Journal of Alzheimer's Disease - Volume 93, issue 3

Authors: Marshall, Anisa J. | Gaubert, Aimee | Kapoor, Arunima | Tan, Alick | McIntosh, Elissa | Jang, Jung Yun | Yew, Belinda | Ho, Jean K. | Blanken, Anna E. | Dutt, Shubir | Sible, Isabel J. | Li, Yanrong | Rodgers, Kathleen | Nation, Daniel A.

Article Type: Research Article

Abstract: Background: Depletion of blood-derived progenitor cells, including so called “early endothelial progenitor cells”, has been observed in individuals with early stage Alzheimer’s disease relative to matched older control subjects. These findings could implicate the loss of angiogenic support from hematopoietic progenitors or endothelial progenitors in cognitive dysfunction. Objective: To investigate links between progenitor cell proliferation and mild levels of cognitive dysfunction. Methods: We conducted in vitro studies of blood-derived progenitor cells using blood samples from sixty-five older adults who were free of stroke or dementia. Peripheral blood mononuclear cells from venous blood samples were cultured …in CFU-Hill media and the number of colony forming units were counted after 5 days in vitro . Neuropsychological testing was administered to all participants. Results: Fewer colony forming units were observed in samples from older adults with a Clinical Dementia Rating global score of 0.5 versus 0. Older adults whose samples developed fewer colony forming units exhibited worse performance on neuropsychological measures of memory, executive functioning, and language ability. Conclusion: These data suggest blood progenitors may represent a vascular resilience marker related to cognitive dysfunction in older adults. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, progenitor cells, vascular resilience

DOI: 10.3233/JAD-220269

Citation: Journal of Alzheimer's Disease, vol. 93, no. 3, pp. 1041-1050, 2023

Authors: Fan, Jialing | Zhu, Zhibao | Chen, Yaojing | Yang, Caishui | Li, Xin | Chen, Kewei | Chen, Xiaochun | Zhang, Zhanjun

Article Type: Research Article

Abstract: Background: Language ability differs between the sexes. However, it is unclear how this sex difference is moderated by genetic factors and how the brain interacts with genetics to support this specific language capacity. Previous studies have demonstrated that the sorting protein-related receptor (SORL1 ) polymorphism influences cognitive function and brain structure differently in males and females and is associated with Alzheimer’s disease risk. Objective: The aim of this study was to investigate the effects of sex and the SORL1 rs1699102 (CC versus T carriers) genotype on language. Methods: 103 non-demented Chinese older adults from Beijing …Aging Brain Rejuvenation Initiative (BABRI) database were included in this study. Participants completed language tests, T1-weighted structural magnetic resonance imaging (MRI) and resting-state functional MRI. Language test performance, gray matter volume, and network connections were compared between genotype and sex groups. Results: The rs1699102 polymorphism moderated the effects of sex on language performance, with the female having reversed language advantages in T carriers. The T allele carriers had lower gray matter volume in the left precentral gyrus. The effect of sex on language network connections was moderated by rs1699102; male CC homozygotes and female T carriers had higher internetwork connections, which were negatively correlated with language performance. Conclusion: These results suggest that SORL1 moderates the effects of sex on language, with T being a risk allele, especially in females. Our findings underscore the importance of considering the influence of genetic factors when examining sex effects. Show more

Keywords: Alzheimer’s disease, functional connectivity, language network, rs1699102, sex, SORL1

DOI: 10.3233/JAD-221133

Citation: Journal of Alzheimer's Disease, vol. 93, no. 3, pp. 1051-1063, 2023

Authors: Hirota, Yu | Sakakibara, Yasufumi | Takei, Kimi | Nishijima, Risa | Sekiya, Michiko | Iijima, Koichi M.

Article Type: Research Article

Abstract: Background: The tau protein phosphorylated at Thr181 (p-tau181) in cerebrospinal fluid and blood is a sensitive biomarker for Alzheimer’s disease (AD). Increased p-tau181 levels correlate well with amyloid-β (Aβ) pathology and precede neurofibrillary tangle formation in the early stage of AD; however, the relationship between p-tau181 and Aβ-mediated pathology is less well understood. We recently reported that p-tau181 represents axonal abnormalities in mice with Aβ pathology (AppNLGF ). However, from which neuronal subtype(s) these p-tau181-positive axons originate remains elusive. Objective: The main purpose of this study is to differentiate neuronal subtype(s) and elucidate damage associated with …p-tau181-positive axons by immunohistochemical analysis of AppNLGF mice brains. Methods: Colocalization between p-tau181 and (1) unmyelinated axons positive for vesicular acetylcholine transporter or norepinephrine transporter and (2) myelinated axons positive for vesicular glutamate transporter, vesicular GABA transporter, or parvalbumin in the brains of 24-month-old AppNLGF and control mice without Aβ pathology were analyzed. The density of these axons was also compared. Results: Unmyelinated axons of cholinergic or noradrenergic neurons did not overlap with p-tau181. By contrast, p-tau181 signals colocalized with myelinated axons of parvalbumin-positive GABAergic interneurons but not of glutamatergic neurons. Interestingly, the density of unmyelinated axons was significantly decreased in AppNLGF mice, whereas that of glutamatergic, GABAergic, or p-tau181-positive axons was less affected. Instead, myelin sheaths surrounding p-tau181-positive axons were significantly reduced in AppNLGF mice. Conclusion: This study demonstrates that p-tau181 signals colocalize with axons of parvalbumin-positive GABAergic interneurons with disrupted myelin sheaths in the brains of a mouse model of Aβ pathology. Show more

Keywords: Alzheimer’s disease, amyloid-β, biomarker, GABAergic interneuron, myelin, parvalbumin, phospho-tau

DOI: 10.3233/JAD-230121

Citation: Journal of Alzheimer's Disease, vol. 93, no. 3, pp. 1065-1081, 2023

Authors: Cheng, Jing | Zheng, Huancheng | Liu, Chenyu | Jin, Jiabin | Xing, Zhenkai | Wu, Yili

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the most common neurodegenerative disease leading to dementia in the elderly. Ubiquitin proteasome system (UPS) is critical for protein homeostasis, while the functional decline of UPS with age contributes to the pathogenesis of AD. Ubiquitin-conjugating enzyme E2O (UBE2O), an E2-E3 hybrid enzyme, is a major component of UPS. However, its role in AD pathogenesis has not been fully defined. Objective: We aimed to identify the age-associated expression of UBE2O and its role AD pathogenesis. Methods: Western blot analysis were used to assess expression of UBE2O in organs/tissues and cell lines. Immunofluorescence …staining was performed to examine the cellular distribution of UBE2O. Neuronal death was determined by the activity of lactate dehydrogenase. Results: UBE2O is highly expressed in the cortex and hippocampus. It is predominantly expressed in neurons but not in glial cells. The peak expression of UBE2O is at postnatal day 17 and 14 in the cortex and hippocampus, respectively. Moreover its expression is gradually reduced with age. Importantly, UBE2O is significantly reduced in both cortex and hippocampus of AD mice. Consistently, overexpression of amyloid-β protein precursor (AβPP) with a pathogenic mutation (AβPPswe) for AD reduces the expression of UBE2O and promotes neuronal death, while increased expression of UBE2O rescues AβPPswe-induced neuronal death. Conclusion: Our study indicates that age-associated reduction of UBE2O may facilitates neuronal death in AD, while increasing UBE2O expression or activity may be a potential approach for AD treatment by inhibiting neuronal death. Show more

Keywords: Alzheimer’s disease, amyloid-β protein precursor, neuronal death, UBE2O, ubiquitin proteasome system

DOI: 10.3233/JAD-221143

Citation: Journal of Alzheimer's Disease, vol. 93, no. 3, pp. 1083-1093, 2023

Authors: Huggins, Lenique K.L. | Min, Se Hee | Kaplan, Samantha | Wei, Jingkai | Welsh-Bohmer, Kathleen | Xu, Hanzhang

Article Type: Research Article

Abstract: Background: Emerging research has shown racial and ethnic variations in the magnitude of association between the apolipoprotein ɛ4 (APOE ɛ4) allele and the risk of developing Alzheimer’s disease and related dementias (ADRD). Studies researching this association among Hispanic groups within and outside of the United States have produced inconsistent results. Objective: To examine the association between the APOE ɛ4 allele and the risk of developing ADRD in global Hispanic populations from different ethnic regions of origin. Methods: PubMed, Embase, Scopus, and PsycInfo were searched for studies relating to Hispanic/Latin American origin, APOE ɛ4, …and ADRD. Odds ratios (OR) of ADRD risk for individuals with APOE ɛ4 versus those without APOE ɛ4 were extracted and calculated using random effects analysis. Results: 20 eligible studies represented Caribbean Hispanic, Mexican, South American, Spanish, and Cuban groups. Overall, APOE ɛ4 was significantly associated with increased risk of ADRD (Odds Ratio [OR] 3.80, 95% CI: 2.38–6.07). The association was only significant in the South American (OR: 4.61, 95% CI: 2.74–7.75) subgroup. Conclusion: There was an association between APOE ɛ4 and increased ADRD risk for the South American subgroup. The strength of this association varied across Hispanic subgroups. Data is limited with more studies especially needed for adjusted analysis on Spanish, Central American, Cuban Hispanic, and Caribbean Hispanic groups. Results suggest additional environmental or genetic risk factors are associated with ethnic variations. Show more

Keywords: Alzheimer disease, apolipoprotein E4, dementia, Hispanic or Latino

DOI: 10.3233/JAD-221167

Citation: Journal of Alzheimer's Disease, vol. 93, no. 3, pp. 1095-1109, 2023

Authors: Jiang, Chunyan | Wang, Yongxiang | Dong, Yi | Liu, Rui | Song, Lin | Wang, Shanshan | Xu, Zhe | Niu, Sijie | Ren, Yifei | Han, Xiaodong | Zhao, Mingqing | Wang, Jiafeng | Li, Xiaohui | Cong, Lin | Hou, Tingting | Zhang, Qinghua | Du, Yifeng | Qiu, Chengxuan

Article Type: Research Article

Abstract: Background: Microvascular dysfunction (MVD) may contribute to cognitive impairment and Alzheimer’s disease, but evidence is limited. Objective: To investigate the association of composite and organ-specific MVD burden with mild cognitive impairment (MCI) and cognition among rural-dwelling Chinese older adults. Methods: In this population-based cross-sectional study, we assessed MVD makers using optical coherence tomographic angiography for retinal microvasculature features, brain magnetic resonance imaging scans for cerebral small vessel disease (CSVD), and serum biomarkers for MVD. A composite MVD score was generated from the aforementioned organ-specific parameters. We used a neuropsychological test battery to assess memory, verbal fluency, …attention, executive function, and global cognitive function. MCI, amnestic MCI (aMCI), and non-amnestic MCI (naMCI) were diagnosed following the Petersen’s criteria. Data was analyzed with the linear and logistic regression models. Results: Of the 274 dementia-free participants (age≥65 years), 56 were diagnosed with MCI, including 47 with aMCI and 9 with naMCI. A composite MVD score was statistically significantly associated with an odds ratio (OR) of 2.70 (95% confidence interval 1.12–6.53) for MCI and β-coefficient of –0.29 (–0.48, –0.10) for global cognitive score after adjustment for socio-demographics, lifestyle factors, APOE genotype, the Geriatric Depression Scale score, serum inflammatory biomarkers, and cardiovascular comorbidity. A composite score of retinal microvascular morphology was associated with a multivariable-adjusted OR of 1.72 (1.09–2.73) for MCI and multivariable-adjusted β-coefficient of –0.11 (–0.22, –0.01) for global cognitive score. A composite CSVD score was associated with a lower global cognitive score (β= –0.10; –0.17, –0.02). Conclusion: Microvascular dysfunction, especially in the brain and retina, is associated with MCI and poor cognitive function among rural-dwelling older adults. Show more

Keywords: Alzheimer’s disease, cerebral small vessel disease, microvascular dysfunction, mild cognitive impairment, population-based study, retinal microvascular lesions

DOI: 10.3233/JAD-221242

Citation: Journal of Alzheimer's Disease, vol. 93, no. 3, pp. 1111-1124, 2023

Authors: Sacchi, Luca | Contarino, Valeria Elisa | Siggillino, Silvia | Carandini, Tiziana | Fumagalli, Giorgio Giulio | Pietroboni, Anna Margherita | Arcaro, Marina | Fenoglio, Chiara | Orunesu, Eva | Castellani, Massimo | Casale, Silvia | Conte, Giorgio | Liu, Chunlei | Triulzi, Fabio | Galimberti, Daniela | Scarpini, Elio | Arighi, Andrea

Article Type: Research Article

Abstract: Background: Brain iron homeostasis is disrupted in neurodegeneration and areas of iron overload partially overlap with regions of amyloid and tau burden in Alzheimer’s disease (AD). Previous studies demonstrated alterations in brain iron accumulation in AD using quantitative susceptibility mapping (QSM). Objective: Here, we investigate brain alterations of QSM values in AD and non-AD patients as compared to healthy controls (HC) in the superior temporal sulcus and its banks (BANKSSTS), one of the top AD-affected regions. Methods: Thirty-four patients who underwent brain MRI including a multi-echo gradient-echo sequence were subdivided into AD (n  = 19) and non-AD …(n  = 15) groups according to their clinical profile, CSF (Aβ42/40 ) and/or amyloid-PET status. Ten HC were also included. QSM values were extracted from left and right BANKSSTS and compared among groups. Correlation and binomial regression analyses between QSM values and CSF-AD biomarkers were conducted. Results: QSM in left BANKSSTS was significantly different among groups (p  = 0.003, H = 11.40), being higher in AD. QSM values in left BANKSSTS were correlated with Aβ42 (rho –0.55, p  = 0.005), Aβ42/40 (rho –0.66, p  < 0.001), pTau (rho 0.63, p  < 0.001), tTau (rho 0.56, p  = 0.005), tTau/Aβ42 (rho 0.68, p  < 0.001) and pTau/Aβ42 (rho 0.71, p  < 0.001). No correlations between QSM values and amyloid-PET SUVR in the left BANKSSTS were found. QSM values in left BANKSSTS showed good accuracy in discriminating AD (AUC = 0.80, CI95 % [0.66–0.93]). Higher QSM values were independent predictors of Aβ42 (B = 0.63, p  = 0.032), Aβ42/40 (B = 0.81, p  = 0.028), pTau (B = 0.96, p  = 0.046), tTau (B = 0.55, p  = 0.027), and tTau/Aβ42 (B = 1.13, p  = 0.042) positivity. Conclusion: Our preliminary data support the potential role of increased QSM values in the left BANKSSTS as an auxiliary imaging biomarker in AD diagnosis. Show more

Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid, iron, magnetic resonance imaging

DOI: 10.3233/JAD-230095

Citation: Journal of Alzheimer's Disease, vol. 93, no. 3, pp. 1125-1134, 2023

Authors: Beadell, Alana V. | Zhang, Zhou | Capuano, Ana W. | Bennett, David A. | He, Chuan | Zhang, Wei | Arvanitakis, Zoe

Article Type: Research Article

Abstract: Background: Diabetes mellitus (DM) is a recognized risk factor for dementia. Because DM is a potentially modifiable condition, greater understanding of the mechanisms linking DM to the clinical expression of Alzheimer’s disease dementia may provide insights into much needed dementia therapeutics. Objective: In this feasibility study, we investigated DM as a dementia risk factor by examining genome-wide distributions of the epigenetic DNA modification 5-hydroxymethylcytosine (5hmC). Methods: We obtained biologic samples from the Rush Memory and Aging Project and used the highly sensitive 5hmC-Seal technique to perform genome-wide profiling of 5hmC in circulating cell-free DNA (cfDNA) from …antemortem serum samples and in genomic DNA from postmortem prefrontal cortex brain tissue from 80 individuals across four groups: Alzheimer’s disease neuropathologically defined (AD), DM clinically defined, AD with DM, and individuals with neither disease (controls). Results: Distinct 5hmC signatures and biological pathways were enriched in persons with both AD and DM versus AD alone, DM alone, or controls, including genes inhibited by EGFR signaling in oligodendroglia and those activated by constitutive RHOA. We also demonstrate the potential diagnostic value of 5hmC profiling in circulating cfDNA. Specifically, an 11-gene weighted model distinguished AD from non-AD/non-DM controls (AUC = 91.8%; 95% CI, 82.9–100.0%), while a 4-gene model distinguished DM-associated AD from AD alone (AUC = 87.9%; 95% CI, 77.5–98.3%). Conclusion: We demonstrate in this small sample, the feasibility of detecting and characterizing 5hmC in DM-associated AD and of using 5hmC information contained in circulating cfDNA to detect AD in high-risk individuals, such as those with diabetes. Show more

Keywords: Alzheimer’s disease, cell-free DNA, dementia, diabetes mellitus, epigenetics, 5-hydroxymethylcytosine

DOI: 10.3233/JAD-221113

Citation: Journal of Alzheimer's Disease, vol. 93, no. 3, pp. 1135-1151, 2023

Authors: Wu, Jianfeng | Su, Yi | Chen, Yanxi | Zhu, Wenhui | Reiman, Eric M. | Caselli, Richard J. | Chen, Kewei | Thompson, Paul M. | Wang, Junwen | Wang, Yalin

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the most common type of age-related dementia, affecting 6.2 million people aged 65 or older according to CDC data. It is commonly agreed that discovering an effective AD diagnosis biomarker could have enormous public health benefits, potentially preventing or delaying up to 40% of dementia cases. Tau neurofibrillary tangles are the primary driver of downstream neurodegeneration and subsequent cognitive impairment in AD, resulting in structural deformations such as hippocampal atrophy that can be observed in magnetic resonance imaging (MRI) scans. Objective: To build a surface-based model to 1) detect differences between APOE …subgroups in patterns of tau deposition and hippocampal atrophy, and 2) use the extracted surface-based features to predict cognitive decline. Methods: Using data obtained from different institutions, we develop a surface-based federated Chow test model to study the synergistic effects of APOE , a previously reported significant risk factor of AD, and tau on hippocampal surface morphometry. Results: We illustrate that the APOE -specific morphometry features correlate with AD progression and better predict future AD conversion than other MRI biomarkers. For example, a strong association between atrophy and abnormal tau was identified in hippocampal subregion cornu ammonis 1 (CA1 subfield) and subiculum in e4 homozygote cohort. Conclusion: Our model allows for identifying MRI biomarkers for AD and cognitive decline prediction and may uncover a corner of the neural mechanism of the influence of APOE and tau deposition on hippocampal morphology. Show more

Keywords: Alzheimer’s disease, APOE, Federated Chow test, hippocampal morphometry, tau deposition

DOI: 10.3233/JAD-230034

Citation: Journal of Alzheimer's Disease, vol. 93, no. 3, pp. 1153-1168, 2023

Authors: Borrego-Écija, Sergi | Montagut, Nuria | Martín-Trias, Pablo | Vaqué-Alcázar, Lídia | Illán-Gala, Ignacio | Balasa, Mircea | Lladó, Albert | Casanova-Mollà, Jordi | Bargalló, Nuria | Valls-Solé, Josep | Lleó, Alberto | Bartrés-Faz, David | Sánchez-Valle, Raquel

Article Type: Research Article

Abstract: Background: Primary progressive aphasia (PPA) is a group of neurodegenerative disorders including Alzheimer’s disease and frontotemporal dementia characterized by language deterioration. Transcranial direct current stimulation (tDCS) is a non-invasive intervention for brain dysfunction. Objective: To evaluate the tolerability and efficacy of tDCS combined with speech therapy in the three variants of PPA. We evaluate changes in fMRI activity in a subset of patients. Methods: Double-blinded, randomized, cross-over, and sham-controlled tDCS study. 15 patients with PPA were included. Each patient underwent two interventions: a) speech therapy + active tDCS and b) speech therapy + sham tDCS stimulation. …A multifocal strategy with anodes placed in the left frontal and parietal regions was used to stimulate the entire language network. Efficacy was evaluated by comparing the results of two independent sets of neuropsychological assessments administered at baseline, immediately after the intervention, and at 1 month and 3 months after the intervention. In a subsample, fMRI scanning was performed before and after each intervention. Results: The interventions were well tolerated. Participants in both arms showed clinical improvement, but no differences were found between active and sham tDCS interventions in any of the evaluations. There were trends toward better outcomes in the active tDCS group for semantic association and reading skills. fMRI identified an activity increase in the right frontal medial cortex and the bilateral paracingulate gyrus after the active tDCS intervention. Conclusion: We did not find differences between active and sham tDCS stimulation in clinical scores of language function in PPA patients. Show more

Keywords: Alzheimer’s disease, brain stimulation, frontotemporal dementia, primary progressive aphasia, speech therapy, transcranial direct current stimulation

DOI: 10.3233/JAD-230069

Citation: Journal of Alzheimer's Disease, vol. 93, no. 3, pp. 1169-1180, 2023

Authors: Vig, Viha | Garg, Itika | Tuz-Zahra, Fatima | Xu, Jia | Tripodis, Yorghos | Nicks, Raymond | Xia, Weiming | Alvarez, Victor E. | Alosco, Michael L. | Stein, Thor D. | Subramanian, Manju L.

Article Type: Research Article

Abstract: Background: Patients with eye disease have an increased risk for developing neurodegenerative disease. Neurodegenerative proteins can be measured in the eye; however, correlations between biomarker levels in eye fluid and neuropathological diagnoses have not been established. Objective: This exploratory, retrospective study examined vitreous humor from 41 postmortem eyes and brain tissue with neuropathological diagnoses of Alzheimer’s disease (AD, n  = 7), chronic traumatic encephalopathy (CTE, n  = 15), both AD + CTE (n  = 10), and without significant neuropathology (controls, n  = 9). Methods: Protein biomarkers i.e., amyloid-β (Aβ40,42 ), total tau (tTau), phosphorylated tau (pTau181,231 ), neurofilament light chain …(NfL), and eotaxin-1 were quantitatively measured by immunoassay. Non-parametric tests were used to compare vitreous biomarker levels between groups. Spearman’s rank correlation tests were used to correlate biomarker levels in vitreous and cortical tissue. The level of significance was set to α= 0.10. Results: In pairwise comparisons, tTau levels were significantly increased in AD and CTE groups versus controls (p  = 0.08 for both) as well as AD versus AD+CTE group and CTE versus AD+CTE group (p  = 0.049 for both). Vitreous NfL levels were significantly increased in low CTE (Stage I/II) versus no CTE (p  = 0.096) and in low CTE versus high CTE stage (p  = 0.03). Vitreous and cortical tissue levels of pTau 231 (p  = 0.02, r  = 0.38) and t-Tau (p  = 0.04, r  = –0.34) were significantly correlated. Conclusion: The postmortem vitreous humor biomarker levels significantly correlate with AD and CTE pathology in corresponding brains, while vitreous NfL was correlated with the CTE staging. This exploratory study indicates that biomarkers in the vitreous humor may serve as a proxy for neuropathological disease. Show more

Keywords: Alzheimer’s disease, amyloid-beta, amyloid-beta protein, biomarker, chemokine CCL11, chronic traumatic encephalopathy, eotaxin-1, neurofilament protein, tau protein, vitreous humor

DOI: 10.3233/JAD-230167

Citation: Journal of Alzheimer's Disease, vol. 93, no. 3, pp. 1181-1193, 2023