Journal of Alzheimer's Disease - Volume 98, issue 4

Authors: Li, Yaqi | Xu, Xinming | Wang, Peilu | Chen, Xiqun | Yang, Qishan | Sun, Liang | Gao, Xiang

Article Type: Research Article

Abstract: Background: The literature presents conflicting results regarding the potential protective effect of prevalent cancer on the development of dementia and Alzheimer’s disease (AD). Objective: Association between cancer and subsequent risk of dementia and/or AD was reported previously, but survival bias has been of concern. Here, we aimed to calculate the lifetime risk of dementia and AD and evaluate the association of cancer history with these two conditions. Methods: In this retrospective analysis, we included 292,654 participants aged 60+ y during the follow-up and free of dementia at baseline, within the UK Biobank cohort. Lifetime risks of dementia …and AD were estimated in individuals with and without cancer history, and different durations of cancer exposure and cancer types. Results: During a median of 12.5 follow-up years, 5,044 new dementia and 2,141 AD cases were reported. Lifetime risks of dementia and AD were lower in cancer survivors compared to those without cancer, and this effect was more pronounced in participants with cancer history exposure≥5 years. Similar relationship was observed in individual cancer types, except for breast cancer. Conclusions: Results suggested an inverse association between cancer history and lifetime risk of dementia and AD, which may be modified by different cancer types and cancer exposure time. Show more

Keywords: Alzheimer’s disease, cancer, dementia, lifetime risk

DOI: 10.3233/JAD-231223

Citation: Journal of Alzheimer's Disease, vol. 98, no. 4, pp. 1319-1328, 2024

Authors: Vijayan, Murali | Reddy, P. Hemachandra

Article Type: Research Article

Abstract: Background: The intricate and complex molecular mechanisms that underlie the progression of Alzheimer’s disease (AD) have prompted a concerted and vigorous research endeavor aimed at uncovering potential avenues for therapeutic intervention. Objective: This study aims to elucidate the role of miRNA PC-5P-12969 in the pathogenesis of AD. Methods: We assessed the differential expression of miRNA PC-5P-12969 in postmortem AD brains, AD animal and cell models using real-time reverse-transcriptase RT-PCR, we also checked the gene and protein expression of GSK3α and APP. Results: Our investigation revealed a notable upregulation of miRNA PC-5P-12969 in postmortem …brains of AD patients, in transgenic mouse models of AD, and in mutant APP overexpressing-HT22 cells. Additionally, our findings indicate that overexpression of miRNA PC-5P-12969 exerts a protective effect on cell survival, while concurrently mitigating apoptotic cell death. Further-more, we established a robust and specific interaction between miRNA PC-5P-12969 and GSK3α . Our luciferase reporter assays provided confirmation of the binding between miRNA PC-5P-12969 and the 3′-UTR of the GSK3α gene. Manipulation of miRNA PC-5P-12969 levels in cellular models of AD yielded noteworthy alterations in the gene and protein expression levels of both GSK3α and APP. Remarkably, the manipulation of miRNA PC-5P-12969 levels yielded significant enhancements in mitochondrial respiration and ATP production, concurrently with a reduction in mitochondrial fragmentation, thus unveiling a potential regulatory role of miRNA PC-5P-12969 in these vital cellular processes. Conclusions: In summary, this study sheds light on the crucial role of miRNA PC-5P-12969 and its direct interaction with GSK3α in the context of AD. Show more

Keywords: Alzheimer’s disease, amyloid-β , AβPP, GSK3α , microRNA, mitochondrial fragmentation, mitochondrial respiration, postmortem brains, therapeutics

DOI: 10.3233/JAD-231281

Citation: Journal of Alzheimer's Disease, vol. 98, no. 4, pp. 1329-1348, 2024

Authors: Acquarone, Erica | Argyrousi, Elentina K. | Arancio, Ottavio | Watterson, D. Martin | Roy, Saktimayee M.

Article Type: Research Article

Abstract: BACKGROUND: Background: Neurodegenerative diseases manifest behavioral dysfunction with disease progression. Intervention with neuropsychiatric drugs is part of most multi-drug treatment paradigms. However, only a fraction of patients responds to the treatments and those responding must deal with drug-drug interactions and tolerance issues generally attributed to off-target activities. Recent efforts have focused on the identification of underexplored targets and exploration of improved outcomes by treatment with selective molecular probes. Objective: As part of ongoing efforts to identify and validate additional targets amenable to therapeutic intervention, we examined levels of the serotonin 5-HT2b receptor (5-HT2bR) in Alzheimer’s disease (AD) …brains and the potential of a selective 5-HT2bR antagonist to counteract synaptic plasticity and memory damage induced by AD-related proteins, amyloid-β, and tau. Methods: This work used a combination of biochemical, chemical biology, electrophysiological, and behavioral techniques. Biochemical methods included analysis of protein levels. Chemical biology methods included the use of an in vivo molecular probe MW071, a selective antagonist for the 5HT2bR. Electrophysiological methods included assessment of long-term potentiation (LTP), a type of synaptic plasticity thought to underlie memory formation. Behavioral studies investigated spatial memory and associative memory. Results: 5HT2bR levels are increased in brain specimens of AD patients compared to controls. 5HT2bR antagonist treatment rescued amyloid-β and tau oligomer-induced impairment of synaptic plasticity and memory. Conclusions: The increased levels of 5HT-2bR in AD patient brains and the attenuation of disease-related synaptic and behavioral dysfunctions by MW071 treatment suggest that the 5HT-2bR is a molecular target worth pursuing as a potential therapeutic target. Show more

Keywords: Alzheimer’s disease, antagonist, 5HT2b receptor, long-term potentiation, memory

DOI: 10.3233/JAD-240063

Citation: Journal of Alzheimer's Disease, vol. 98, no. 4, pp. 1349-1360, 2024

Authors: Dauar, Marina Tedeschi | Picard, Cynthia | Labonté, Anne | Breitner, John | Rosa-Neto, Pedro | Villeneuve, Sylvia | Poirier, Judes

Article Type: Research Article

Abstract: Background: Apolipoproteins and contactin 5 are proteins associated with Alzheimer’s disease (AD) pathophysiology. Apolipoproteins act on transport and clearance of cholesterol and phospholipids during synaptic turnover and terminal proliferation. Contactin 5 is a neuronal membrane protein involved in key processes of neurodevelopment. Objective: To investigate the interactions between contactin 5 and apolipoproteins in AD, and the role of these proteins in response to neuronal damage. Methods: Apolipoproteins (measured by Luminex), contactin 5 (measured by Olink’s proximity extension assay), and cholesterol (measured by liquid chromatography mass spectrometry) were assessed in the cerebrospinal fluid (CSF) and plasma of …cognitively unimpaired participants (n  = 93). Gene expression was measured using polymerase chain reaction in the frontal cortex of autopsied-confirmed AD (n  = 57) and control subjects (n  = 31) and in the hippocampi of mice following entorhinal cortex lesions. Results: Contactin 5 positively correlated with apolipoproteins B (p  = 5.4×10–8 ), D (p  = 1.86×10–4 ), E (p  = 2.92×10–9 ), J (p  = 2.65×10–9 ), and with cholesterol (p  = 0.0096) in the CSF, and with cholesterol (p  = 0.02), HDL (p  = 0.0143), and LDL (p  = 0.0121) in the plasma. Negative correlations were seen between CNTN5 , APOB (p  = 0.034) and APOE (p  = 0.015) mRNA levels in the brains of control subjects. In the mouse model, apoe and apoj gene expression increased during the reinnervation phase (p  <  0.05), while apob (p  = 0.023) and apod (p  = 0.006) increased in the deafferentation stage. Conclusions: Extensive interactions were observed between contactin 5 and apolipoproteins and cholesterol, possibly due to neuronal damage. The alterations in gene expression of apolipoproteins suggest a role in axonal, terminal, and synaptic remodeling in response to entorhinal cortex damage. Show more

Keywords: Alzheimer’s disease, apolipoprotein B, apolipoprotein D, apolipoprotein E, apolipoprotein J, apolipoproteins, CNTN5 , contactin 5, contactins, gene expression

DOI: 10.3233/JAD-231003

Citation: Journal of Alzheimer's Disease, vol. 98, no. 4, pp. 1361-1375, 2024

Authors: Mao, Jiesheng | Hu, Haoxiang | Zhao, Yunhan | Zhou, Mi | Yang, Xiaokai

Article Type: Research Article

Abstract: Background: Antioxidant diets are considered to be protective factors for cognitive function. However, comprehensive measures of antioxidant diets are lacking. Objective: To examine the association between the Composite Dietary Antioxidant Index (CDAI) and cognitive function in the elderly. Methods: This cross-sectional study included a total of 2,456 participants (≥60 years old) from NHANES 2011–2014. Calculation of CDAI based on 6 minerals and vitamins (manganese, selenium, zinc, vitamins A, C, and E). Cognitive function was measured by the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) Word Learning sub-test, Animal Fluency Test (AFT), and Digit Symbol …Substitution Test (DSST). We also created a composite cognitive z-score to represent global cognition. The statistical analyses we used included multiple linear regression analyses, subgroup analyses, curve-fitting analyses, and threshold effects analyses. Results: After controlling for demographic characteristics, lifestyle factors, and disease history, multivariate linear regression analyses showed that increased CDAI was positively associated with scores on global cognitive function and each cognitive domain (p  < 0.05), with subgroup analyses suggesting that this association was more pronounced in stroke patients (p for interaction < 0.05). Curve-fitting analyses and threshold effect analyses showed saturation effects between CDAI and CREAD Test, AFT, and composite Z-score, and an inverted U-shaped relationship with DSST, with inflection points of –1.89, 0.79, 1.13, and 1.77, respectively. Conclusions: Our findings support that higher levels of CDAI are correlated with significantly elevated cognitive function. Maintaining CDAI in an appropriate range may contribute to cognitive health in elderly. Show more

Keywords: Alzheimer’s disease, cognitive function, composite dietary antioxidant index, cross-sectional study, NHANES

DOI: 10.3233/JAD-231189

Citation: Journal of Alzheimer's Disease, vol. 98, no. 4, pp. 1377-1389, 2024

Authors: Mattsson, Patrik | Cselényi, Zsolt | Forsberg Morén, Anton | Freund-Levi, Yvonne | Wahlund, Lars-Olof | Halldin, Christer | Farde, Lars

Article Type: Research Article

Abstract: Background: Deposits of amyloid-β (Aβ) appear early in Alzheimer’s disease (AD). Objective: The aim of the present study was to compare the presence of cortical and subcortical Aβ in early AD using positron emission tomography (PET). Methods: Eight cognitively unimpaired (CU) subjects, 8 with mild cognitive impairment (MCI) and 8 with mild AD were examined with PET and [11 C]AZD2184. A data driven cut-point for Aβ positivity was defined by Gaussian mixture model of isocortex binding potential (BP ND ) values. Results: Sixteen subjects (3 CU, 5 MCI and 8 AD) were Aβ-positive. BP …ND was lower in subcortical and allocortical regions compared to isocortex. Fifteen of the 16 Aβ-positive subjects displayed Aβ binding in striatum, 14 in thalamus and 10 in allocortical regions. Conclusions: Aβ deposits appear to be widespread in early AD. It cannot be excluded that deposits appear simultaneously throughout the whole brain which has implications for improved diagnostics and disease monitoring. Show more

Keywords: Alzheimer’s disease, amygdala, amyloid deposits, entorhinal cortex, hippocampus, positron emission tomography, striatum, thalamus

DOI: 10.3233/JAD-231013

Citation: Journal of Alzheimer's Disease, vol. 98, no. 4, pp. 1391-1401, 2024

Authors: Mattke, Soeren | Jun, Hankyung | Chu, Samantha | Hanson, Mark

Article Type: Research Article

Abstract: Background: Individuals dually eligible for Medicare and Medicaid (duals) may face greater obstacles to access to disease-modifying Alzheimer’s treatments in spite of their higher disease burden, because of clinicians’ reluctance to accept Medicaid and the so-called “lesser of” policy, under which Medicaid may pay providers lower rates. Objective: To project differential wait times for duals compared to Medicare-only beneficiaries by state. Methods: We used State Medicaid payment policy and Medicare enrollment data and a Markov model to predict differential wait times for duals and non-duals from 2023 to 2050. We estimated available diagnostic appointments by state …for both groups based on reluctance of clinicians to accept Medicaid and the “lesser of” policy for each year. Results: We estimate overall average wait times of almost two years (22.9 months) but almost three times as long for duals (59.8 months) than non-duals (20.7 months) because of higher disease burden. The effects of Medicaid payment policy would increase average wait times for duals to 89 months with 20 states having wait times of 99 months or more, which would effectively deprive duals of access. Conclusions: The added average wait times in many states would effectively deprive duals from access to treatment and translate into avoidable disease progression and mortality. Policy interventions to reduce financial and nonfinancial obstacles are dearly needed to avoid deepening disparities. Examples are coverage arrangements that integrate Medicare and Medicaid coverage, covering the co-payment for physician services in full, and stricter network adequacy requirements for Medicaid Managed Care plans. Show more

Keywords: Access to care, Alzheimer’s disease, diagnosis, disease-modifying treatment, disparities, dual eligibility, medicare, medicaid, payment policy, wait times

DOI: 10.3233/JAD-231134

Citation: Journal of Alzheimer's Disease, vol. 98, no. 4, pp. 1403-1414, 2024

Authors: Chen, Yanxi | Su, Yi | Wu, Jianfeng | Chen, Kewei | Atri, Alireza | Caselli, Richard J. | Reiman, Eric M. | Wang, Yalin

Article Type: Research Article

Abstract: Background: Amyloid-β (Aβ) plaques play a pivotal role in Alzheimer’s disease. The current positron emission tomography (PET) is expensive and limited in availability. In contrast, blood-based biomarkers (BBBMs) show potential for characterizing Aβ plaques more affordably. We have previously proposed an MRI-based hippocampal morphometry measure to be an indicator of Aβ plaques. Objective: To develop and validate an integrated model to predict brain amyloid PET positivity combining MRI feature and plasma Aβ42/40 ratio. Methods: We extracted hippocampal multivariate morphometry statistics from MR images and together with plasma Aβ42/40 trained a random …forest classifier to perform a binary classification of participant brain amyloid PET positivity. We evaluated the model performance using two distinct cohorts, one from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the other from the Banner Alzheimer’s Institute (BAI), including prediction accuracy, precision, recall rate, F1 score, and AUC score. Results: Results from ADNI (mean age 72.6, Aβ+ rate 49.5%) and BAI (mean age 66.2, Aβ+ rate 36.9%) datasets revealed the integrated multimodal (IMM) model’s superior performance over unimodal models. The IMM model achieved prediction accuracies of 0.86 in ADNI and 0.92 in BAI, surpassing unimodal models based solely on structural MRI (0.81 and 0.87) or plasma Aβ42/40 (0.73 and 0.81) predictors. CONCLUSIONS: Our IMM model, combining MRI and BBBM data, offers a highly accurate approach to predict brain amyloid PET positivity. This innovative multiplex biomarker strategy presents an accessible and cost-effective avenue for advancing Alzheimer’s disease diagnostics, leveraging diverse pathologic features related to Aβ plaques and structural MRI. Show more

Keywords: Aβ positivity, amyloid PET, blood-based biomarkers, image features, MRI

DOI: 10.3233/JAD-231162

Citation: Journal of Alzheimer's Disease, vol. 98, no. 4, pp. 1415-1426, 2024

Authors: Mueller, Susanne G.

Article Type: Research Article

Abstract: Background: Traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) are potential risk factors for the development of dementia including Alzheimer’s disease (AD) in later life. The findings of studies investigating this question are inconsistent though. Objective: To investigate if these inconsistencies are caused by the existence of subgroups with different vulnerability for AD pathology and if these subgroups are characterized by atypical tau load/atrophy pattern. Methods: The MRI and PET data of 89 subjects with or without previous TBI and/or PTSD from the DoD ADNI database were used to calculate an age-corrected …gray matter tau mismatch metric (ageN-T mismatch-score and matrix) for each subject. This metric provides a measure to what degree regional tau accumulation drives regional gray matter atrophy (matrix) and can be used to calculate a summary score (score) reflecting the severity of AD pathology in an individual. Results: The ageN-T mismatch summary score was positively correlated with whole brain beta-amyloid load and general cognitive function but not with PTSD or TBI severity. Hierarchical cluster analysis identified five different spatial patterns of tau-gray matter interactions. These clusters reflected the different stages of the typical AD tau progression pattern. None was exclusively associated with PTSD and/or TBI. Conclusions: These findings suggest that a) although subsets of patients with PTSD and/or TBI develop AD-pathology, a history of TBI or PTSD alone or both is not associated with a significantly higher risk to develop AD pathology in later life. b) remote TBI or PTSD do not modify the typical AD pathology distribution pattern. Show more

Keywords: Alzheimer’s disease, MRI, PET, posttraumatic stress disorder, risk factor, traumatic brain injury

DOI: 10.3233/JAD-231183

Citation: Journal of Alzheimer's Disease, vol. 98, no. 4, pp. 1427-1441, 2024

Authors: Buchholz, Maresa | Zöllinger, Isabel | Thyrian, Jochen René | Luppa, Melanie | Zülke, Andrea | Döhring, Juliane | Lunden, Laura | Sanftenberg, Linda | Brettschneider, Christian | Czock, David | Frese, Thomas | Gensichen, Jochen | Hoffmann, Wolfgang | Kaduszkiewicz, Hanna | König, Hans-Helmut | Wiese, Birgitt | Riedel-Heller, Steffi G. | Blotenberg, Iris

Article Type: Research Article

Abstract: Background: Studies demonstrate associations between low social activity in older adults and cognitive decline. Little has been investigated regarding which factors are associated with low social activity in older adults at increased risk of dementia. Objective: We investigate which sociodemographic, psychological, health-related, and environmental factors are associated with low social activity in older adults at increased risk of dementia. Additionally, we describe the stages of health behavior change, the types of social activities, and the duration of the current level of social activity. Methods: We used baseline data of 1,015 participants from the …AgeWell.de trial. We conducted logistic and Poisson regression analyses to investigate factors associated with low social activity. We report descriptive statistics on the stages of change in the sample, the types of social activities most frequently pursued, and the duration of the current level of social activity. Results: Lower income, non-usage of public transport, depressive symptoms, cognitive, mobility, and hearing impairment were negatively associated with social activity. The majority of the sample was in the maintenance stage, followed by the precontemplation stage. The most common social activities were traveling and hobbies with others. Participants have maintained their current level of social activity for several years. Conclusions: We identified a lack of resources (income, transport), depressive symptoms and poorer health (cognitive, mobility and hearing impairment) as barriers to social activity. Interventions promoting social activity in older adults at risk of dementia may specifically target individuals with these risk factors. Low-threshold opportunities for social activity may be particularly beneficial. Show more

Keywords: Alzheimer’s disease, dementia, lifestyle, older adults, prevention, risk factors, social engagement, social health, social participation, transtheoretical model

DOI: 10.3233/JAD-231226

Citation: Journal of Alzheimer's Disease, vol. 98, no. 4, pp. 1443-1455, 2024

Authors: Robinson, Andrew C. | Bin Rizwan, Tawfique | Davidson, Yvonne S. | Minshull, James | Tinkler, Phillip | Payton, Antony | Mann, David M.A. | Roncaroli, Federico

Article Type: Research Article

Abstract: Background: While mid-life hypertension represents a risk factor for the development of Alzheimer’s disease (AD), the risk after the age of 65 is less certain. Establishing relationships between late life hypertension and the pathological changes of AD could be crucial in understanding the relevance of blood pressure as a risk factor for this disorder. Objective: We investigated associations between self-reported late-life hypertension, cognitive status and AD pathology at death. The impact of antihypertensive medication was also examined. Methods: Using the Cornell Medical Index questionnaire, we ascertained whether participants had ever reported hypertension. We also noted use …of antihypertensive medication. The donated brains of 108 individuals were assessed for AD pathology using consensus guidelines. Statistical analysis aimed to elucidate relationships between hypertension and AD pathology. Results: We found no associations between self-reported hypertension and cognitive impairment at death. However, those with hypertension were significantly more likely to exhibit lower levels of AD pathology as measured by Thal phase, Braak stage, CERAD score, and NIA-AA criteria—even after controlling for sex, level of education and presence of APOE ɛ 4 allele(s). No significant associations could be found when examining use of antihypertensive medications. Conclusions: Our findings suggest that late-life hypertension is associated with less severe AD pathology. We postulate that AD pathology may be promoted by reduced cerebral blood flow. Show more

Keywords: Alzheimer’s disease, dementia, hypertension, neuropathology

DOI: 10.3233/JAD-231429

Citation: Journal of Alzheimer's Disease, vol. 98, no. 4, pp. 1457-1466, 2024

Authors: Hojjati, Seyed Hani | Chiang, Gloria C. | Butler, Tracy A. | de Leon, Mony | Gupta, Ajay | Li, Yi | Sabuncu, Mert R. | Feiz, Farnia | Nayak, Siddharth | Shteingart, Jacob | Ozoria, Sindy | Gholipour Picha, Saman | Stern, Yaakov | Luchsinger, José A. | Devanand, Davangere P. | Razlighi, Qolamreza R.

Article Type: Research Article

Abstract: Background: Histopathologic studies of Alzheimer’s disease (AD) suggest that extracellular amyloid-β (Aβ) plaques promote the spread of neurofibrillary tau tangles. However, these two proteinopathies initiate in spatially distinct brain regions, so how they interact during AD progression is unclear. Objective: In this study, we utilized Aβ and tau positron emission tomography (PET) scans from 572 older subjects (476 healthy controls (HC), 14 with mild cognitive impairment (MCI), 82 with mild AD), at varying stages of the disease, to investigate to what degree tau is associated with cortical Aβ deposition. Methods: Using multiple linear …regression models and a pseudo-longitudinal ordering technique, we investigated remote tau-Aβ associations in four pathologic phases of AD progression based on tau spread: 1) no-tau, 2) pre-acceleration, 3) acceleration, and 4) post-acceleration. Results: No significant tau-Aβ association was detected in the no-tau phase. In the pre-acceleration phase, the earliest stage of tau deposition, associations emerged between regional tau in medial temporal lobe (MTL) (i.e., entorhinal cortex, parahippocampal gyrus) and cortical Aβ in lateral temporal lobe regions. The strongest tau-Aβ associations were found in the acceleration phase, in which tau in MTL regions was strongly associated with cortical Aβ (i.e., temporal and frontal lobes regions). Strikingly, in the post-acceleration phase, including 96% of symptomatic subjects, tau-Aβ associations were no longer significant. Conclusions: The results indicate that associations between tau and Aβ are stage-dependent, which could have important implications for understanding the interplay between these two proteinopathies during the progressive stages of AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, PET, remote association, tau

DOI: 10.3233/JAD-231362

Citation: Journal of Alzheimer's Disease, vol. 98, no. 4, pp. 1467-1482, 2024

Authors: Galankin, Timofey L. | Bespalov, Anton Y. | Moebius, Hans Y.

Article Type: Research Article

Abstract: Background: The term Behavioral and Psychological Symptoms of Dementia (BPSD) covers a group of phenomenologically and medically distinct symptoms that rarely occur in isolation. Their therapy represents a major unmet medical need across dementias of different types, including Alzheimer’s disease. Understanding of the symptom occurrence and their clusterization can inform clinical drug development and use of existing and future BPSD treatments. Objective: The primary aim of the present study was to investigate the ability of a commonly used principal component analysis to identify BPSD patterns as assessed by Neuropsychiatric Inventory (NPI). Methods: NPI scores from the …Aging, Demographics, and Memory Study (ADAMS) were used to characterize reported occurrence of individual symptoms and their combinations. Based on this information, we have designed and conducted a simulation experiment to compare Principal Component analysis (PCA) and zero-inflated PCA (ZI PCA) by their ability to reveal true symptom associations. Results: Exploratory analysis of the ADAMS database revealed overlapping multivariate distributions of NPI symptom scores. Simulation experiments have indicated that PCA and ZI PCA cannot handle data with multiple overlapping patterns. Although the principal component analysis approach is commonly applied to NPI scores, it is at risk to reveal BPSD clusters that are a statistical phenomenon rather than symptom associations occurring in clinical practice. Conclusions: We recommend the thorough characterization of multivariate distributions before subjecting any dataset to Principal Component Analysis. Show more

Keywords: Alzheimer’s disease, dementia, neurobehavioral signs and symptoms, Neuropsychiatric inventory, principal component analysis

DOI: 10.3233/JAD-231008

Citation: Journal of Alzheimer's Disease, vol. 98, no. 4, pp. 1483-1491, 2024

Authors: Wen, Jiaqi | Hao, Xiwa | Jia, Yanhong | Wang, Baojun | Pang, Jiangxia | Liang, Furu

Article Type: Research Article

Abstract: Background: Lipids have a significant impact on the development and functioning of the nervous system, but the sex differences between the association of LDL/HDL, which reflects lipid metabolic status, and cognitive impairment remains unclear. Objective: We aimed to determine if there were sex differences between the association of LDL/HDL and cognitive function in US older adults. Methods: This population-based cross-sectional study used data from the National Health and Nutrition Examination Survey (NHANES) 2011–2012 and 2013–2014 cycles. The main outcome was poor cognitive performance defined by the Digit Symbol Substitution Test (DSST) <  34 based …on published literature. Results: A total of 1,225 participants were included in the study, with a cognitive impairment incidence of 25.6% (314/1,225). Multivariate regression models demonstrated a significant association between cognitive decline and each 1-unit increase in LDL/HDL, after adjusting for all covariates (adjusted odds ratio [OR] = 1.36, 95% confidence interval [CI]: 1.11–1.67). Furthermore, subgroup analysis revealed an interaction between LDL/HDL and cognitive impairment in sex subgroups. Conclusions: LDL/HDL was associated with cognitive impairment in the US older adult population in adjusted models, although the significance of this association was not observed in females. Show more

Keywords: Alzheimer’s disease, cognition, LDL/HDL cholesterol ratio, National Health and Nutrition Examination Survey (NHANES), older adults, sex differences

DOI: 10.3233/JAD-231195

Citation: Journal of Alzheimer's Disease, vol. 98, no. 4, pp. 1493-1502, 2024

Authors: Janbek, Janet | Laursen, Thomas Munk | Frimodt-Møller, Niels | Magyari, Melinda | Haas, Jürgen G. | Lathe, Richard | Waldemar, Gunhild

Article Type: Research Article

Abstract: Background: Population-based studies have shown an increased risk of dementia after infections, but weaker links were reported for autoimmune diseases. Evidence is scarce for whether the links may be modified by the dementia or exposure subtype. Objective: We aimed to investigate the association between infections and/or autoimmune diseases and rates of major types of dementias in the short- and long terms. Methods: Nationwide nested case-control study of dementia cases (65+ years) diagnosed in Denmark 2016–2020 and dementia-free controls. Exposures were hospital-diagnosed infections and autoimmune diseases in the preceding 35 years. Two groups of dementia cases were …those diagnosed in memory clinics (MC) and those diagnosed outside memory clinics (non-memory clinic cases, NMC). Results: In total, 26,738 individuals were MC and 12,534 were NMC cases. Following any infection, the incidence rate ratio (IRR) for MC cases was 1.23 (95% CI 1.20–1.27) and 1.70 for NMC cases (1.62–1.76). Long-term increased rates were seen for vascular dementia and NMC cases. IRRs for autoimmune diseases were overall statistically insignificant. Conclusions: Cases with vascular dementia and not Alzheimer’s disease, and a subgroup of cases identified with poorer health have increased long-term risk following infections. Autoimmune diseases were not associated with any type of dementia. Notably increased risks (attributed to the short term) and for NMC cases may indicate that immunosenescence rather than de novo infection explains the links. Future focus on such groups and on the role of vascular pathology will explain the infection-dementia links, especially in the long term. Show more

Keywords: Alzheimer’s disease, autoimmune disease, epidemiology, immunosenescence, infection, population-based, reverse causality, vascular dementia

DOI: 10.3233/JAD-231349

Citation: Journal of Alzheimer's Disease, vol. 98, no. 4, pp. 1503-1514, 2024

Authors: Moreno-Rodriguez, Marta | Perez, Sylvia E. | Martinez-Gardeazabal, Jonatan | Manuel, Ivan | Malek-Ahmadi, Michael | Rodriguez-Puertas, Rafael | Mufson, Elliott J.

Article Type: Research Article

Abstract: Background: Although sporadic Alzheimer’s disease (AD) is a neurodegenerative disorder of unknown etiology, familial AD is associated with specific gene mutations. A commonality between these forms of AD is that both display multiple pathogenic events including cholinergic and lipid dysregulation. Objective: We aimed to identify the relevant lipids and the activity of their related receptors in the frontal cortex and correlating them with cognition during the progression of AD. Methods: MALDI-mass spectrometry imaging (MSI) and functional autoradiography was used to evaluate the distribution of phospholipids/sphingolipids and the activity of cannabinoid 1 (CB1 ), sphingosine 1-phosphate 1 …(S1P1 ), and muscarinic M2 /M4 receptors in the frontal cortex (FC) of people that come to autopsy with premortem clinical diagnosis of AD, mild cognitive impairment (MCI), and no cognitive impairment (NCI). Results: MALDI-MSI revealed an increase in myelin-related lipids, such as diacylglycerol (DG) 36:1, DG 38:5, and phosphatidic acid (PA) 40:6 in the white matter (WM) in MCI compared to NCI, and a downregulation of WM phosphatidylinositol (PI) 38:4 and PI 38:5 levels in AD compared to NCI. Elevated levels of phosphatidylcholine (PC) 32:1, PC 34:0, and sphingomyelin 38:1 were observed in discrete lipid accumulations in the FC supragranular layers during disease progression. Muscarinic M2 /M4 receptor activation in layers V-VI decreased in AD compared to MCI. CB1 receptor activity was upregulated in layers V-VI, while S1P1 was downregulated within WM in AD relative to NCI. Conclusions: FC WM lipidomic alterations are associated with myelin dyshomeostasis in prodromal AD, suggesting WM lipid maintenance as a potential therapeutic target for dementia. Show more

Keywords: Alzheimer’s disease, autoradiography, cholinergic, lipidomic, MALDI-MSI, mild cognitive impairment, muscarinic receptor

DOI: 10.3233/JAD-231485

Citation: Journal of Alzheimer's Disease, vol. 98, no. 4, pp. 1515-1532, 2024

Authors: Costa, Cinzia | Nardi Cesarini, Elena | Eusebi, Paolo | Franchini, David | Casucci, Paola | De Giorgi, Marcello F. | Calvello, Carmen | Paolini Paoletti, Federico | Romoli, Michele | Parnetti, Lucilla

Article Type: Research Article

Abstract: Background: Dementia is prevalent among the elderly, also representing a risk for seizures/epilepsy. Estimations of epilepsy risk in dementia patients are not widely available. Objective: Our research aims to ascertain the incidence of epilepsy and its associated risk factors in subjects with dementia in the Umbria region, based on data from healthcare databases. Methods: In this retrospective study based on the healthcare administrative database of Umbria, we identified all patients diagnosed with dementia from 2013 to 2017, based on ICD-9-CM codes. For epilepsy ascertainment, we used a validated algorithm that required an EEG …and the prescription of one or more anti-seizure medications post-dementia diagnosis. A case-control analysis was conducted, matching five non-dementia subjects by gender and age to each dementia patient. Cox proportional hazards models were then utilized in the analysis. Results: We identified 7,314 dementia cases, also including 35,280 age- and sex-matched control subjects. Out of patients with dementia, 148 individuals (2.02%) were diagnosed with epilepsy. We observed a progressive increase in the cumulative incidence of seizures over time, registering 1.45% in the first year following the diagnosis, and rising to 1.96% after three years. Analysis using Cox regression revealed a significant association between the development of epilepsy and dementia (HR = 4.58, 95% CI = 3.67–5.72). Additional risk factors were male gender (HR = 1.35, 95% CI = 1.07–1.69) and a younger age at dementia onset (HR = 1.03, 95% CI=1.02-1.04). Conclusions: Dementia increases epilepsy risk, especially with early onset and male gender. Clinicians should have a low threshold to suspect seizures in dementia cases. Show more

Keywords: Administrative databases, Alzheimer’s disease, antiseizure medications, dementia, epilepsy

DOI: 10.3233/JAD-231309

Citation: Journal of Alzheimer's Disease, vol. 98, no. 4, pp. 1533-1542, 2024

Article Type: Correction

DOI: 10.3233/JAD-249007

Citation: Journal of Alzheimer's Disease, vol. 98, no. 4, pp. 1543-1546, 2024