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