Journal of Alzheimer's Disease - Volume 90, issue 4

Authors: Zhou, Wen | Zhan, Libin | Xu, Huiying | Zhang, Lijing

Article Type: Research Article

Abstract: Background: Chronic psychological stress (PS) hinders the treatment of diabetes-associated cognitive decline (DACD). However, the impact of chronic PS on the risk of developing DACD remains unclear. There is growing evidence that gut flora interventions are promising targets for treating stress-related diseases. Objective: We examined whether chronic PS triggers or exacerbates the onset of DACD in rats and aimed to elucidate whether ZiBuPiYin recipe (ZBPYR) prevents and treats chronic PS-aggravated DACD by dynamically maintaining the components of the gut microbiota. Methods: We performed chronic PS (restraint, rotation, and congestion) on ZDF rats to establish a model. …Cognitive function was evaluated by behavioral experiments, and activation of the hypothalamic-pituitary-adrenal axis was detected by ELISA. Weekly feces from rats were collected for 16 S RNA sequencing. Results: We found that chronic PS promoted cognitive abnormalities and exacerbated DACD phenotypes. Additionally, chronic PS altered intestinal flora diversity, dynamically elevating the abundance of Alistipes and Coprococcus ; enriching Module 1 (Dorea, Blautia, Ruminococcus ) and Module 48 (Blautia ); and inhibiting Module 20 (Lactobacillus, SMB53 ), and Module 42 (Akkermansia ). ZBPYR significantly alleviated hyperglycemia and cognitive impairment in chronic PS-aggravated DACD rats and dynamically reduced the abundance of Alistipes and Coprococcus ; significantly enriched Module 3 (Ruminococcus ) and Module 45 (Lactobacillus, Coprococcus, SMB53 ); and suppressed Module 2 (Lactobacillus ), Module 16 (Turicibacter, Trichococcus, Lactobacillus, 02d06, Clostridium ), Module 23 (Bifidobacterium ), and Module 43 (Clostridium ). Conclusion: ZBPYR might prevent and treat chronic PS-aggravated DACD by dynamically regulating Lactobacillus, Alistipes , and Coprococcus . Show more

Keywords: Chronic psychological stress, diabetes-associated cognitive decline, gut microbiota, traditional Chinese medicine

DOI: 10.3233/JAD-220692

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1465-1483, 2022

Authors: Zhu, Chi | Zhu, Jie | Xiang, Yang | Bu, Xian-Le | Jin, Wang-Sheng | Wang, Yan-Jiang

Article Type: Research Article

Abstract: Background: Abnormal intracellular expression and aggregation of α-synuclein (α-syn) is the histopathological hallmark of several neurodegenerative diseases especially Parkinson’s disease. However, safe and efficient approaches to clear α-syn remain unavailable. Objective: This study aimed to investigate the process of peripheral catabolism of brain-derived α-syn. Methods: Thirty patients with atrioventricular reentrant tachycardia (AVRT) (left accessory pathways) who underwent radiofrequency catheter ablation (RFCA) were enrolled in this study. Blood was collected via catheters from superior vena cava (SVC), inferior vena cava (IVC) proximal to the hepatic vein (HV), the right femoral vein (FV), and femoral artery (FA) simultaneously …during RFCA. Plasma α-syn levels of AVRT patients and soluble α-syn levels of the brain samples were measured using enzyme-linked immunosorbent assay kits. Results: The α-syn concentrations in different locations of veins were divided by time-matched arterial α-syn concentrations to generate the venous/arterial (V/A) ratio. The V/A ratio of α-syn from the SVC was 1.204 (1.069–1.339, 95% CI), while the V/A ratio of α-syn from IVC was 0.831 (0.734–0.928, 95% CI), suggesting that brain-derived α-syn in the arterial blood was physiologically cleared while going through the peripheral organs and tissues. And it was estimated that about half of brain soluble α-syn could efflux and be cleared in the periphery. Moreover, the glomerular filtration rate was found correlated with V-A difference (FA-ICV) (p  = 0.0272). Conclusion: Under physiological conditions, brain-derived α-syn could efflux into and be catabolized by the peripheral system. The kidney may play a potential role in the clearance of α-syn. Show more

Keywords: α-synuclein, kidney, peripheral clearance, plasma

DOI: 10.3233/JAD-220742

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1485-1492, 2022

Authors: Wang, Ye-Ran | Wang, Meng-Ting | Zeng, Xiao-Qin | Liu, Yu-Hui | Wang, Yan-Jiang

Article Type: Research Article

Abstract: Background: Imbalance between the production and clearance of amyloid-β (Aβ) promotes the development of Alzheimer’s disease (AD). Presenilin-1 (PS1) is the catalytic subunit of γ-secretase, which is involved in the process of Aβ production. The profiles of autoantibodies are dysregulated in AD patients. Objective: This study aims to investigate the relative levels and clinical relevance of naturally occurring antibodies to PS1 (NAbs-PS1) in AD. Methods: A total of 55 subjects with AD (including both dementia and mild cognitive impairment due to AD), 28 subjects with cognitive impairment (including both dementia and mild cognitive impairment) not due …to AD (non-AD CI), and 70 cognitively normal (CN) subjects were recruited. One-site ELISA was utilized to determine the relative levels of NAbs-PS1 in plasma. Results: AD subjects had lower plasma levels of NAbs-PS1 than CN and non-AD CI subjects. Plasma NAbs-PS1 were negatively associated with the brain Aβ load, as reflected by PET-PiB SUVR, and were positively associated with cognitive functions of participants. Plasma NAbs-PS1 discriminated AD patients from CN with an area under the curve (AUC) of 0.730, a sensitivity of 69.09%, and a specificity of 67.14%, and they discriminated AD patients from non-AD CI subjects with an AUC of 0.750, a specificity of 70.91%, and a sensitivity of 71.43%. Conclusion: This study found an aberrant immunological phenotype in AD patients. Further investigations are needed to determine the pathophysiological functions of NAbs-PS1 in AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, γ-secretase, naturally occurring antibodies, presenilin-1

DOI: 10.3233/JAD-220775

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1493-1500, 2022

Authors: Pontrello, Crystal G. | McWhirt, Joshua M. | Glabe, Charles G. | Brewer, Gregory J.

Article Type: Research Article

Abstract: Background: Many identified mechanisms could be upstream of the prominent amyloid-β (Aβ) plaques in Alzheimer’s disease (AD). Objective: To profile the progression of pathology in AD. Methods: We monitored metabolic signaling, redox stress, intraneuronal amyloid-β (iAβ) accumulation, and extracellular plaque deposition in the brains of 3xTg-AD mice across the lifespan. Results: Intracellular accumulation of aggregated Aβ in the CA1 pyramidal cells at 9 months preceded extracellular plaques that first presented in the CA1 at 16 months of age. In biochemical assays, brain glutathione (GSH) declined with age in both 3xTg-AD and non-transgenic controls, but …the decline was accelerated in 3xTg-AD brains from 2 to 4 months. The decline in GSH correlated exponentially with the rise in iAβ. Integrated metabolic signaling as the ratio of phospho-Akt (pAkt) to total Akt (tAkt) in the PI3kinase and mTOR pathway declined at 6, 9, and 12 months, before rising at 16 and 20 months. These pAkt/tAkt ratios correlated with both iAβ and GSH levels in a U-shaped relationship. Selective vulnerability of age-related AD-genotype-specific pAkt changes was greatest in the CA1 pyramidal cell layer. To demonstrate redox causation, iAβ accumulation was lowered in cultured middle-age adult 3xTg-AD neurons by treatment of the oxidized redox state in the neurons with exogenous cysteine. Conclusion: The order of pathologic progression in the 3xTg-AD mouse was loss of GSH (oxidative redox shift) followed by a pAkt/tAkt metabolic shift in CA1, iAβ accumulation in CA1, and extracellular Aβ deposition. Upstream targets may prove strategically more effective for therapy before irreversible changes. Show more

Keywords: Alzheimer disease, glutathione, intracellular amyloid, lifespan, mechanism, pAkt, pathogenesis, redox

DOI: 10.3233/JAD-220824

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1501-1521, 2022

Authors: Röhr, Susanne | Pabst, Alexander | Baber, Ronny | Engel, Christoph | Glaesmer, Heide | Hinz, Andreas | Schroeter, Matthias L. | Witte, A. Veronica | Zeynalova, Samira | Villringer, Arno | Löffler, Markus | Riedel-Heller, Steffi G.

Article Type: Research Article

Abstract: Background: There are socioeconomic inequalities in dementia risk. Underlying pathways are not well known. Objective: To investigate whether modifiable health and lifestyle factors for brain health mediate the association of socioeconomic status (SES) and cognitive functioning in a population without dementia. Methods: The “LIfestyle for BRAin health” (LIBRA) score was computed for 6,203 baseline participants of the LIFE-Adult-Study. LIBRA predicts dementia in midlife and early late life, based on 12 modifiable factors. Associations of SES (education, net equivalence income, and occupational status) and LIBRA with cognitive functioning (composite score) were investigated using adjusted linear regression models. …Bootstrapped structural equation modelling (SEM) was used to investigate whether LIBRA mediated the association of SES and cognitive functioning. Results: Participants were M  = 57.4 (SD  = 10.6, range: 40-79) years old; 50.3% were female. Both, SES (Wald: F (2)=52.5, p  < 0.001) and LIBRA (Wald: F (1)=5.9, p  < 0.05) were independently associated with cognitive functioning; there was no interaction (Wald: F (2)=2.9, p  = 0.060). Lower SES and higher LIBRA scores indicated lower cognitive functioning. LIBRA partially mediated the association of SES and cognitive functioning (IE: =0.02, 95% CI [0.02, 0.03], p  < 0.001). The proportion mediated was 12.7%. Conclusion: Differences in cognitive functioning due to SES can be partially attributed to differences in modifiable health and lifestyle factors; but to a small extent. This suggests that lifestyle interventions could attenuate socioeconomic inequalities in cognitive functioning. However, directly intervening on the social determinants of health may yield greater benefits for dementia risk reduction. Show more

Keywords: Cognitive function, dementia, epidemiology, lifestyle, prevention, public health, risk factors, social inequalities, socioeconomic status

DOI: 10.3233/JAD-220474

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1523-1534, 2022

Authors: Waziry, Reem | Claus, Jacqueline J. | Hofman, Albert

Article Type: Research Article

Abstract: Background: The majority of stroke cases are ischemic in origin and ischemic stroke survivors represent a high-risk population for progression to dementia. Objective: To determine incidence rates and predictors of dementia after ischemic stroke. Methods: A systematic review and meta-analysis compliant with Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). Results: 5,843 studies were screened for title and abstract. 292 eligible studies were screened for full text. A total of 22 studies met the inclusion criteria and were included, representing 55,929 ischemic stroke survivors. Cumulative incidence of dementia after stroke was 20% at …5 years, 30% at 15 years, and 48% at 25 years of follow-up. Dementia incidence rates were 1.5 times higher among patients with recurrent ischemic stroke compared to patients with first-time stroke. Predictors of dementia after ischemic stroke included female gender (OR 1.2, 95% CI (1.1, 1.4)), hypertension (1.4, (1.1, 2.0)), diabetes mellitus (1.6, (1.3, 2.1)), atrial fibrillation (1.9, (1.2, 3.0)), previous stroke (2.0, (1.6, 2.6)), presence of stroke lesion in dominant hemisphere (2.4, (1.3, 4.5)), brain stem or cerebellum (OR 0.5, (0.3, 0.9)) or frontal lobe (3.7, (1.2, 12.0)), presence of aphasia (OR 7.9, (2.4, 26.0)), dysphasia (5.8, (3.0, 11.3)), gait impairment (1.7, (1.1, 2.7)), presence of white matter hyperintensities (3.2, (2.0, 5.3)), and medial temporal lobe atrophy (3.9, (1.9, 8.3)). Conclusion: Factors routinely collected for stroke patients are a useful resource for monitoring dementia progression in this population. In the present meta-analysis, cardiovascular factors, stroke location, stroke-related disability and chronic brain changes were predictors of dementia after ischemic stroke. Show more

Keywords: Dementia, ischemic stroke, meta-analysis, systematic review

DOI: 10.3233/JAD-220317

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1535-1546, 2022

Authors: Huang, Xiangyuan | Alcantara, Leicester Shawn | Tan, Chuen Seng | Ng, Yi Lin | van Dam, Rob M. | Hilal, Saima

Article Type: Research Article

Abstract: Background: Handgrip strength (HGS) is an important marker of frailty but there is limited research on lifestyle and vascular determinants of HGS and its relationship with cognitive impairment. Objective: To identify determinants of HGS and the association of HGS with cognitive impairment in a multiethnic cohort from Singapore. Methods: This study (n  = 2,109, median [Q1, Q3] age: 53 [48, 60] years, 59.6% women) was based on cross-sectional data from Singapore Multi-Ethnic Cohort. HGS was collected using hand-held Electronic Dynamometer. The potential determinants of HGS included age, sex, ethnicity, smoking, physical activity, serum cholesterol and history of …hypertension, diabetes, and stroke. Cognition, assessed with the Mini-Mental State Examination (MMSE), was analyzed as both continuous and binary outcome (cognitively impaired [scores < 26] and cognitively normal [scores≥26]). Results: In total, 239 (11.3%) participants were cognitively impaired. Older age, female sex, Malay or Indian compared with Chinese ethnicity, and diabetes history were associated with decreased HGS, whereas higher education, higher body mass index, and more physical activity were associated with higher HGS. Higher HGS was associated with higher MMSE scores (β: 0.34, 95% CI: 0.20, 0.49) and 37% lower odds of cognitive impairment (OR: 0.63, 95% CI: 0.49–0.82). These associations were significantly stronger in participants who were older (50–90 years), female, of Malay and Indian ethnicity (compared with Chinese), and less educated. Conclusion: In this multi-ethnic Asian population, demographics, vascular risk factors, and lifestyle behaviors were associated with HGS. Additionally, higher HGS was associated with substantially better cognitive function, which association was modified by age, sex, ethnicity, and education level. Show more

Keywords: Asians, cognitive dysfunction, hand strength, Mental Status and Dementia Tests

DOI: 10.3233/JAD-220531

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1547-1555, 2022

Authors: Gaitán, Julian M. | Asthana, Sanjay | Carlsson, Cynthia M. | Engelman, Corinne D. | Johnson, Sterling C. | Sager, Mark A. | Wang, Dan | Dubal, Dena B. | Okonkwo, Ozioma C.

Article Type: Research Article

Abstract: Background: Klotho is a longevity and neuroprotective hormone encoded by the KLOTHO gene, and heterozygosity for the KL-VS variant confers a protective effect against neurodegenerative disease. Objective: Test whether klotho concentrations in serum or cerebrospinal fluid (CSF) vary as a function of KLOTHO KL-VS genotype, determine whether circulating klotho concentrations from serum and CSF differ from one another, and evaluate whether klotho levels are associated with Alzheimer’s disease risk factors. Methods: Circulating klotho was measured in serum (n  = 1,116) and CSF (n  = 183) of cognitively intact participants (aged 62.4 ± 6.5 years; 69.5% female). …KLOTHO KL-VS zygosity (non-carrier; heterozygote; homozygote) was also determined. Linear regression was used to test whether klotho hormone concentration varied as a function of KL-VS genotype, specimen source, and demographic and clinical characteristics. Results: Serum and CSF klotho were higher in KL-VS carriers than non-carriers. Klotho concentration was higher in CSF than in serum. Females had higher serum and CSF klotho, while younger age was associated with higher klotho in CSF. Conclusion: In a cohort enriched for risk for Alzheimer’s disease, heterozygotic and homozygotic carriers of the KL-VS allele, females, and younger individuals have higher circulating klotho. Fluid source, KL-VS genotype, age, and sex should be considered in analyses of circulating klotho on brain health. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid, KL-VS, Klotho, serum

DOI: 10.3233/JAD-220571

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1557-1569, 2022

Authors: Dissanayake, Andrew S. | Tan, Yu Bin | Bowie, Christopher R. | Butters, Meryl A. | Flint, Alastair J. | Gallagher, Damien | Golas, Angela C. | Herrmann, Nathan | Ismail, Zahinoor | Kennedy, James L. | Kumar, Sanjeev | Lanctot, Krista L. | Mah, Linda | Mulsant, Benoit H. | Pollock, Bruce G. | Rajji, Tarek K. | Tau, Michael | Maraj, Anika | Churchill, Nathan W. | Tsuang, Debby | Schweizer, Tom A. | Munoz, David G. | Fischer, Corinne E.

Article Type: Research Article

Abstract: Background: Recent work suggests that APOE ɛ 4/4 females with Alzheimer’s disease (AD) are more susceptible to developing neuropsychiatric symptoms (NPS). Objective: To examine the interaction of sex and APOE ɛ 4 status on NPS burden using two independent cohorts: 1) patients at risk for AD with mild cognitive impairment and/or major depressive disorder (n  = 252) and 2) patients with probable AD (n  = 7,261). Methods: Regression models examined the interactive effects of sex and APOE ɛ 4 on the number of NPS experienced and NPS Severity. APOE ɛ 3/4 and APOE …ɛ 4/4 were pooled in the at-risk cohort due to the sample size. Results: In the at-risk cohort, there was a significant sex*APOE ɛ 4 interaction (p  = 0.007) such that the association of APOE ɛ 4 with NPS was greater in females than in males (incident rate ratio (IRR) = 2.0). APOE ɛ 4/4 females had the most NPS (mean = 1.9) and the highest severity scores (mean = 3.5) of any subgroup. In the clinical cohort, APOE ɛ 4/4 females had significantly more NPS (IRR = 1.1, p  = 0.001, mean = 3.1) and higher severity scores (b  = 0.31, p  = 0.015, mean = 3.7) than APOE ɛ 3/3 females (meanNPS  = 2.9, meanSeverity  = 3.3). No association was found in males. Conclusion: Our study suggests that sex modifies the association of APOE ɛ 4 on NPS burden. APOE ɛ 4/4 females may be particularly susceptible to increased NPS burden among individuals with AD and among individuals at risk for AD. Further investigation into the mechanisms behind these associations are needed. Show more

Keywords: Alzheimer’s disease, APOE4, behavioral and psychological symptoms of dementia, biomarkers, gender differences, major depressive disorder, mild cognitive impairment, neuropsychiatry, Neuropsychiatric Inventory Questionnaire, psychosis

DOI: 10.3233/JAD-220586

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1571-1588, 2022

Authors: Hughes, Timothy M. | Lockhart, Samuel N. | Suerken, Cynthia K. | Jung, Youngkyoo | Whitlow, Christopher T. | Bateman, James R. | Williams, Benjamin J. | Espeland, Mark A. | Sachs, Bonnie C. | Williamson, Jeff | Cleveland, Maryjo | Yang, Mia | Rogers, Samantha | Hayden, Kathleen M. | Baker, Laura D. | Craft, Suzanne

Article Type: Research Article

Abstract: Background: Cardiometabolic disorders (hypertension, diabetes) are key modifiable risk factors for Alzheimer’s disease and related disorders. They often co-occur; yet, the extent to which they independently affect brain structure and function is unclear. Objective: We hypothesized their combined effect is greater in associations with cognitive function and neuroimaging biomarkers of white matter (WM) health and cerebral perfusion in a diverse older adult cohort. Methods: Participants aged 50-85 years received: clinical evaluation, oral glucose tolerance testing, neuroimaging, cognitive testing, and adjudication. Neuroimaging included: T1 (gray [GM]/WM segmentation, regional volumes/thicknesses); FLAIR (WM hyperintensity volume [WMHv]; arterial spin labeling …(cerebral blood flow); diffusion tensor imaging (fractional anisotropy [FA]); and neurite orientation dispersion and density imaging (Free Water). Hypertension (HTN) and impaired glucose tolerance (IGT) were staged and cardiometabolic status was categorized (HTN only, IGT only, IGT+HTN, neither). Multivariable linear regression modeled associations with cognitive and neuroimaging measures (covariates: age, gender, race). Results: MRI was available for 478 participants (35% mild cognitive impairment, 10% dementia) with mean age 70±8 years, 74% with HTN, 61% with IGT, and 15% self-identified as Black/African-American. IGT+HTN was significantly associated with cognitive impairment, higher WM Free Water and WMHv, lower FA, and lower GM perfusion compared to neither factor. HTN alone was associated with poorer cognition and lower GM perfusion. Cardiometabolic factors were not associated with GM macrostructure (volumes, temporal lobe cortical thickness) or cognitive status. Conclusion: HTN and its co-occurrence with IGT (HTN+IGT) were associated with lower global cognitive performance and reduced GM perfusion and impaired WM microstructure. Show more

Keywords: Brain, cognition, hyperglycemia, hypertension

DOI: 10.3233/JAD-220646

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1589-1599, 2022