Journal of Alzheimer's Disease - Volume 89, issue 4

Authors: Yang, Jingjing | Oveisgharan, Shahram | Liu, Xizhu | Wilson, Robert S. | Bennett, David A. | Buchman, Aron S.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a progressive disorder without a cure. Develop risk prediction models for detecting presymptomatic AD using non-cognitive measures is necessary to enable early interventions. Objective: Examine if non-cognitive metrics alone can be used to construct risk models to identify adults at risk for AD dementia and cognitive impairment. Methods: Clinical data from older adults without dementia from the Memory and Aging Project (MAP, n  = 1,179) and Religious Orders Study (ROS, n  = 1,103) were analyzed using Cox proportional hazard models to develop risk prediction models for AD dementia and cognitive impairment. Models using …only non-cognitive covariates were compared to models that added cognitive covariates. All models were trained in MAP, tested in ROS, and evaluated by the AUC of ROC curve. Results: Models based on non-cognitive covariates alone achieved AUC (0.800,0.785) for predicting AD dementia (3.5) years from baseline. Including additional cognitive covariates improved AUC to (0.916,0.881). A model with a single covariate of composite cognition score achieved AUC (0.905,0.863). Models based on non-cognitive covariates alone achieved AUC (0.717,0.714) for predicting cognitive impairment (3.5) years from baseline. Including additional cognitive covariates improved AUC to (0.783,0.770). A model with a single covariate of composite cognition score achieved AUC (0.754,0.730). Conclusion: Risk models based on non-cognitive metrics predict both AD dementia and cognitive impairment. However, non-cognitive covariates do not provide incremental predictivity for models that include cognitive metrics in predicting AD dementia, but do in models predicting cognitive impairment. Further improved risk prediction models for cognitive impairment are needed. Show more

Keywords: Alzheimer’s disease, cognitive aging, cohort study, Cox proportional hazard model, mild cognitive impairment

DOI: 10.3233/JAD-220446

Citation: Journal of Alzheimer's Disease, vol. 89, no. 4, pp. 1249-1262, 2022

Authors: Shkirkova, Kristina | Lamorie-Foote, Krista | Zhang, Nathan | Li, Andrew | Diaz, Arnold | Liu, Qinghai | Thorwald, Max A. | Godoy-Lugo, Jose A. | Ge, Brandon | D’Agostino, Carla | Zhang, Zijiao | Mack, Wendy J. | Sioutas, Constantinos | Finch, Caleb E. | Mack, William J. | Zhang, Hongqiao

Article Type: Research Article

Abstract: Background: Air pollution particulate matter (PM) is strongly associated with risks of accelerated cognitive decline, dementia and Alzheimer’s disease. Ambient PM batches have variable neurotoxicity by collection site and season, which limits replicability of findings within and between research groups for analysis of mechanisms and interventions. Diesel exhaust particles (DEP) offer a replicable model that we define in further detail. Objective: Define dose- and time course neurotoxic responses of mice to DEP from the National Institute of Science and Technology (NIST) for neurotoxic responses shared by DEP and ambient PM. Methods: For dose-response, adult C57BL/6 male …mice were exposed to 0, 25, 50, and 100μg/m3 of re-aerosolized DEP (NIST SRM 2975) for 5 h. Then, mice were exposed to 100μg/m3 DEP for 5, 100, and 200 h and assayed for amyloid-β peptides, inflammation, oxidative damage, and microglial activity and morphology. Results: DEP exposure at 100μg/m3 for 5 h, but not lower doses, caused oxidative damage, complement and microglia activation in cerebral cortex and corpus callosum. Longer DEP exposure for 8 weeks/200 h caused further oxidative damage, increased soluble Aβ, white matter injury, and microglial soma enlargement that differed by cortical layer. Conclusion: Exposure to 100μg/m3 DEP NIST SRM 2975 caused robust neurotoxic responses that are shared with prior studies using DEP or ambient PM0.2. DEP provides a replicable model to study neurotoxic mechanisms of ambient PM and interventions relevant to cognitive decline and dementia. Show more

Keywords: Air pollution, Alzheimer’s disease, brain, dementia, diesel exhaust particle, neurotoxicity

DOI: 10.3233/JAD-220493

Citation: Journal of Alzheimer's Disease, vol. 89, no. 4, pp. 1263-1278, 2022

Authors: Kanagasingam, Shalini | von Ruhland, Christopher | Welbury, Richard | Singhrao, Sim K.

Article Type: Research Article

Abstract: Background: Tau is an established substrate for gingipains secreted by Porphyromonas gingivalis . Hyperphosphorylation of tau and neurofibrillary tangle (NFT) formation is a defining lesion of Alzheimer’s disease (AD) where NFT distribution is related to Braak stage and disease severity. Objective: To assess gingipains’-fragmented tau peptides for their antimicrobial properties and for the likelihood of paired helical/straight filament (PHF/SF) formation with implications for the NFT lesion. Methods: Seven non-phosphorylated (A-G) and three phosphorylated (A-C) tau peptides, were tested for antimicrobial properties against P. gingivalis . Polarizing light properties were determined using Congo Red staining. Secondary and …tertiary structures of peptides B-F were determined using transmission electron microscopy (TEM) and circular dichroism (CD) was undertaken for the soluble peptides A in phosphorylated and non-phosphorylated states. Results: Phosphorylated tau peptide A displayed a significant effect against planktonic P. gingivalis . The CD results demonstrated that both peptides A, in phosphorylated and non-phosphorylated states, in aqueous solution, adopted mainly β-type structures. Non-phosphorylated peptides B-F and phosphorylated peptides B-C were insoluble and fibrillar under the TEM. The secondary and tertiary structures of the non-phosphorylated peptide B demonstrated fewer helical twists, whereas peptide C displayed significantly more helical twists along the whole fiber(s) length following its phosphorylation. Conclusion: Phosphorylated peptide A reduced P. gingivalis viability. CD spectroscopy demonstrated the phosphorylated and the non-phosphorylated peptide A predominantly formed from β-sheet structures in aqueous solution with potential antimicrobial activity. Phosphorylation of tau peptides physically changed their tertiary structure into PHFs with potential for self-aggregation and binding to the NFT lesion. Show more

Keywords: Antimicrobial, β-sheet, birefringence, gingipains, neurofibrillary tangles, Porphyromonas gingivalis, tau

DOI: 10.3233/JAD-220486

Citation: Journal of Alzheimer's Disease, vol. 89, no. 4, pp. 1279-1291, 2022

Authors: Gentreau, Mélissa | Reynes, Christelle | Sabatier, Robert | Maller, Jerome J. | Meslin, Chantal | Deverdun, Jeremy | Le Bars, Emmanuelle | Raymond, Michel | Berticat, Claire | Artero, Sylvaine

Article Type: Research Article

Abstract: Background: Glucometabolic changes, such as high glycemic load (GL) diet and insulin resistance (IR), are potential risk factor of Alzheimer’s disease (AD). Yet, the effect of these factors on brain alterations that contribute to AD pathology has not been clearly demonstrated. Objective: We aimed to assess the relationship of GL and IR with gray matter volumes involved in prodromal dementia. Methods: GL and Triglyceride-Glucose (TyG) index, an IR surrogate marker, were calculated in 497 participants who underwent magnetic resonance imaging (MRI). The gray matter volumes most related to prodromal dementia/mild cognitive impairment (diagnosed in 18/158 participants …during the 7-year follow-up) were identified using a data-driven machine learning algorithm. Results: Higher GL diet was associated with reduced amygdala volume. The TyG index was negatively associated with the hippocampus, amygdala, and putamen volumes. Conclusion: These results suggest that GL and IR are associated with lower gray matter volumes in brain regions involved in AD pathology. Show more

Keywords: Amygdala, dementia, glycemic load, hippocampus, insulin resistance, magnetic resonance imaging, putamen

DOI: 10.3233/JAD-220490

Citation: Journal of Alzheimer's Disease, vol. 89, no. 4, pp. 1293-1302, 2022

Authors: Michopoulou, Sofia | Prosser, Angus | Kipps, Christopher | Dickson, John | Guy, Matthew | Teeling, Jessica

Article Type: Research Article

Abstract: Background: Neuroinflammation is an integral part of Alzheimer’s disease (AD) pathology. Inflammatory mediators can exacerbate the production of amyloid-β (Aβ), the propagation of tau pathology and neuronal loss. Objective: To evaluate the relationship between inflammation markers and established markers of AD in a mixed memory clinic cohort. Methods: 105 cerebrospinal fluid (CSF) samples from a clinical cohort under investigation for cognitive complaints were analyzed. Levels of Aβ42 , total tau, and phosphorylated tau were measured as part of the clinical pathway. Analysis of inflammation markers in CSF samples was performed using multiplex immune assays. Participants were …grouped according to their Aβ, tau, and neurodegeneration status and the Paris-Lille-Montpellier (PLM) scale was used to assess the likelihood of AD. Results: From 102 inflammatory markers analyzed, 19 and 23 markers were significantly associated with CSF total tau and phosphorylated tau levels respectively (p  < 0.001), while none were associated with Aβ42 . The CSF concentrations of 4 inflammation markers were markedly elevated with increasing PLM class indicating increased likelihood of AD (p  < 0.001). Adenosine deaminase, an enzyme involved in sleep homeostasis, was the single best predictor of high likelihood of AD (AUROC 0.788). Functional pathway analysis demonstrated a widespread role for inflammation in neurodegeneration, with certain pathways explaining over 30% of the variability in tau values. Conclusion: CSF inflammation markers increase significantly with tau and neurodegeneration, but not with Aβ in this mixed memory clinic cohort. Thus, such markers could become useful for the clinical diagnosis of neurodegenerative disorders alongside the established Aβ and tau measures. Show more

Keywords: Amyloid-β, dementia, inflammation, tau protein

DOI: 10.3233/JAD-220523

Citation: Journal of Alzheimer's Disease, vol. 89, no. 4, pp. 1303-1314, 2022

Authors: Li, Sijie | Liu, Bian | Li, Qing-hao | Zhang, Yan | Zhang, Haihua | Gao, Shan | Wang, Longcai | Wang, Tao | Han, Zhifa | Liu, Guiyou | Wang, Kun

Article Type: Research Article

Abstract: Background: Until now, both cross-sectional and longitudinal studies have identified controversial findings about the association between daytime napping and Alzheimer’s disease (AD) or cognitive decline. Therefore, it remains unclear about the causal association between daytime napping and AD or cognitive decline. Objective: We aim to investigate the causal association between daytime napping and AD. Methods: Here, we conduct a bidirectional Mendelian randomization (MR) analysis to investigate the causal association between daytime napping and AD using large-scale GWAS datasets from daytime napping including 452,633 individuals of European ancestry and AD including 35,274 AD and 59,163 controls of …European ancestry. A total of five MR methods are selected including inverse-variance weighted (IVW), weighted median, MR-Egger, MR-PRESSO, and contamination mixture method. Results: MR analysis highlights significant causal association of AD with daytime napping using IVW (beta = -0.006, 95% CI [–0.009, –0.002], p  = 2.00E-03), but no significant causal association of daytime napping with AD using IVW (OR = 0.76, 95% CI 0.53-1.10, p  = 1.40E-01). Conclusion: Our bidirectional MR analysis demonstrates the causal effect of AD on daytime napping. However, there is no causal effect of daytime napping on AD. Our current findings are consistent with recent evidence from other MR studies that highlight little evidence supporting a causal effect of sleep traits on AD and support the causal effect of AD on sleep traits. Show more

Keywords: Alzheimer’s disease, daytime napping, genome-wide association study, Mendelian randomization

DOI: 10.3233/JAD-220497

Citation: Journal of Alzheimer's Disease, vol. 89, no. 4, pp. 1315-1322, 2022

Authors: Pang, Ting | Chong, Eddie Jun Yi | Wong, Zi Xuen | Chew, Kimberly Ann | Venketasubramanian, Narayanaswamy | Chen, Christopher | Xu, Xin

Article Type: Research Article

Abstract: Background: The Quick Dementia Rating System (QDRS) is a brief and rapid tool that can be administered by an informant without the need for a trained assessor. Objective: Our objective was to examine the validity, reliability, and cost-effectiveness of the informant QDRS in a Singapore memory clinic sample. Methods: We assessed a total of 177 older adults, among whom, 32 had no cognitive impairment (NCI), 61 had mild cognitive impairment (MCI), and 84 had dementia. Elderly underwent 1) the informant QDRS, 2) the Clinical Dementia Rating (CDR) as the gold standard diagnosis, 3) the Mini-Mental State …Examination (MMSE), and 4) the Ascertain Dementia 8 (AD8) as comparisons to the QDRS. The extent to which the QDRS may reduce the recruitment cost (time) of clinical trials was also calculated. Results: The QDRS had excellent internal consistency (Cronbach alpha = 0.939). It correlated highly with the CDR-global (R = 0.897), CDR Sum-of-Boxes (R = 0.915), MMSE (R = –0.848), and the AD8 (R = 0.747), showing good concurrent validity. With an optimal cut-off of 1.5 for MCI (sensitivity 85.2%, specificity 96.3%) and 6 for dementia (sensitivity 90.1%, specificity 89.2%), the QDRS achieved a higher overall accuracy of 85.0%, as compared to MMSE (71.2%) and AD8 (73.4%). A simulated clinical trial recruitment scenario demonstrated that pre-screening with the QDRS followed by a confirmatory CDR would reduce the time needed to identify NCI subjects by 23.3% and MCI subjects by 75.3%. Conclusion: The QDRS is a reliable cognitive impairment screening tool which is suitable for informant-administration, especially for identification of MCI. Show more

Keywords: Cost-effectiveness, discriminant utility, mild cognitive impairment, Quick Dementia Rating System, staging tool

DOI: 10.3233/JAD-220520

Citation: Journal of Alzheimer's Disease, vol. 89, no. 4, pp. 1323-1330, 2022

Authors: Bardenheier, Barbara Helen | Resnik, Linda J. | Jutkowitz, Eric | Gravenstein, Stefan

Article Type: Research Article

Abstract: Background: To reduce the increasing societal and financial burden of Alzheimer’s disease and related dementias (ADRD), prevention is critical. Even small improvements of the modifiable dementia risk factors on the individual level have the potential to lead to a substantial reduction of dementia cases at the population level. Objective: To determine if pattern(s) of functional decline in midlife associate with late-onset ADRD years later. Methods: Using a longitudinal study of adults aged 51–59 years in 1998 without symptoms of ADRD by 2002 and followed them from 2002 to 2016 (n  = 5404). The outcome was incident ADRD …identified by the Lange-Weir algorithm, death, or alive with no ADRD. We used cluster analysis to identify patterns of functional impairment at baseline and multinomial regression to assess their association with future ADRD. Results: Three groups of adults with differing patterns of functional impairment were at greater risk of future ADRD. Difficulty with climbing one flight of stairs was observed in all adults in two of these groups. In the third group, 100% had difficulty with lifting 10 pounds and pushing or pulling a large object, but only one-fourth had difficulty in climbing stairs. Conclusion: Results imply that improved large muscle strength could decrease future risk of ADRD. If confirmed in other studies, screening for four self-reported measures of function among adults in midlife may be used for targeted interventions. Show more

Keywords: Alzheimer’s disease and related dementias, Health and Retirement Study, late midlife, physical function limitation

DOI: 10.3233/JAD-220573

Citation: Journal of Alzheimer's Disease, vol. 89, no. 4, pp. 1331-1338, 2022

Authors: Kurasz, Andrea M. | De Wit, Liselotte | Smith, Glenn E. | Armstrong, Melissa J.

Article Type: Research Article

Abstract: Background: Survival and associated clinical and pathological characteristics in Lewy body disease (LBD)-related dementias are understudied. Available studies focus primarily on white non-Hispanic samples. Objective: We investigated demographic, clinical, and pathological correlates of survival by race and ethnicity in an autopsy-confirmed cohort of LBD cases. Methods: Using National Alzheimer’s Coordinating Center data, we selected participants who self-identified as Black, Hispanic, or white who had neuropathological assessments showing transitional or diffuse LBD pathology. We used Kruskal-Wallis and Pearson χ2 analyses to investigate group differences in demographic and presenting clinical and pathological characteristics. We used linear regressions …to identify predictors of survival with sex, age at symptom onset, education, ethnoracial status, LBD pathology type, and Braak tangle stage included in the model. Results: Data from 1,441 white, 60 Black, and 54 Hispanic participants were available for analysis. Hispanics were more likely to have transitional LBD pathology and had a longer survival than white and Black participants. After controlling for demographic and pathological variables, length of survival did not differ between Hispanics and Black or white participants. Additional key findings demonstrated discrepancies between clinical diagnoses received at last visit and pathological findings, particularly among Black participants. Conclusion: LBD survival differences by race and ethnicity can be accounted for by LBD pathology type and co-occurring Alzheimer’s disease pathology. The discrepancies between clinical diagnoses and pathological findings raise the concern that dementia with Lewy bodies is underdiagnosed in NACC, especially for Black older adults. Show more

Keywords: Cognitive dysfunction, dementia, ethnicity, Lewy body disease, neuropathology, racial groups

DOI: 10.3233/JAD-220297

Citation: Journal of Alzheimer's Disease, vol. 89, no. 4, pp. 1339-1349, 2022

Authors: Wawrziczny, Emilie | Picard, Sandrine | Buquet, Amandine | Traversac, Elodie | Puisieux, François | Pasquier, Florence | Huvent-Grelle, Dominique | Doba, Karyn

Article Type: Research Article

Abstract: Background: Dementia has a negative impact on the quality of life of the person with dementia and their spouse caregivers, as well as on the couple’s relationship, which can lead to high levels of distress for both partners. Hypnosis has been shown to be effective in managing distress and increasing the quality of the relationship. Objective: The aim was to develop a standardized hypnosis intervention for couples confronted with Alzheimer’s disease and evaluate its feasibility, acceptability, and helpfulness in managing the distress of both partners and increasing the quality of the relationship. Methods: In a single-arm …study, sixteen couples received the 8-week intervention. Qualitative and quantitative assessments were conducted pre- and post-intervention as well as three months after. Results: 88.9% of couples (n  = 16) of the final sample (n  = 18) completed the intervention. Despite the negative representations of hypnosis, several factors led couples to accept to participate in this study: positive expectations, professional endorsement, medical application, non-drug approach, home-based, free, flexible, and couple-based intervention. The results showed a significant decrease in distress for both partners. These effects were maintained three months after the intervention. Couples felt more relaxed, had fewer negative emotions, accepted difficulties more easily, were more patient, and reported better communication and more affection in the relationship. Conclusion: Overall, this pilot study shows the feasibility and acceptability of hypnosis with couples confronted with Alzheimer’s disease. Although measures of the preliminary pre- and post-intervention effects are encouraging, confirmatory testing with a randomized controlled trial is needed. Show more

Keywords: Alzheimer’s disease, couple, distress, hypnosis

DOI: 10.3233/JAD-220430

Citation: Journal of Alzheimer's Disease, vol. 89, no. 4, pp. 1351-1366, 2022