blockers, and diuretics (antihypertensives) were associated with reduced risk of disease progression, and SSRIs (antidepressant) were associated with increased progression risk only with CDRSOB. Additionally, metformin (antidiabetic medication) was associated with reduced MCI-to-Dementia progression risk only with clinical diagnosis as the outcome. Conclusions: Although the magnitude and direction of the effect were primarily similar for both diagnostic outcomes, we demonstrate that choice of diagnostic measure can influence the significance of risk/protection attributed to drug classes and consequently the conclusion of findings. A consensus must be reached within the research community with respect to the most accurate diagnostic outcome to identify risk and improve reproducibility. Show more

Keywords: Alzheimer’s disease, anticoagulants, antidepressants, antihypertensives, CDRSOB, dementia, diagnosis, metformin, mild cognitive impairment, risk factors

DOI: 10.3233/JAD-230456

Citation: Journal of Alzheimer's Disease, vol. 100, no. 2, pp. 631-644, 2024

Authors: Mar, Javier | Zubiagirre, Uxue | Larrañaga, Igor | Soto-Gordoa, Myriam | Mar-Barrutia, Lorea | González-Pinto, Ana | Ibarrondo, Oliver

Article Type: Research Article

Abstract: Background: Antipsychotics are widely used in the elderly due to the high prevalence of neuropsychiatric associated with dementia. Objective: To analyze potential disparities in antipsychotic use in the general population of Gipuzkoa by socioeconomic status (SES) and diagnosis of Alzheimer’s disease and related dementia (ADRD) adjusting for somatic and psychiatric comorbidities, age, and sex. Methods: A retrospective observational study was carried out in all the 221,777 individuals over 60 years of age (Gipuzkoa, Spain) to collect diagnosis of ADRD, the Charlson Comorbidity Index, and psychiatric comorbidities considering all primary, outpatient, emergency and inpatient care episodes and …first- and second-generation antipsychotics, and sociodemographic variables, namely, age, sex, SES and living in a nursing home. Logistic regression was used for multivariate statisticalanalysis. Results: Use of any antipsychotic was greater in women, individuals over 80 years old, living in a nursing home, with a diagnosis of dementia, somatic and psychiatric comorbidities, and low SES. Quetiapine was the most used drug. The likelihood of any antipsychotic use was significantly associated with low SES (odds ratio [OR]: 1.60; confidence interval [CI]: 1.52–1.68), age over 80 years (OR: 1.56; CI: 1.47–1.65), institutionalization (OR: 12.61; CI: 11.64–13.65), diagnosis of dementia (OR: 10.18; CI: 9.55–10.85) and the comorbidities of depression (OR: 3.79; CI: 3.58–4.01) and psychosis (OR: 4.96; CI: 4.64–5.30). Conclusions: The greater levels of antipsychotic use and institutionalization in people of low SES indicate inequity in the management of neuropsychiatric symptoms. Increasing the offer of non-pharmacological treatments in the health system might help reduce inequity. Show more

Keywords: Alzheimer’s disease, antipsychotics agents, comorbidity, dementia, disparities, nursing home, quetiapine fumarate, social class

DOI: 10.3233/JAD-240004

Citation: Journal of Alzheimer's Disease, vol. 100, no. 2, pp. 645-655, 2024

Authors: Hu, Yufei | Wang, Xupeng | Zhao, Zijun | Liu, Menglin | Ren, Xiaoqin | Xian, Xiaohui | Liu, Chunxiao | Wang, Qiujun

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the most common sort of neurodegenerative dementia, characterized by its challenging, diverse, and progressive nature. Despite significant progress in neuroscience, the current treatment strategies remain suboptimal. Objective: Identifying a more accurate molecular target for the involvement of microglia in the pathogenic process of AD and exploring potential mechanisms via which it could influence disease. Methods: We utilized single-cell RNA sequencing (scRNA-seq) analysis in conjunction with APP/PS1 mouse models to find out the molecular mechanism of AD. With the goal of investigating the cellular heterogeneity of AD, we downloaded the scRNA-seq data …from the Gene Expression Omnibus (GEO) database and identified differentially expressed genes (DEGs). Additionally, we evaluated learning and memory capacity using the behavioral experiment. We also examined the expression of proteins associated with memory using western blotting. Immunofluorescence was employed to investigate alterations in amyloid plaques and microglia. Results: Our findings revealed an upregulation of ITGAX expression in APP/PS1 transgenic mice, which coincided with a downregulation of synaptic plasticity-related proteins, an increase in amyloid-β (Aβ) plaques, and an elevation in the number of M1 microglia. Interestingly, deletion of ITGAX resulted in increased Aβ plaque deposition, a rise in the M1 microglial phenotype, and decreased production of synaptic plasticity-related proteins, all of which contributed to a decline in learning and memory. Conclusions: This research suggested that ITGAX may have a beneficial impact on the APP/PS1 mice model, as its decreased expression could exacerbate the impairment of synaptic plasticity and worsen cognitive dysfunction. Show more

Keywords: Alzheimer’s disease, M1 microglia, neurodegeneration, scRNA-seq

DOI: 10.3233/JAD-240118

Citation: Journal of Alzheimer's Disease, vol. 100, no. 2, pp. 657-673, 2024