Journal of Alzheimer's Disease - Volume 86, issue 4

Authors: Payne, Sarah | Shofer, Jane B. | Shutes-David, Andrew | Li, Ge | Jankowski, Adrienne | Dean, Pamela | Tsuang, Debby

Article Type: Research Article

Abstract: Background: Many patients with dementia with Lewy bodies (DLB) miss out on the best standards of care and psychosocial support due to diagnostic delays or inaccuracies following symptom onset. Objective: This study seeks to identify baseline characteristics in individuals with mild cognitive impairment (MCI) that correlate with eventual conversion to DLB or Alzheimer’s disease (AD). Methods: Baseline neuropsychological and neuropsychiatric data were analyzed in National Alzheimer’s Coordinating Center participants who completed the Uniform Data Set between 2006 and 2020 and subsequently converted from MCI to DLB or AD (n  = 1632). Results: Only 6% of …participants with MCI converted to DLB. Among those who converted to DLB, multidomain amnestic MCI (aMCI) was the most common subtype at study entry. As part of logistic regression analyses, odds ratios (ORs) were estimated for conversion to DLB versus AD based on study-entry characteristics, adjusting for age, sex, education, and years to diagnosis. The strongest predictors of conversion to DLB (p ≤0.0001) were nonamnestic MCI versus aMCI (OR 8.2, CI [5.0, 14]), multidomain MCI versus single-domain MCI (OR 2.7, CI [1.7. 4.2]), male sex (OR 4.2, CI [2.5, 7.1]), and presence of nighttime behaviors (OR 4.4 CI [2.8, 6.9]). Conclusion: A diagnosis of prodromal DLB should be considered in individuals with MCI who present with prominent executive/visuospatial deficits, neuropsychiatric symptoms, and less memory impairment. Early diagnosis of DLB may guide treatment planning, including the avoidance of antipsychotic medications in patients who develop psychotic symptoms, caregiver support, and initiation of early treatment(s) once medications become available. Show more

Keywords: Alzheimer’s disease, amnestic, dementia with Lewy bodies, mild cognitive impairment, multidomain, NACC, nonamnestic, single domain

DOI: 10.3233/JAD-215428

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1643-1654, 2022

Authors: Zhao, Ying | Yang, Yang | Wang, Dongxue | Wang, Jie | Gao, Weiying

Article Type: Research Article

Abstract: Background: Diabetic cognitive dysfunction (DCD) is one of severe diabetic complications and might develop to irreversible dementia. Early diagnosis and detection of DCD is significant for prevention and treatment. Objective: The main objective of this study was to investigate the amino acid profiles of rat with DCD in the cerebrospinal fluid (CSF) to distinguish the early specific biomarkers. Methods: In total, rats were assigned into control and model groups. Model was induced by intraperitoneal injection of streptozotocin. The Morris water maze (MWM) method was used to evaluate learning and memory in rats on the 13th week …after the model established. CSF samples were collected via cisterna magna puncture at the 0th, 5th, 9th, and 13th week, and amino acids profiling of CSF samples were performed via ultra performance liquid chromatography multiple reaction monitoring mass spectrometry (UPLC-MRM-MS). The amino acid profile was processed through multivariate analysis to identify potential biomarkers, and the related metabolic pathways were analyzed by MetaboAnalyst 5.0. Results: Compared to the control group, the escape latency of the MWM was significantly prolonged in model group rats (p  < 0.05). Different amino acid profiles were obtained between two groups. L-Alanine, L-Glutamine, L-Lysine, L-Serine, and L-Threonine were identified as potential biomarkers for DCD. These biomarkers are principally involved in glycine, serine, and threonine metabolism, aminoacyl-tRNA biosynthesis, alanine, aspartate, and glutamate metabolism, and glyoxylate and dicarboxylate metabolism. Conclusion: There are amino acid biomarkers in the CSF of rat with DCD. The mechanism of DCD is related to those pathways, which provide help for the early diagnosis and treatment and mechanism research. Show more

Keywords: Amino acid profiles, cerebrospinal fluid, diabetic cognitive dysfunction, target metabolomics, UPLC-MRM-MS

DOI: 10.3233/JAD-215725

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1655-1665, 2022

Authors: Noel, Margaret A. | Lackey, Elizabeth | Labi, Vanna | Bouldin, Erin D.

Article Type: Research Article

Abstract: Background: Family caregivers of people with dementia often experience negative impacts including stress and burden. Psychoeducational programs can reduce these negative outcomes. Objective: To evaluate whether this virtual caregiver education program changes caregiver confidence, self-efficacy, and burden relative to controls. Methods: This was a pre-post comparison of a five-week, synchronous, virtual caregiver education program delivered by a clinician and caregiver support specialist covering aspects of dementia, including changes in cognition, behavior, functional abilities, caregiver-care recipient roles, communication, and caregiver self-care. Caregivers (n  = 90) were surveyed at baseline, at completion of intervention, and three months thereafter; controls …(n  = 44) were surveyed at two points six weeks apart. We compared validated measures of caregiver confidence, self-efficacy, and burden using generalized estimating equations. Results: Participants’ confidence and self-efficacy increased over follow-up compared with controls (p  < 0.01 for intervention* time in regression models). There was no difference in burden. All participants (100%) reported perceived increased knowledge, 97% perceived increased confidence, and 95% perceived increased ability to manage dementia-related behaviors after the course. Conclusion: This virtual caregiver education program was effective in improving caregiver confidence and self-efficacy and participants’ self-reported impact was equivalent to those who had taken previous courses in person. Caregivers with greater confidence and self-efficacy have been shown to have better health outcomes and decreased stress and depressive symptoms. Health professionals, health care organizations, and public health agencies should consider using efficacious virtual caregiver education programs in rural and other community settings, during public health crises, or in standard practice as an alternative to in-person programs. Show more

Keywords: Alzheimer’s disease, caregiver education, dementia, health education, internet-based intervention, program evaluation, rural population, self-concept, self efficacy

DOI: 10.3233/JAD-215359

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1667-1678, 2022

Authors: Li, Chaolin | Liu, Mianxin | Xia, Jing | Mei, Lang | Yang, Qing | Shi, Feng | Zhang, Han | Shen, Dinggang

Article Type: Research Article

Abstract: Background: The detection of amyloid-β (Aβ) deposition in the brain provides crucial evidence in the clinical diagnosis of Alzheimer’s disease (AD). However, the current positron emission tomography (PET)-based brain Aβ examination suffers from the problems of coarse visual inspection (in many cases, with 2-class stratification) and high scanning cost. Objective: 1) To characterize the non-binary Aβ deposition levels in the AD continuum based on clustering of PET data, and 2) to explore the feasibility of predicting individual Aβ deposition grades with non-invasive functional magnetic resonance imaging (fMRI). Methods: 1) Individual whole-brain Aβ-PET images from the OASIS-3 …dataset (N  = 258) were grouped into three clusters (grades) with t -SNE and k -means. The demographical data as well as global and regional standard uptake value ratios (SUVRs) were compared among the three clusters with Chi-square tests or ANOVA tests. 2) From resting-state fMRI, both conventional functional connectivity (FC) and high-order FC networks were constructed and the topological architectures of the two networks were jointly learned with graph convolutional networks (GCNs) to predict the Aβ-PET grades for each individual. Results: We found three clearly separated clusters, indicating three Aβ-PET grades. There were significant differences in gender, age, cognitive ability, APOE type, as well as global and regional SUVRs among the three grades we found. The prediction of Aβ-PET grades with GCNs on FC for the 258 samples in the AD continuum reached a satisfactory averaged accuracy (78.8%) in the two-class classification tasks. Conclusion: The results demonstrated the feasibility of using deep learning on a non-invasive brain functional imaging technique to approximate PET-based Aβ deposition grading. Show more

Keywords: Amyloid-β, brain network, functional connectivity, graph convolutional neural network, positron emission tomography

DOI: 10.3233/JAD-215497

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1679-1693, 2022

Authors: Zhang, Lingyu | Fu, Yu | Zhao, Ziyang | Cong, Zhaoyang | Zheng, Weihao | Zhang, Qin | Yao, Zhijun | Hu, Bin | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Mild cognitive impairment (MCI), which is generally regarded as the prodromal stage of Alzheimer’s disease (AD), is associated with morphological changes in brain structures, particularly the hippocampus. However, the indicators for characterizing the deformation of hippocampus in conventional methods are not precise enough and ignore the evolution information with the course of disease. Objective: The purpose of this study was to investigate the temporal evolution pattern of MCI and predict the conversion of MCI to AD by using the multivariate morphometry statistics (MMS) as fine features. Methods: First, we extracted MMS features from MRI scans …of 64 MCI converters (MCIc), 81 MCI patients who remained stable (MCIs), and 90 healthy controls (HC). To make full use of the time information, the dynamic MMS (DMMS) features were defined. Then, the areas with significant differences between pairs of the three groups were analyzed using statistical methods and the atrophy/expansion were identified by comparing the metrics. In parallel, patch selection, sparse coding, dictionary learning and maximum pooling were used for the dimensionality reduction and the ensemble classifier GentleBoost was used to classify MCIc and MCIs. Results: The longitudinal analysis revealed that the atrophy of both MCIc and MCIs mainly distributed in dorsal CA1, then spread to subiculum and other regions gradually, while the atrophy area of MCIc was larger and more significant. And the introduction of longitudinal information promoted the accuracy to 91.76% for conversion prediction. Conclusion: The dynamic information of hippocampus holds a huge potential for understanding the pathology of MCI. Show more

Keywords: Alzheimer’s disease, classification, hippocampus, longitudinal study, mild cognitive impairment

DOI: 10.3233/JAD-215568

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1695-1710, 2022

Authors: Khandia, Rekha | Ali Khan, Azmat | Alexiou, Athanasios | Povetkin, Sergey Nikolaevich | Verevkina, Marina Nikolaevna

Article Type: Research Article

Abstract: Background: Bim is a Bcl-2 homology 3 (BH3)-only proteins, a group of pro-apoptotic proteins involved in physiological and pathological conditions. Both the overexpression and under-expression of Bim protein are associated with the diseased condition, and various isoforms of Bim protein are present with differential apoptotic potential. Objective: The present study attempted to envisage the association of various molecular signatures with the codon choices of Bim isoforms. Methods: Molecular signatures like composition, codon usage, nucleotide skews, the free energy of mRNA transcript, physical properties of proteins, codon adaptation index, relative synonymous codon usage, and dinucleotide …odds ratio were determined and analyzed for their associations with codon choices of Bim gene. Results: Skew analysis of the Bim gene indicated the preference of C nucleotide over G, A, and T and preference of G over T and A nucleotides was observed. An increase in C content at the first and third codon position increased gene expression while it decreased at the second codon position. Compositional constraints on nucleotide C at all three codon positions affected gene expression. The analysis revealed an exceptionally high usage of CpC dinucleotide in all the envisaged 31 isoforms of Bim . We correlated it with the requirement of rapid demethylation machinery to fine-tune the Bim gene expression. Also, mutational pressure played a dominant role in shaping codon usage bias in Bim isoforms. Conclusion: An exceptionally high usage of CpC dinucleotide in all the envisaged 31 isoforms of Bim indicates a high order selectional force to fine tune Bim gene expression. Show more

Keywords: Bim gene, CAI, CpC dinucleotide, codon usage, pro-apoptotic gene

DOI: 10.3233/JAD-215691

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1711-1725, 2022

Authors: Sandberg, Alexandra A. | Manning, Evan | Wilkins, Heather M. | Mazzarino, Randall | Minckley, Taylor | Swerdlow, Russell H. | Patterson, David | Qin, Yan | Linseman, Daniel A.

Article Type: Research Article

Abstract: Background: Amyloid-β (Aβ) is a principal cleavage product of amyloid-β protein precursor (AβPP) and is widely recognized as a key pathogenic player in Alzheimer’s disease (AD). Yet, there is increasing evidence of a neurotoxic role for the AβPP intracellular domain (AICD) which has been proposed to occur through its nuclear function. Intriguingly, there is a γ-secretase resident at the mitochondria which could produce AICD locally. Objective: We examined the potential of AICD to induce neuronal apoptosis when targeted specifically to the mitochondria and compared its mechanism of neurotoxicity to that of Aβ. Methods: We utilized transient …transfection of HT22 neuronal cells with bicistronic plasmids coding for DsRed and either empty vector (Ires), Aβ, AICD59 , or mitochondrial-targeted AICD (mitoAICD) in combination with various inhibitors of pathways involved in apoptosis. Results: AICD induced significant neuronal apoptosis only when targeted to the mitochondria. Apoptosis required functional mitochondria as neither Aβ nor mitoAICD induced significant toxicity in cells devoid of mitochondrial DNA. Both glutathione and a Bax inhibitor protected HT22 cells from either peptide. However, inhibition of the mitochondrial permeability transition pore only protected from Aβ, while pan-caspase inhibitors uniquely rescued cells from mitoAICD. Conclusion: Our results show that AICD displays a novel neurotoxic function when targeted to mitochondria. Moreover, mitoAICD induces apoptosis via a mechanism that is distinct from that of Aβ. These findings suggest that AICD produced locally at mitochondria via organelle-specific γ-secretase could act in a synergistic manner with Aβ to cause mitochondrial dysfunction and neuronal death in AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, amyloid-β protein precursor intracellular domain (AICD), caspase, mitochondria

DOI: 10.3233/JAD-215108

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1727-1744, 2022

Authors: O’Bryant, Sid E. | Petersen, Melissa | Hall, James | Johnson, Leigh | for the HABS-HD Study Team

Article Type: Research Article

Abstract: Background: Despite the tremendous amount of research on Alzheimer’s disease (AD) biomarkers, very little data is available regarding the fundamental biomarkers of AD among Mexican Americans. Objective: Here we sought to examine the link between metabolic markers and brain amyloid among Mexican Americans as compared to non-Hispanic whites from the Health & Aging Brain Study –Health Disparities (HABS-HD) cohort. Methods: PET amyloid (florbetaben) data was analyzed from 34 Mexican American and 22 non-Hispanic white participants. Results: Glucagon (t  = 3.84, p  < 0.001) and insulin (t  = –2.56, p  = 0.02) were both significantly related to global SUVR …levels among Mexican Americans. Glucagon and insulin were both related to most ROIs. No metabolic markers were significantly related to brain amyloid levels among non-Hispanic whites. Conclusion: Metabolic markers are related to brain amyloid burden among Mexican Americans. Given the increased risk for diabetes, additional research is needed to determine the impact of diabetes on core AD biomarkers among this underserved population. Show more

Keywords: Alzheimer’s disease, amyloid, health disparities, Hispanic

DOI: 10.3233/JAD-215620

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1745-1750, 2022

Authors: Ibarrondo, Oliver | Huerta, José María | Amiano, Pilar | Andreu-Reinón, María Encarnación | Mokoroa, Olatz | Ardanaz, Eva | Larumbe, Rosa | Colorado-Yohar, Sandra M. | Navarro-Mateu, Fernando | Chirlaque, María Dolores | Mar, Javier

Article Type: Research Article

Abstract: Background: Dementia prevention can be addressed if the intervention is applied early. Objective: The objective of this study was to develop and validate competing risk models to predict the late risk of dementia based on variables assessed in middle age in a southern European population. Methods: We conducted a prospective observational study of the EPIC-Spain cohort that included 25,015 participants. Dementia cases were identified from electronic health records and validated by neurologists. Data were gathered on sociodemographic characteristics and cardiovascular risk factors. To stratify dementia risk, Fine and Gray competing risk prediction models were constructed for …the entire sample and for over-55-year-olds. Risk scores were calculated for low (the 30% of the sample with the lowest risk), moderate (> 30% –60%), and high (> 60% –100%) risk. Results: The 755 cases of dementia identified represented a cumulative incidence of 3.1% throughout the study period. The AUC of the model for over-55-year-olds was much higher (80.8%) than the overall AUC (68.5%) in the first 15 years of follow-up and remained that way in the subsequent follow-up. The weight of the competing risk of death was greater than that of dementia and especially when the entire population was included. Conclusion: This study presents the first dementia risk score calculated in a southern European population in mid-life and followed up for 20 years. The score makes it feasible to achieve the early identification of individuals in a southern European population who could be targeted for the prevention of dementia based on the intensive control of risk factors. Show more

Keywords: Alzheimer’s disease, competing risks, dementia, predictive models, prevention, risk score

DOI: 10.3233/JAD-215211

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1751-1762, 2022

Authors: Jester, Dylan J. | Vyhnálek, Martin | Andel, Ross | Marková, Hana | Nikolai, Tomás | Laczó, Jan | Matusková, Veronika | Cechová, Katerina | Sheardova, Katerina | Hort, Jakub

Article Type: Research Article

Abstract: Background: Older adults with subjective cognitive decline (SCD) are at an increased risk of progression to mild cognitive impairment (MCI) or dementia. However, few have examined the specific cognitive tests that are associated with progression. Objective: This study examined performance on 18 neuropsychological tests among participants with SCD who later progressed to MCI or dementia. Methods: We included 131 participants from the Czech Brain Aging Study that had SCD at baseline. They completed a comprehensive neuropsychological battery including cognitive tests from the Uniform Data Set 2.0 enriched by the verbal memory test Rey Auditory Verbal Learning …Test (RAVLT) and Rey-Osterrieth Complex Figure Test (ROCFT). Results: Fifty-five participants progressed: 53% to non-amnestic MCI (naMCI), 44% to amnestic MCI (aMCI), and 4% to dementia. Scoring one SD below the mean at baseline on the RAVLT 1 and RAVLT 1–5 was associated with 133% (RAVLT 1; HR: 2.33 [1.50, 3.62 ]) and 122% (RAVLT 1–5; HR: 2.22 [1.55, 3.16 ]) greater risk of progression to MCI or dementia over 3.84 years on average. Worse performance on the RAVLT 5, RAVLT 1–5, RAVLT 30, and ROCFT–Recall was associated with progression to aMCI whereas worse performance on the RAVLT 1, TMT B, and Boston Naming Test was associated with progression to naMCI. Conclusion: At baseline, lower verbal memory performance was most strongly associated with progression to aMCI whereas lower executive or language performance was most strongly associated with progression to naMCI. Show more

Keywords: Cognitive aging, immediate recall, subjective memory complaints, verbal memory

DOI: 10.3233/JAD-215291

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1763-1774, 2022

Authors: Takechi, Hajime | Yoshino, Hiroshi | Kawakita, Hitomi

Article Type: Research Article

Abstract: Background: Dementia cafés have been attracting attention as a new approach to dementia care, but the effects of the participation of medical professionals remain unclear. Objective: To clarify the significance of collaboration between medical professionals and dementia cafés. Methods: Questionnaires regarding the numbers of staff and guests, whether medical professionals introduced guests, whether cafés announced their activities to medical institutions, and whether people with dementia played a role were sent to dementia cafés throughout Japan. The responding dementia cafés were then divided into two groups according to the presence or involvement of medical professionals and institutions …and compared. Results: Responses were received from 148 dementia cafés, among which, medical professionals participated in 96 (64.9%). Significantly more people with dementia living at home attended cafés run or staffed with medical professionals (p  = 0.021 and p  = 0.017, respectively), as well as when medical professionals introduced guests to the café or when the café announced their activities to medical institutions (p  = 0.001 and p  = 0.002, respectively). Significantly more people with dementia played a role in cafés where medical professionals were administrators or staff (p  = 0.008 and p  = 0.018, respectively). Similar effects were observed for family caregivers. Conclusion: The participation and involvement of medical professionals and institutions in dementia cafés increased the attendance of people with dementia, especially those living at home. These results suggest that dementia cafés are an effective hub for connecting care for dementia with medical care, and thus help avoid fragmentation in dementia care. Show more

Keywords: Caregiver, community network, dementia, psychosocial intervention, social support

DOI: 10.3233/JAD-215472

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1775-1782, 2022

Authors: Ji, Xintong | Li, Chenxia | Zhu, Xiaozheng | Yu, Wenlei | Cai, Yanyu | Zhu, Xinyi | Lu, Linjie | Qian, Qiwei | Hu, Yu | Zhu, Xuan | Wang, Huanhuan

Article Type: Research Article

Abstract: Background: Fine particulate matter (particulate matter 2.5, PM2.5 ) is considered one of the harmful factors to neuronal functions. Apoptosis is one of the mechanisms of neuronal injury induced by PM2.5 . Methylcobalamine (MeCbl) has been shown to have anti-apoptotic and neuroprotective effects. Objective: The current work tried to explore the neuroprotective effects and mechanisms that MeCbl protects mice against cognitive impairment and neuronal apoptosis induced by chronic real-time PM2.5 exposure. Methods: Twenty-four 6-week-old male C57BL/6 mice were exposed to ambient PM2.5 and fed with MeCbl for 6 months. Morris water maze was used …to evaluate the changes of spatial learning and memory ability in mice. PC12 cells and primary hippocampal neurons were applied as the in vitro model. Cell viability, cellular reactive oxygen species (ROS) and the expressions of apoptosis-related proteins were examined. And cells were stained with JC-1 and mitochondrial membrane potential was evaluated. Results: In C57BL/6 mice, MeCbl supplementation alleviated cognitive impairment and apoptosis-related protein expression induced by PM2.5 exposure. In in vitro cell model, MeCbl supplementation could effectively rescue the downregulation of cell viability induced by PM2.5 , and inhibited the increased levels of ROS, cellular apoptosis, and the expressions of apoptosis related proteins related to PM2.5 treatment, which may be associated with modulation of mitochondrial function. Conclusion: MeCbl treatment alleviated cognitive impairment and neuronal apoptosis induced by PM2.5 both in vivo and in vitro . The mechanism for the neuroprotective effects of MeCbl may at least be partially dependent on the regulation of mitochondrial apoptosis. Show more

Keywords: Methylcobalamine, mitochondria, neuronal apoptosis, PM2.5

DOI: 10.3233/JAD-215384

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1783-1796, 2022

Authors: Abdullah, Shahbaz | Critchfield, Matthew | Maltby, John | Mukaetova-Ladinska, Elizabeta B.

Article Type: Research Article

Abstract: Background: Cognitive decline is classically attributed to organic causes such as dementia; however, depression can play a role in cognitive decline. Objective: To evaluate cognitive screening tools and the 4-item Geriatric Depression Scale (GDS-4) for use in primary care to distinguish cognitive decline secondary to depression. Method: Clinical data collected over 2.5 years for assessed patients in a secondary clinical service for younger adults. Cognitive screening tools (General Practitioner Assessment of Cognition, Addenbrooke’s Cognitive Examination-III, Rowland Universal Dementia Assessment Scale, Salzburg Dementia Test Prediction) and GDS-4 were analyzed for their accuracy to differentiate …patients with cognitive decline due to depression from those with subjective cognitive complaints. Results: 180 young adults seen in a memory clinic setting (< 65 years) were included. These individuals either had a diagnosis of depression (n  = 46) or no cognitive impairment on assessment (n  = 134) despite having subjective cognitive complaints. All used cognitive tools had poor accuracy in differentiating cognitive decline secondary to depression from subjective cognitive complaints. The GDS-4 alone, however, was able to differentiate with high accuracy (AUC = 0.818) individuals who had cognitive problems secondary to depression. Conclusion: Cognitive screening tools used alone are ineffective in discriminating cognitive decline secondary to depression. Incorporating the GDS-4 into the screening process by primary practitioners could facilitate early identification and treatment of depression in younger people, avoiding unnecessary referrals memory services. Show more

Keywords: Cognitive decline, cognitive tools, depression, 4-item geriatric depression score

DOI: 10.3233/JAD-215552

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1797-1804, 2022

Authors: Li, Wenchao | Yang, Defu | Yan, Chenggang | Chen, Minghan | Li, Quefeng | Zhu, Wentao | Wu, Guorong | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Mounting evidence shows that the neuropathological burdens manifest preference in affecting brain regions during the dynamic progression of Alzheimer’s disease (AD). Since the distinct brain regions are physically wired by white matter fibers, it is reasonable to hypothesize the differential spreading pattern of neuropathological burdens may underlie the wiring topology, which can be characterized using neuroimaging and network science technologies. Objective: To study the dynamic spreading patterns of neuropathological events in AD. Methods: We first examine whether hub nodes with high connectivity in the brain network (assemble of white matter wirings) are susceptible to a …higher level of pathological burdens than other regions that are less involved in the process of information exchange in the network. Moreover, we propose a novel linear mixed-effect model to characterize the multi-factorial spreading process of neuropathological burdens from hub nodes to non-hub nodes, where age, sex, and APOE4 indicators are considered as confounders. We apply our statistical model to the longitudinal neuroimaging data of amyloid-PET and tau-PET, respectively. Results: Our meta-data analysis results show that 1) AD differentially affects hub nodes with a significantly higher level of pathology, and 2) the longitudinal increase of neuropathological burdens on non-hub nodes is strongly correlated with the connectome distance to hub nodes rather than the spatial proximity. Conclusion: The spreading pathway of AD neuropathological burdens might start from hub regions and propagate through the white matter fibers in a prion-like manner. Show more

Keywords: Alzheimer’s disease, brain networks, hub node, linear mixed-effect model, longitudinal neuroimages

DOI: 10.3233/JAD-215596

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1805-1816, 2022

Authors: Vacher, Michael | Porter, Tenielle | Milicic, Lidija | Bourgeat, Pierrick | Dore, Vincent | Villemagne, Victor L | Laws, Simon M. | Doecke, James D.

Article Type: Research Article

Abstract: Background: The blood-brain barrier (BBB) is formed by a high-density lining of endothelial cells, providing a border between circulating blood and the brain interstitial fluid. This structure plays a key role in protecting the brain microenvironment by restricting passage of certain molecules and circulating pathogens. Objective: To identify associations between brain volumetric changes and a set of 355 BBB-related single nucleotide polymorphisms (SNP). Method: In a population of 721 unrelated individuals, linear mixed effect models were used to assess if specific variants were linked to regional rates of atrophy over a 12-year time span. Four brain …regions were investigated, including cortical grey matter, cortical white matter, ventricle, and hippocampus. Further, we also investigated the potential impact of history of hypertension, diabetes, and the incidence of stroke on regional brain volume change. Results: History of hypertension, diabetes, and stroke was not associated with longitudinal brain volume change. However, we identified a series of genetic variants associated with regional brain volume changes. The associations were independent of variation due to the APOE ɛ 4 allele and were significant post correction for multiple comparisons. Conclusion: This study suggests that key genes involved in the regulation of BBB integrity may be associated with longitudinal changes in specific brain regions. The derived polygenic risk scores indicate that these interactions are multigenic. Further research needs to be conducted to investigate how BBB functions maybe compromised by genetic variation. Show more

Keywords: Alzheimer’s disease, blood-brain barrier, brain atrophy, linear mixed model, MRI, single nucleotide polymorphisms

DOI: 10.3233/JAD-210644

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1817-1829, 2022

Authors: Rahmani, Farzaneh | Wang, Qing | McKay, Nicole S. | Keefe, Sarah | Hantler, Nancy | Hornbeck, Russ | Wang, Yong | Hassenstab, Jason | Schindler, Suzanne | Xiong, Chengjie | Morris, John C. | Benzinger, Tammie L.S. | Raji, Cyrus A.

Article Type: Research Article

Abstract: Background: Obesity is an increasingly recognized modifiable risk factor for Alzheimer’s disease (AD). Increased body mass index (BMI) is related to distinct changes in white matter (WM) fiber density and connectivity. Objective: We investigated whether sex differentially affects the relationship between BMI and WM structural connectivity. Methods: A cross-sectional sample of 231 cognitively normal participants were enrolled from the Knight Alzheimer Disease Research Center. Connectome analyses were done with diffusion data reconstructed using q-space diffeomorphic reconstruction to obtain the spin distribution function and tracts were selected using a deterministic fiber tracking algorithm. Results: We …identified an inverse relationship between higher BMI and lower connectivity in the associational fibers of the temporal lobe in overweight and obese men. Normal to overweight women showed a significant positive association between BMI and connectivity in a wide array of WM fibers, an association that reversed in obese and morbidly obese women. Interaction analyses revealed that with increasing BMI, women showed higher WM connectivity in the bilateral frontoparietal and parahippocampal parts of the cingulum, while men showed lower connectivity in right sided corticostriatal and corticopontine tracts. Subgroup analyses demonstrated comparable results in participants with and without positron emission tomography or cerebrospinal fluid evidence of brain amyloidosis, indicating that the relationship between BMI and structural connectivity in men and women is independent of AD biomarker status. Conclusion: BMI influences structural connectivity of WM differently in men and women across BMI categories and this relationship does not vary as a function of preclinical AD. Show more

Keywords: Aging, Alzheimer’s disease, body mass index, connectome, diffusion magnetic resonance imaging, white matter

DOI: 10.3233/JAD-215329

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1831-1848, 2022

Authors: Hu, Hao | Fu, Jun-Ting | Bi, Yan-Lin | Ma, Ya-Hui | Huang, Yu-Yuan | Wang, Xin | Tan, Lan | Yu, Jin-Tai

Article Type: Research Article

Abstract: Background: Although cigarette smoking is an important modifiable factor of cognitive impairment, the roles of the Alzheimer’s disease (AD) core pathologies in modulating this process have not been fully delineated. Objective: This study aimed to explore associations of cigarette smoking with cognition and cerebrospinal fluid (CSF) AD biomarkers. Methods: A total of 1,079 non-demented participants were included from the Chinese Alzheimer’s Biomarker and LifestylE (CABLE) study. Associations of cigarette smoking with cognition and CSF AD biomarkers were explored by multiple linear regression models. The mediation analyses with 10,000 bootstrapped iterations were conducted to explore the mediation …effects. Results: Heavy cigarette smokers (pack-years > 20) had poorer global cognition as well as higher levels of CSF p-tau and t-tau compared with the non-smokers (p  < 0.01). Time-dose effect analysis among smokers also suggested that both cognitive impairment and tau pathologies markedly deteriorated with greater cumulative cigarette exposure, independently of the Aβ pathology (p  < 0.01). In addition, smokers with older age or APOE ɛ 4 showed more obvious influences on CSF tau pathologies but not on cognition. Overall, the influence of smoking on cognition was partially mediated by tau pathologies (estimated proportion: 12%), which still remained in late-life (10% ∼11%) and increased in APOE ɛ 4 carriers (18% ∼24%). Encouragingly, long-term smoking cessation mitigated both cognitive impairment and tau pathologies (p  < 0.05). Conclusion: Cigarette smoking was associated with both cognitive impairment and tau pathologies, which were accompanied by time-dose effects. Tau pathology might be a key mediator for influences of cigarette smoking on cognitive impairments. Show more

Keywords: Alzheimer’s diseases, cerebrospinal fluid biomarkers, cigarette smoking, cognitive impairment

DOI: 10.3233/JAD-215618

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1849-1859, 2022

Authors: Cao, Han | Zhou, Xiaopu | Chen, Yu | Ip, Fanny C.F. | Chen, Yuewen | Lai, Nicole C.H. | Lo, Ronnie M.N. | Tong, Estella P.S. | Mok, Vincent C.T. | Kwok, Timothy C.Y. | Alzheimer’s Disease Neuroimaging Initiative | Fu, Amy K.Y. | Ip, Nancy Y.

Article Type: Research Article

Abstract: Background: Genetic studies reveal that single-nucleotide polymorphisms (SNPs) of SPI1 are associated with Alzheimer’s disease (AD), while their effects in the Chinese population remain unclear. Objective: We aimed to examine the AD-association of SPI1 SNPs in the Chinese population and investigate the underlying mechanisms of these SNPs in modulating AD risk. Methods: We conducted a genetic analysis of three SPI1 SNPs (i.e., rs1057233, rs3740688, and rs78245530) in a Chinese cohort (n  = 333 patients with AD, n  = 721 normal controls). We also probed public European-descent AD cohorts and gene expression datasets to investigate the …putative functions of those SNPs. Results: We showed that SPI1 SNP rs3740688 is significantly associated with AD in the Chinese population (odds ratio [OR] = 0.72 [0.58–0.89]) and identified AD-protective SPI1 haplotypes β (tagged by rs1057233 and rs3740688) and γ (tagged by rs3740688 and rs78245530). Specifically, haplotypes β and γ are associated with decreased SPI1 gene expression level in the blood and brain tissues, respectively. The regulatory roles of these haplotypes are potentially mediated by changes in miRNA binding and the epigenetic landscape. Our results suggest that the AD-protective SPI1 haplotypes regulate pathways involved in immune and neuronal functions. Conclusion: This study is the first to report a significant association of SPI1 with AD in the Chinese population. It also identifies SPI1 haplotypes that are associated with SPI1 gene expression and decreased AD risk. Show more

Keywords: Alzheimer’s disease, genetics, haplotype analysis, SPI1, transcriptome

DOI: 10.3233/JAD-215311

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1861-1873, 2022

Authors: Kalecký, Karel | German, Dwight C. | Montillo, Albert A. | Bottiglieri, Teodoro

Article Type: Research Article

Abstract: Background: Metabolites are biological compounds reflecting the functional activity of organs and tissues. Understanding metabolic changes in Alzheimer’s disease (AD) can provide insight into potential risk factors in this multifactorial disease and suggest new intervention strategies or improve non-invasive diagnosis. Objective: In this study, we searched for changes in AD metabolism in plasma and frontal brain cortex tissue samples and evaluated the performance of plasma measurements as biomarkers. Methods: This is a case-control study with two tissue cohorts: 158 plasma samples (94 AD, 64 controls; Texas Alzheimer’s Research and Care Consortium – TARCC) and 71 postmortem …cortex samples (35 AD, 36 controls; Banner Sun Health Research Institute brain bank). We performed targeted mass spectrometry analysis of 630 compounds (106 small molecules: UHPLC-MS/MS, 524 lipids: FIA-MS/MS) and 232 calculated metabolic indicators with a metabolomic kit (Biocrates MxP® Quant 500). Results: We discovered disturbances (FDR≤0.05) in multiple metabolic pathways in AD in both cohorts including microbiome-related metabolites with pro-toxic changes, methylhistidine metabolism, polyamines, corticosteroids, omega-3 fatty acids, acylcarnitines, ceramides, and diglycerides. In AD, plasma reveals elevated triglycerides, and cortex shows altered amino acid metabolism. A cross-validated diagnostic prediction model from plasma achieves AUC = 82% (CI95  = 75–88%); for females specifically, AUC = 88% (CI95  = 80–95%). A reduced model using 20 features achieves AUC = 79% (CI95  = 71–85%); for females AUC = 84% (CI95  = 74–92%). Conclusion: Our findings support the involvement of gut environment in AD and encourage targeting multiple metabolic areas in the design of intervention strategies, including microbiome composition, hormonal balance, nutrients, and muscle homeostasis. Show more

Keywords: Alzheimer’s disease, antioxidants, bacterial toxins, biomarkers, human microbiome, hyperlipidemia, lipidomics, metabolic pathways, metabolomics, polyamines

DOI: 10.3233/JAD-215448

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1875-1895, 2022

Authors: Sha, Feng | Zhao, Ziyi | Wei, Chang | Li, Bingyu

Article Type: Research Article

Abstract: Background: Previous studies found that about 24% of the mild cognitive impairment (MCI) patients reverse to cognitive normal (CN) status. However, it is unclear which modifiable factors are associated with this reversion. Objective: To identify potential modifiable factors associated with the reversion of MCI to CN status. Methods: We conducted a prospective community-based cohort study based on 2002–2018 Chinese Longitudinal Health Longevity Survey (CLHLS). Multivariable Cox regression with least absolute shrinkage and selection operator (LASSO) penalty for variable selection was adopted to investigate the associations between reversion to CN and potential modifiable dietary/lifestyle, …cardiometabolic, and psychological factors. Results: Our analysis included 7,422 MCI participants [average age: 90.0 (SD 9.5) years]. Among these participants, 1,604 (21.6%) reversed from MCI to CN with a mean (SD) follow-up of 2.9 (1.8) years. Several dietary/lifestyle factors, including daily consumption of fresh fruits (Hazard Ratio [HR]: 1.28, 95% CI: 1.15 to 1.42), engagement in reading (HR: 1.24, 95% CI: 1.00 to 1.54), housework (HR: 1.21, 95% CI: 1.08 to 1.35), and mah-jongg or other card games (HR: 1.23, 95% CI: 1.08 to 1.39), were positively associated with possibility of reversion. Cigarette smoking (HR: 0.92, 95% CI: 0.84 to 1.00) and duration of alcohol drinking (HR: 0.97, 95% CI: 0.94 to 0.99) were negatively associated with possibility of reversion. None of the modifiable cardiometabolic and psychological factors was found to be significantly associated with reversion to CN. Conclusion: This study identified several dietary/lifestyle factors associated with MCI reversion that may transfer into large-scale dementia prevention practices. Show more

Keywords: Cognitive health, dementia prevention, dietary/lifestyle factors, mild cognitive impairment, modifiable factors

DOI: 10.3233/JAD-215677

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1897-1906, 2022

Authors: Broussard, John I. | Redell, John B. | Maynard, Mark E. | Zhao, Jing | Moore, Anthony | Mills, Rachel W. | Hood, Kimberly N. | Underwood, Erica | Roysam, Badrinath | Dash, Pramod K.

Article Type: Research Article

Abstract: Background: Hippocampal place cells play an integral role in generating spatial maps. Impaired spatial memory is a characteristic pathology of Alzheimer’s disease (AD), yet it remains unclear how AD influences the properties of hippocampal place cells. Objective: To record electrophysiological activity in hippocampal CA1 neurons in freely-moving 18-month-old male TgF344-AD and age-matched wild-type (WT) littermates to examine place cell properties. Methods: We implanted 32-channel electrode arrays into the CA1 subfield of 18-month-old male WT and TgF344-AD (n  = 6/group) rats. Ten days after implantation, single unit activity in an open field arena was recorded across days. The …spatial information content, in-field firing rate, and stability of each place cell was compared across groups. Pathology was assessed by immunohistochemical staining, and a deep neural network approach was used to count cell profiles. Results: Aged TgF344-AD rats exhibited hippocampal amyloid-β deposition, and a significant increase in Iba1 immunoreactivity and microglia cell counts. Place cells from WT and TgF344-AD rat showed equivalent spatial information, in-field firing rates, and place field stability when initially exposed to the arena. However, by day 3, the place cells in aged WT rats showed characteristic spatial tuning as evidenced by higher spatial information content, stability, and in-field firing rates, an effect not seen in TgF344-AD rats. Conclusion: These findings support the notion that altered electrophysiological properties of place cells may contribute to the learning and memory deficits observed in AD. Show more

Keywords: Amyloid-β, place cell stability, rat AD model, spatial information

DOI: 10.3233/JAD-215023

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1907-1916, 2022

Authors: Alves, Steven R. | da Cruz e Silva, Cristóvão | Rosa, Ilka M. | Henriques, Ana Gabriela | da Cruz e Silva, Odete A.B.

Article Type: Research Article

Abstract: Background: Increasing evidence links impaired brain insulin signaling and insulin resistance to the development of Alzheimer’s disease (AD). Objective: This evidence prompted a search for molecular players common to AD and diabetes mellitus (DM). Methods: The work incorporated studies based on a primary care-based cohort (pcb-Cohort) and a bioinformatics analysis to identify central nodes, that are key players in AD and insulin signaling (IS) pathways. The interactome for each of these key proteins was retrieved and network maps were developed for AD and IS. Synaptic enrichment was performed to reveal synaptic common hubs. Results: …Cohort analysis showed that individuals with DM exhibited a correlation with poor performance in the Mini-Mental State Examination (MMSE) cognitive test. Additionally, APOE ɛ2 allele carriers appear to potentially be relatively more protected against both DM and cognitive deficits. Ten clusters were identified in this network and 32 key synaptic proteins were common to AD and IS. Given the relevance of signaling pathways, another network was constructed focusing on protein kinases and protein phosphatases, and the top 6 kinase nodes (LRRK2, GSK3B, AKT1, EGFR, MAPK1, and FYN) were further analyzed. Conclusion: This allowed the elaboration of signaling cascades directly impacting AβPP and tau, whereby distinct signaling pathway play a major role and strengthen an AD-IS link at a molecular level. Show more

Keywords: Alzheimer’s disease, apolipoprotein E, insulin, leucine-rich repeat serine-threonine protein kinase-2, type 2 diabetes mellitus

DOI: 10.3233/JAD-215059

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1917-1933, 2022

Authors: Armstrong, Melissa J. | Song, Shangchen | Kurasz, Andrea M. | Li, Zhigang

Article Type: Research Article

Abstract: Background: Dementia is one of the top causes of death worldwide, but individuals with dementia and their caregivers report that knowing what to expect, including regarding approaching end of life, is an unmet need. Objective: To identify predictors of death in individuals with Alzheimer disease (AD) dementia, Lewy body dementia (LBD), vascular dementia, and frontotemporal dementia. Methods: The study used data from National Alzheimer’s Coordinating Center participants with dementia and an etiologic diagnosis of AD, Lewy body disease, frontotemporal lobar degeneration (FTLD, with or without motor neuron disease), or vascular dementia. Analyses included …median survival across dementia types and predictors of death at 5 years based on baseline demographics and clinical measure performance. Five-year survival probability tables were stratified by predictor values. Results: Individuals with AD had the longest survival (median 6 years), followed by FTLD (5 years), and vascular dementia and LBD (each 4 years). The strongest predictors of death for the full cohort were dementia type (higher risk with non-AD dementias), sex (higher risk with male sex), and race and ethnicity (higher risk with white and non-Hispanic participants). Age was associated with higher mortality risk across the non-Alzheimer dementias; other significant associations included worse cognitive status (FTLD, LBD) and more depression (LBD). Conclusion: Results can help clinicians counsel individuals with dementia and families regarding average dementia trajectories; findings regarding individual risk factors can aid individualizing expectations. Further research is needed to investigate drivers of mortality in the non-AD dementias to improve counseling and help identify potentially modifiable factors. Show more

Keywords: Alzheimer’s disease, death, dementia, frontotemporal dementia, Lewy body disease, survival analysis, vascular dementia

DOI: 10.3233/JAD-215587

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1935-1946, 2022

Authors: Saji, Naoki | Saito, Yoshihiro | Yamashita, Tomoya | Murotani, Kenta | Tsuduki, Tsuyoshi | Hisada, Takayoshi | Sugimoto, Taiki | Niida, Shumpei | Toba, Kenji | Sakurai, Takashi

Article Type: Research Article

Abstract: Background: Previous studies have demonstrated associations between gut microbiota, microbial metabolites, and cognitive decline. However, relationships between these factors and lipopolysaccharides (LPS; molecules of the outer membrane of gram-negative bacteria) remain controversial. Objective: To evaluate associations between plasma LPS, gut microbiota, and cognitive function. Methods: We performed a cross-sectional sub-analysis of data of 127 participants (women: 58%, mean age: 76 years) from our prospective cohort study regarding the relationship between gut microbiota and cognitive function. We enrolled patients who visited our memory clinic and assessed demographics, dementia-related risk factors, cognitive function, brain imaging, gut microbiomes, and …microbial metabolites. We evaluated relationships between cognitive decline and plasma LPS using multivariable logistic regression analyses. Results: Plasma LPS concentration increased with increasing degree of cognitive decline and total cerebral small vessel disease (SVD) score (Kruskal-Wallis test; p  = 0.016 and 0.007, respectively). Participants with high plasma LPS concentrations tended to have lower concentrations of gut microbial metabolites, such as lactic acid and acetic acid, and were less likely to consume fish and shellfish (44.7% versus 69.6%, p  = 0.027) than those with low plasma LPS concentrations. Multivariable analyses revealed that plasma LPS concentration was independently associated with the presence of mild cognitive impairment in participants without dementia (odds ratio: 2.09, 95% confidence interval: 1.14–3.84, p  = 0.007). Conclusion: In this preliminary study, plasma LPS concentration was associated with both cognitive decline and cerebral SVD and significantly correlated with beneficial gut microbial metabolites. Plasma LPS may be a risk factor for cognitive decline. Show more

Keywords: Biomarkers, cerebral small vessel disease, cognitive decline, dementia, gut microbiota

DOI: 10.3233/JAD-215653

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1947-1957, 2022

Authors: Xiao, Yifan | Gong, Xiaokang | Deng, Ronghua | Liu, Wei | Yang, Youhua | Wang, Xiaochuan | Wang, Jianzhi | Bao, Jian | Shu, Xiji

Article Type: Research Article

Abstract: Background: Obesity is a worldwide health problem that has been implicated in many diseases, including Alzheimer’s disease (AD). AD is one of the most common neurodegenerative disorders and is characterized by two pathologies, including extracellular senior plaques composed of amyloid-β (Aβ) and intracellular neurofibrillary tangles (NFTs) consisting of abnormally hyperphosphorylated tau. According to current research, a high-fat diet (HFD) could exacerbate Aβ accumulation, oxidative damage, and cognitive defects in AD mice. However, the accurate role of HFD in the pathogenesis of AD is far more unclear. Objective: To explore the accurate role of HFD in the pathogenesis of …AD. Methods: Open Field, Barns Maze, Elevated zero-maze, Contextual fear condition, Tail suspension test, western blotting, immunofluorescence, Fluoro-Jade C Labeling, Perls’ Prussian blue staining, and ELISA were used. Results: HFD caused nonheme iron overload in the brains of APPswe/PS1dE9 (APP/PS1) mice. Furthermore, the administration of M30 (0.5 mg/kg) for iron chelation once every 2 days per os (p.o.) for 1 month remitted memory deficits caused by HFD in APP/PS1 mice. Notably, a variety of hematological parameters in whole blood had no difference after iron chelation. In addition, iron chelation effectively reduced synaptic impairment in hippocampus and neuronal degeneration in cortex in the HFD-fed APP/PS1 mice. Meanwhile, iron chelation decreased Aβ1–40 and Aβ1–42 level as well as neuroinflammation in HFD-fed APP/PS1 mice. Conclusion: These data enhance our understanding of how HFD aggravates AD pathology and cognitive impairments and might shed light on future preclinical studies. Show more

Keywords: Alzheimer’s disease, amyloid-β, APP/PS1, high-fat diet, iron

DOI: 10.3233/JAD-215705

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1959-1971, 2022

Authors: Feng, Tian | Hu, Xinran | Fukui, Yusuke | Bian, Zhihong | Bian, Yuting | Sun, Hongming | Takemoto, Mami | Yunoki, Taijun | Nakano, Yumiko | Morihara, Ryuta | Abe, Koji | Yamashita, Toru

Article Type: Research Article

Abstract: Background: The oral ingestion of scallop-derived plasmalogen (sPlas) significantly improved cognitive function in Alzheimer’s disease (AD) patients. Objective: However, the effects and mechanisms of sPlas on AD with chronic cerebral hypoperfusion (CCH), a class of mixed dementia contributing to 20–30% among the dementia society, were still elusive. Methods: In the present study, we applied a novel mouse model of AD with CCH to investigate the potential effects of sPlas on AD with CCH. Results: The present study demonstrated that sPlas significantly recovered cerebral blood flow, improved motor and cognitive deficits, reduced amyloid-β pathology, regulated …neuroinflammation, ameliorated neural oxidative stress, and inhibited neuronal loss in AD with CCH mice at 12 M. Conclusion: These findings suggest that sPlas possesses clinical and pathological benefits for AD with CCH in the novel model mice. Furthermore, sPlas could have promising prevention and therapeutic effects on patients of AD with CCH. Show more

Keywords: Alzheimer’s disease, amyloid-β pathology, chronic cerebral hypoperfusion, neural oxidative stress, neuroinflammation, scallop-derived plasmalogen

DOI: 10.3233/JAD-215246

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1973-1982, 2022

Article Type: Correction

DOI: 10.3233/JAD-229003

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1983-1984, 2022