Journal of Alzheimer's Disease - Volume 92, issue 2

Authors: Royall, Donald R. | Palmer, Raymond F.

Article Type: Research Article

Abstract: Background: We have explored dementia’s blood-based protein biomarkers in the Texas Alzheimer’s Research and Care Consortium (TARCC) study. Among them are adipokines, i.e., proteins secreted by adipose tissue some of which have been associated with cognitive impairment. Objective: To associate adipokines with dementia severity and replicate their association across cohorts and biofluids (serum /plasma). Methods: We used eight rationally chosen blood-based protein biomarkers as indicators of a latent variable, i.e., “Adipokines”. We then associated that construct with dementia severity as measured by the latent dementia-specific phenotype “δ” in structural equation models (SEM). Significant factor loadings and …Adipokines’ association with δ were replicated across biofluids in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Results: Eight adipokine proteins loaded significantly on the Adipokines construct. Adipokines measured in plasma (ADNI) or serum (TARCC) explained 24 and 70% of δ’s variance, respectively. An Adipokine composite score, derived from the latent variables, rose significantly across clinical diagnoses and achieved high areas under the receiver operating characteristic curve (ROC/AUC) for discrimination of Alzheimer’s disease from normal controls (NC) or cases of mild cognitive impairment (MCI) and between NC and MCI. Conclusion: These results again suggest that SEM can be used to create latent biomarker classifiers that replicate across samples and biofluids, and that a substantial fraction of dementia’s variance is attributable to peripheral blood-based protein levels via the patterns codified in those latent constructs. Show more

Keywords: Adipokines, adiponectin, Alzheimer’s disease, Alzheimer’s Disease Neuroimaging Initiative, cognition, dementia, g, intelligence, leptin, resistin, Texas Alzheimer’s Research and Care Consortium

DOI: 10.3233/JAD-221052

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 639-652, 2023

Authors: Agger, Mikkel Pejstrup | Danielsen, Else Rubæk | Carstensen, Marcus Schultz | Nguyen, N. Mai | Horning, Maibritt | Henney, Mark Alexander | Jensen, Christopher Boe Ravn | Baandrup, Anders Ohlhues | Kjær, Troels Wesenberg | Madsen, Kristoffer Hougaard | Miskowiak, Kamilla | Petersen, Paul Michael | Høgh, Peter

Article Type: Research Article

Abstract: Background: Recent studies suggested induction of 40 Hz neural activity as a potential treatment for Alzheimer’s disease (AD). However, prolonged exposure to flickering light raises adherence and safety concerns, encouraging investigation of tolerable light stimulation protocols. Objective: To investigate the safety, feasibility, and exploratory measures of efficacy. Methods: This two-stage randomized placebo-controlled double-blinded clinical trial, recruited first cognitive healthy participants (n  = 3/2 active/placebo), and subsequently patients with mild-to-moderate AD (n  = 5/6, active/placebo). Participants were randomized 1:1 to receive either active intervention with 40 Hz Invisible Spectral Flicker (ISF) or placebo intervention with color and intensity matched non-flickering white …light. Results: Few and mild adverse events were observed. Adherence was above 86.1% of intended treatment days, with participants remaining in front of the device for >51.3 min (60 max) and directed gaze >34.9 min. Secondary outcomes of cognition indicate a tendency towards improvement in the active group compared to placebo (mean: –2.6/1.5, SD: 6.58/6.53, active/placebo) at week 6. Changes in hippocampal and ventricular volume also showed no tendency of improvement in the active group at week 6 compared to placebo. At week 12, a potential delayed effect of the intervention was seen on the volume of the hippocampus in the active group compared to placebo (mean: 0.34/–2.03, SD: 3.26/1.18, active/placebo), and the ventricular volume active group (mean: –0.36/2.50, SD: 1.89/2.05, active/placebo), compared to placebo. Conclusion: Treatment with 40 Hz ISF offers no significant safety or adherence concerns. Potential impact on secondary outcomes must be tested in larger scale clinical trials. Show more

Keywords: 40 Hz, Alzheimer’s disease, gamma entrainment, invisible spectral flicker, light-based neurostimulation

DOI: 10.3233/JAD-221238

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 653-665, 2023

Authors: Sun, Huimin | Liu, Min | Liu, Jue

Article Type: Research Article

Abstract: Background: Dementia is a critical global public health problem. Previous cohort studies have found that influenza vaccination can decrease the risk of dementia. Objective: This meta-analysis aimed to systematically examine the relationship between influenza vaccination and dementia risk. Methods: We searched PubMed, Embase, Web of Science, ScienceDirect, medRxiv, and bioRxiv for studies investigating dementia risk based on influenza vaccination status, up to September 14, 2022. Relative risks (RRs) and 95% confidence intervals (95% CIs) were pooled in the meta-analysis. Subgroup analyses and sensitivity analyses were conducted as well. Results: Of the 4,087 articles initially …reviewed, 6 cohort studies were included in the final meta-analysis, and all eligible studies were at low risk of bias. There were 2,087,195 participants without dementia at baseline (mean age: 61.8–75.5 years, 57.05% males), and 149,804 (7.18%) cases of dementia occurred during 4.00–13.00 years of follow-up. Pooled analysis of adjusted RRs found that influenza vaccination could reduce dementia risk by 31% (RR = 0.69, 95% CI: 0.57–0.83). Subgroup analyses showed that in the study with a mean age of 75–80 years or 75%–100% males, the association was generally weakened compared with studies with a mean age of 60–75 years or 25%–50% males. The results were stable in the sensitivity analyses, and no publication bias was observed. Conclusion: Influenza vaccination in older adults was markedly associated with a decreased risk of dementia. More mechanistic studies and epidemiological studies are needed to clarify the association between influenza vaccination and decreased dementia risk. Show more

Keywords: Alzheimer’s disease, dementia, influenza, meta-analysis, vaccination

DOI: 10.3233/JAD-221036

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 667-678, 2023

Authors: Andersson, John | Sundström, Anna | Nordin, Maria | Segersson, David | Forsberg, Bertil | Adolfsson, Rolf | Oudin, Anna

Article Type: Research Article

Abstract: Background: Growing evidence show that long term exposure to air pollution increases the risk of dementia. Objective: The aim of this study was to investigate associations between PM2.5 exposure and dementia in a low exposure area, and to investigate the role of olfaction and the APOE ɛ4 allele in these associations. Methods: Data were drawn from the Betula project, a longitudinal study on aging, memory, and dementia in Sweden. Odor identification ability was assessed using the Scandinavian Odor Identification Test (SOIT). Annual mean PM2.5 concentrations were obtained from a dispersion-model and matched at …the participants’ residential address. Proportional hazard regression was used to calculate hazard ratios. Results: Of 1,846 participants, 348 developed dementia during the 21-year follow-up period. The average annual mean PM2.5 exposure at baseline was 6.77μg/m3 , which is 1.77μg/m3 above the WHO definition of clean air. In a fully adjusted model (adjusted for age, sex, APOE , SOIT, cardiovascular diseases and risk factors, and education) each 1μg/m3 difference in annual mean PM2.5 -concentration was associated with a hazard ratio of 1.23 for dementia (95% CI: 1.01–1.50). Analyses stratified by APOE status (ɛ4 carriers versus non-carriers), and odor identification ability (high versus low), showed associations only for ɛ4 carriers, and for low performance on odor identification ability. Conclusion: PM2.5 was associated with an increased risk of dementia in this low pollution setting. The associations between PM2.5 and dementia seemed stronger in APOE carriers and those with below average odor identification ability. Show more

Keywords: Alzheimer’s disease, Apolipoprotein E, olfaction, particulate matter, vascular dementia

DOI: 10.3233/JAD-220469

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 679-689, 2023

Authors: Tang, Mingyu | Su, Ning | Zhang, Dingding | Dai, Yi | Yao, Ming | Zhou, Lixin | Cui, Liying | Zhang, Shuyang | Zhu, Yicheng | Ni, Jun

Article Type: Research Article

Abstract: Background: Apolipoprotein E (APOE) is closely related to Alzheimer’s disease and other age-related diseases. In recent years, several studies have shown an interaction of APOE by age on brain volume. However, validation in larger cohorts is required. Objective: We explored the age-related effect of APOE on brain volumes in a community-dwelling cohort. Methods: Inhabitants in Shunyi District in Beijing aged≥35 years were invited to join this study from 2013 to 2016. The baseline assessments, APOE genotyping and brain magnetic resonance imaging were performed. Neuroimaging small vessel disease characteristics and brain volumes (global …measures, cerebral lobes, hippocampus, brainstem, and subcortical nuclei) were acquired. The general linear model was used to analyze the interaction of APOE genotypes by age on brain volumes, and the age of 60 years was chosen as a cut-off value for stratification analysis. Results: A total of 1,105 subjects were enrolled in the final analysis with a mean age of 56.18 (9.30) years, and 37.7% were men. APOE ɛ 3/ɛ 3 carriers account for 71.8%, ɛ 2 (+) 14.0%, and ɛ 4 (+) 14.2%. Compared with APOE ɛ 3/ɛ 3, a significant protective effect for APOE ɛ 4 (+) on brain parenchyma fraction (β  =  0.450, p  = 0.048) was observed in subjects aged≤60 years; in participants aged > 60 years, a negative effect for APOE ɛ 4 (+) on hippocampus (β  =  1.087, p  = 0.021) was found. Conclusion: Our study reveals that APOE ɛ 4 has differential effects on cerebral structures in different stages of lifespan, suggesting its complicated biological function and underlying antagonistic pleiotropy. Show more

Keywords: Age stratification, antagonistic pleiotropy, APOE ɛ4, brain structure, interaction

DOI: 10.3233/JAD-220834

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 691-700, 2023

Authors: Mann, Frank D. | Clouston, Sean A.P. | Cuevas, Adolfo | Waszczuk, Monika A. | Kuan, Pei-Fen | Carr, Melissa A. | Docherty, Anna R. | Shabalin, Andrea A. | Gandy, Sam E. | Luft, Benjamin J.

Article Type: Research Article

Abstract: Background: There is a high incidence of cognitive impairment among World Trade Center (WTC) responders, comorbid with post-traumatic stress disorder (PTSD). Yet, it remains unknown whether genetic liability for Alzheimer’s disease, PTSD, educational attainment, or for a combination of these phenotypes, is associated with cognitive impairment in this high-risk population. Similarly, whether the effects of genetic liability are comparable to PTSD and indicators of exposure severity remains unknown. Objective: In a study of 3,997 WTC responders, polygenic scores for Alzheimer’s disease, PTSD, and educational attainment were used to test whether genome-wide risk for one or more …of these phenotypes is associated with cognitive impairment, controlling for population stratification, while simultaneously estimating the effects of demographic factors and indicators of 9/11 exposure severity, including symptoms of PTSD. Results: Polygenic scores for Alzheimer’s disease and educational attainment were significantly associated with an increase and decrease, respectively, in the hazard rate of mild cognitive impairment. The polygenic score for Alzheimer’s disease was marginally associated with an increase in the hazard rate of severe cognitive impairment, but only age, exposure severity, and symptoms of PTSD were statistically significant predictors. Conclusion: These results add to the emerging evidence that many WTC responders are suffering from mild cognitive impairments that resemble symptoms of Alzheimer’s disease, as genetic liability for Alzheimer’s disease predicted incidence of mild cognitive impairment. However, compared to polygenic scores, effect sizes were larger for PTSD and the type of work that responders completed during rescue and recovery efforts. Show more

Keywords: Alzheimer’s disease, educational attainment, mild cognitive impairment, polygenic score, post-traumatic stress disorder

DOI: 10.3233/JAD-220892

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 701-712, 2023

Authors: Wang, Zebin | Zeng, Shan | Jing, Yan | Mao, Wenjuan | Li, Hongyan

Article Type: Research Article

Abstract: Background: Sarm1 (Sterile alpha and TIR motif-containing 1) is a key protein that regulates neurodegenerative pathologies. Alzheimer’s disease (AD) is highly associated with neurodegenerative lesions and biorhythmic disturbances. Objective: This study aims to decipher the role of Sarm1 in AD-induced circadian rhythm disturbances and AD progression. Methods: Open field and water maze tests were used to assess the cognitive function of mice. Thioflavin-S staining was used to assess amyloid-β (Aβ) plaque deposition in the hippocampus and cortex. Rhythmic waveform of home cage activity and temperature was recorded to evaluate circadian rhythm. Expression of clock molecules including …Bmal1 and Per2 in the hippocampus were analyzed using western blot and real-time PCR. Further, HT22 cells with Sam1 knockout were treated with Aβ31–35 treatment to initiate circadian rhythm disorder in the cellular level to assess the changes in Bmal1 and Per2. Results: Our data suggested that Sarm1 deficiency rescued cognitive disorder, decreased Aβ plaque deposition in the hippocampus and cortex, inhibited astrocyte activation, improved circadian rhythm, altered clock molecule expression in the cortex and hippocampus in APP/PS1 mice. Conclusion: Sarm1 attenuates circadian rhythm disturbances and reduces AD progression. These data support the potential use of Sarm1 as a therapeutic target to improve circadian rhythm to impede AD progression. Show more

Keywords: Alzheimer’s disease, circadian rhythm, sarm1

DOI: 10.3233/JAD-221027

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 713-722, 2023

Article Type: Correction

DOI: 10.3233/JAD-229021

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 723-723, 2023

Authors: Abdelhamid, Mona | Zhou, Chunyu | Ohno, Kazuya | Kuhara, Tetsuya | Taslima, Ferdous | Abdullah, Mohammad | Jung, Cha-Gyun | Michikawa, Makoto

Article Type: Correction

DOI: 10.3233/JAD-229022

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 725-725, 2023

Authors: Figueiredo, Cláudia P. | Bicca, Maíra A. | Latini, Alexandra | Prediger, Rui Daniel S. | Medeiros, Rodrigo | Calixto, João B.

Article Type: Correction

DOI: 10.3233/JAD-229023

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 727-728, 2023