Journal of Alzheimer's Disease - Volume 95, issue 2

Authors: Che, Xiang-Qian | Lin, Guo-Zhen | Liu, Xiao-Hong | Wang, Gang | Zhao, Qian-Hua | Ren, Ru-Jing

Article Type: Research Article

Abstract: Background: Recently, Sigma nonopioid intracellular receptor 1 (SIGMAR1 ) variants have been shown harboring C9orf72 pathogenic repeat expansions in some frontotemporal dementia (FTD) cases. However, no SIGMAR1 genotype analysis has been reported in a cohort absent of C9orf72 pathogenic repeat expansions to date. Objective: The present study investigated the contribution of SIGMAR1 independent of C9orf72 gene status to FTD spectrum syndromes. Methods: We directly sequencing the entire coding region and a minimum of 50 bp from each of the flanking introns of SIGMAR1 gene in 82 sporadic FTD patients …(female: male = 42 : 40) and 417 controls. For the patient carrying SIGMAR1 variant, a follow-up 3T MR imaging was performed in the study. Results: Gene sequencing of SIGMAR1 revealed a rare 3′ UTR nucleotide variation rs192856872 in a male patient with semantic dementia independent of C9orf72 gene status. The MR imaging showed asymmetrical atrophy in the anterior temporal lobes and the degeneration extends caudally into the posterior temporal lobes as the disease progresses. ESEFinder analysis showed new SRSF1 and SRSF1-IgM-BRCA1 binding sites with significant scores, which is predicted to affect normal splicing. Conclusion: We found a novel SIGMAR1 variant independent of C9orf72 gene status associated with semantic dementia phenotype. Show more

Keywords: Alzheimer’s disease, frontotemporal dementia, genetic analysis, magnetic resonance imaging, SIGMAR1

DOI: 10.3233/JAD-221195

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 469-475, 2023

Authors: Rosales-Lagarde, Alejandra | Cubero-Rego, Lourdes | Menéndez-Conde, Federico | Rodríguez-Torres, Erika E. | Itzá-Ortiz, Benjamín | Martínez-Alcalá, Claudia | Vázquez-Tagle, Génesis | Vázquez-Mendoza, Enrique | Eraña Díaz, Marta L.

Article Type: Research Article

Abstract: Background: Sleep disruption in elderly has been associated with an increased risk of cognitive impairment and its transition into Alzheimer’s disease (AD). High arousal indices (AIs) during sleep may serve as an early-stage biomarker of cognitive impairment non-dementia (CIND). Objective: Using full-night polysomnography (PSG), we investigated whether CIND is related to different AIs between NREM and REM sleep stages. Methods: Fourteen older adults voluntarily participated in this population-based study that included Mini-Mental State Examination, Neuropsi battery, Katz Index of Independence in Activities of Daily Living, and single-night PSG. Subjects were divided into two groups (n  = 7 …each) according to their results in Neuropsi memory and attention subtests: cognitively unimpaired (CU), with normal results; and CIND, with –2.5 standard deviations in memory and/or attention subtests. AIs per hour of sleep during N1, N2, N3, and REM stages were obtained and correlated with Neuropsi total score (NTS). Results: AI (REM)  was significantly higher in CU group than in CIND group. For the total sample, a positive correlation between AI (REM)  and NTS was found (r  = 0.68, p  = 0.006), which remained significant when controlling for the effect of age and education. In CIND group, the AI (N2)  was significantly higher than the AI (REM)  . Conclusion: In CIND older adults, this attenuation of normal arousal mechanisms in REM sleep are dissociated from the relative excess of arousals observed in stage N2. We propose as probable etiology an early hypoactivity at the locus coeruleus noradrenergic system, associated to its early pathological damage, present in the AD continuum. Show more

Keywords: Alzheimer’s disease, arousals, locus coeruleus, mild cognitive impairment, neuropsychological testing, polysomnography, REM sleep

DOI: 10.3233/JAD-230101

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 477-491, 2023

Authors: Ng, Pei Y. | Zhang, Cheng | Li, Hu | Baker, Darren J.

Article Type: Research Article

Abstract: Background: The existence and contribution of microglia with senescent-like alterations in the pathogenesis of age-related neurodegenerative diseases like Alzheimer’s disease (AD) have been suggested in recent years. However, the identification of this distinct microglial population in vivo has proven challenging, largely due to overlaps in the inflammatory phenotype of activated and senescent microglia. Furthermore, attempts at recapitulating senescence in microglia in vitro are limited. Objective: To identify and characterize senescent microglia that occur in vivo in an animal model of neurodegeneration driven by pathologic tau. Methods: We analyzed the RNA expression patterns of …individual microglia from normal mice and the pathogenic tau P301 S PS19 mouse model. We have previously demonstrated that p16-expressing senescent microglia occur in these mice when neurodegeneration has occurred. Results: Here we identify a subset of disease-associated microglia with senescent features, notably characterized by the expression of Ccl4 . This signature overlaps with established markers of senescence from other cell types. Conclusion: Our characterization of senescent microglia can be used to better understand the role of senescent microglia in various age-related contexts, including whether clearance of senescent microglia represents a viable therapeutic option. Show more

Keywords: Alzheimer’s disease, cellular senescence, microglia, tauopathy

DOI: 10.3233/JAD-230109

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 493-507, 2023

Authors: Guevara, Jasmin E. | Kurniadi, Natalie E. | Duff, Kevin

Article Type: Research Article

Abstract: Background: Cognitive change in mild cognitive impairment (MCI), a likely prodrome to Alzheimer’s disease, can be tracked with repeated neuropsychological assessments, but there has been little work quantifying these changes over time. Cognitive change can be statistically examined using standardized regression-based (SRB) formulas, which yield a z-score indicating amount of change compared to a normative group. Objective: To use SRB z-scores to quantify cognitive change in a sample of patients classified as MCI at baseline, and to compare cognitive change in those who remained MCI on follow-up (MCI-Stable) and those who progressed to dementia (MCI-Decline). Methods: …Using 283 MCI patients from a cognitive disorders clinic who were re-assessed after approximately one- and one-half years, SRB z-scores were calculated for each test in a comprehensive neuropsychological battery for each participant. Results: There was a significant decline between timepoints across all cognitive tests, with the greatest amount of decline on tests of learning and memory. Group differences were seen on nearly all cognitive tests, with the MCI-Decline group showing more decline (i.e., significantly larger and negative z-scores) than the MCI-Stable participants. Notable cognitive decline was also observed in the MCI-Stable group, with z-scores ranging from –0.01 – –2.24 compared to normative data. Conclusion: This study highlights the amount of cognitive decline that occurs in MCI, including for those who remain “stable” and those who progress to dementia. It also demonstrates the value of the SRB method in more clearly quantifying cognitive decline, which may help identify individuals most vulnerable to MCI progression. Show more

Keywords: Alzheimer’s disease, cognitive decline, cognitive testing, dementia, mild cognitive impairment

DOI: 10.3233/JAD-230160

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 509-521, 2023

Authors: Zhuo, Bingting | Zheng, Dashan | Cai, Miao | Wang, Chongjian | Zhang, Shiyu | Zhang, Zilong | Tian, Fei | Wang, Xiaojie | Lin, Hualiang

Article Type: Research Article

Abstract: Background: Studies have reported the associations between inflammation, brain volume, and cognition separately. It is reasonable to assume peripheral inflammation may contribute to cognitive decline through brain volume atrophy. Objective: To examine the associations between peripheral inflammation, brain volume, and cognition among adults, and to investigate whether brain volume atrophy mediates the inflammation-cognition relationship Methods: We retrieved 20,381 participants with available data on peripheral inflammation, brain volume, and cognition from the UK Biobank cohort. Cognitive function was assessed by performance on cognitive tasks probing various cognitive domains. Brain volumes were measured by magnetic resonance imaging (MRI). …Multivariable linear models were used to investigate the associations between three peripheral inflammatory indexes (C-reactive protein, systemic immune-inflammatory index, neutrophil-to-lymphocyte ratio), brain volume, and cognition. Mediation analyses were conducted to assess the potential mediating effect of brain volume atrophy. All results were corrected for multiple comparisons using the false-discovery rate (FDR). Results: Peripheral inflammation was inversely associated with grey matter volume (GMV), white matter volume (WMV), and cognition after adjusting for potential covariates. For instance, CRP was associated with the GMV of left parahippocampal gyrus (β= –0.05, 95% confidence interval [CI]: –0.06 to –0.04, p FDR =1.07×10-16 ) and general cognitive factor (β= –0.03, 95% CI: –0. –0.04 to –0.01, p FDR  = 0.001). Brain volume atrophy mediated the inflammation-cognitive decline relationship, accounting for 15–29% of the overall impact. Conclusion: In this cohort study, peripheral inflammation was associated with brain volume atrophy and cognitive decline. Brain atrophy may mediate the inflammation-cognitive decline relationship. Show more

Keywords: Alzheimer’s disease, brain volume, cognitive function, inflammation, mediation effect

DOI: 10.3233/JAD-230253

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 523-533, 2023

Authors: Song, Shangchen | Asken, Breton | Armstrong, Melissa J. | Yang, Yang | Li, Zhigang

Article Type: Research Article

Abstract: Background: Assessing the risk of developing clinical Alzheimer’s disease (AD) dementia, by machine learning survival analysis approaches, among participants registered in Alzheimer’s Disease Centers is important for AD dementia management. Objective: To construct a prediction model for the onset time of clinical AD dementia using the National Alzheimer Coordinating Center (NACC) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI) registered cohorts. Methods: A model was constructed using the Random Survival Forest (RSF) approach and internally and externally validated on the NACC cohort and the ADNI cohort. An R package and a Shiny app were provided for accessing …the model. Results: We built a predictive model having the six predictors: delayed logical memory score (story recall), CDR® Dementia Staging Instrument - Sum of Boxes, general orientation in CDR®, ability to remember dates and ability to pay bills in the Functional Activities Questionnaire, and patient age. The C indices of the model were 90.82% (SE = 0.71%) and 86.51% (SE = 0.75%) in NACC and ADNI respectively. The time-dependent AUC and accuracy at 48 months were 92.48% (SE = 1.12%) and 88.66% (SE = 1.00%) respectively in NACC, and 90.16% (SE = 1.12%) and 85.00% (SE = 1.14%) respectively in ADNI. Conclusion: The model showed good prediction performance and the six predictors were easy to obtain, cost-effective, and non-invasive. The model could be used to inform clinicians and patients on the probability of developing clinical AD dementia in 4 years with high accuracy. Show more

Keywords: Alzheimer’s disease, dementia, machine learning, survival analysis

DOI: 10.3233/JAD-230208

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 535-548, 2023

Authors: Conti, Elisa | Grana, Denise | Angiulli, Federica | Karantzoulis, Aristotelis | Villa, Chiara | Combi, Romina | Appollonio, Ildebrando | Ferrarese, Carlo | Tremolizzo, Lucio

Article Type: Research Article

Abstract: Background: Neuroinflammation is one of the cardinal mechanisms of Alzheimer’s disease (AD). with amyloid-β (Aβ) playing a critical role by activating microglia to produce soluble inflammatory mediators, including several chemokines. Peripheral monocytes are, therefore, attracted into the central nervous system (CNS), where they change into blood-born microglia and participate in the attempt of removing toxic Aβ species. The translocator protein-18 kDa (TSPO) is a transmembrane protein overexpressed in response to neuroinflammation and known to regulate human monocyte chemotaxis. Objective: We aimed to evaluate the role of the oligomeric Aβ1-42 isoform at inducing peripheral monocyte chemotaxis, and the …possible involvement of TSPO in this process. Methods: In vitro cell lines, and ex vivo monocytes from consecutive AD patients (n  = 60), and comparable cognitively intact controls (n  = 30) were used. Chemotaxis analyses were carried out through both μ -slide chambers and Boyden assays, using 125 pM oligomeric Aβ1-42 as chemoattractant. TSPO agonists and antagonists were tested (Ro5-4864, Emapunil, PK11195). Results: Oligomeric Aβ directly promoted chemotaxis in all our models. Interestingly, AD monocytes displayed a stronger response (about twofold) with respect to controls. Aβ-induced chemotaxis was prevented by the TSPO antagonist PK11195; the expression of the TSPO and of the C-C chemokine receptor type 2 (CCR2) was unchanged by drug exposure. Conclusion: Oligomeric Aβ1-42 is able to recruit peripheral monocytes, and we provide initial evidence sustaining a role for TSPO in modulating this process. This data may be of value for future therapeutic interventions aimed at modulating monocytes motility toward the CNS. Show more

Keywords: Alzheimer’s disease, amyloid-β, chemotaxis, monocytes, neuroinflammation, PK11195, TSPO

DOI: 10.3233/JAD-230239

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 549-559, 2023

Authors: Spartano, Nicole L. | Wang, Ruiqi | Yang, Qiong | Chernofsky, Ariel | Murabito, Joanne M. | Levy, Daniel | Vasan, Ramachandran S. | DeCarli, Charles | Maillard, Pauline | Seshadri, Sudha | Beiser, Alexa S.

Article Type: Research Article

Abstract: Introduction: Cardiometabolic risk factors and epigenetic patterns, increased in physically inactive individuals, are associated with an accelerated brain aging process. Objective: To determine whether cardiometabolic risk factors and epigenetic patterns mediate the association of physical inactivity with unfavorable brain morphology. Methods: We included dementia and stroke free participants from the Framingham Heart Study Third Generation and Offspring cohorts who had accelerometery and brain MRI data (n  = 2,507, 53.9% women, mean age 53.9 years). We examined mediation by the 2017-revised Framingham Stroke Risk Profile (FSRP, using weights for age, cardiovascular disease, atrial fibrillation, diabetes and smoking status, …antihypertension medications, and systolic blood pressure) and the homeostatic model of insulin resistance (HOMA-IR) in models of the association of physical inactivity with brain aging, adjusting for age, age-squared, sex, accelerometer wear time, cohort, time from exam-to-MRI, and season. We similarly assessed mediation by an epigenetic age-prediction algorithm, GrimAge, in a smaller sample of participants who had DNA methylation data (n  = 1,418). Results: FSRP and HOMA-IR explained 8.3–20.5% of associations of higher moderate-to-vigorous physical activity (MVPA), higher steps, and lower sedentary time with higher brain volume. Additionally, FSRP and GrimAge explained 10.3–22.0% of associations of physical inactivity with lower white matter diffusivity and FSRP explained 19.7% of the association of MVPA with lower free water accumulation. Conclusion: Our results suggest that cardiometabolic risk factors and epigenetic patterns partially mediate the associations of physical inactivity with lower brain volume, higher white matter diffusivity, and aggregation of free water in the extracellular compartments of the brain. Show more

Keywords: Alzheimer’s disease, dementia, exercise, physical activity, sedentary time

DOI: 10.3233/JAD-230289

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 561-572, 2023

Authors: Miyawaki, Christina E. | McClellan, Angela | Bouldin, Erin D. | Brohard, Cheryl | Spencer, Helen | Tahija, Nina | Kunik, Mark E.

Article Type: Research Article

Abstract: Background: Due to the high prevalence of depressive symptoms and Alzheimer’s disease and related dementias in older Americans (≥65 years), we developed a six-week depression intervention, Caregiver-Provided Life Review (C-PLR) for care recipients (CRs) with early-stage dementia and mild depression. Objective: The objective of the study was to examine the feasibility and efficacy of C-PLR delivered by virtually-trained caregivers (CGs) on CRs who live with dementia and depression in community and long-term care settings (N = 25 CG-CR dyads). Methods: We used fidelity scores as a measure of CG’s feasibility to provide C-PLR. We collected the pre- …and post-measures on CRs’ depression (primary outcome), life satisfaction, CGs’ burden, positive aspects of caregiving, and CG-CR relationship quality (secondary outcomes) and compared them using paired t-tests. We evaluated if the effect differed by race/ethnicity, residential setting, or living alone. Results: The average fidelity check-in score was 14.8±0.78 indicating high feasibility. CGs were 52 years old (mean), 88% female, 64% working, 72% college-educated, and 72% in good-excellent health. CRs were 81 years old (mean), 84% female, and 56% in poor-fair health. CRs’ depression significantly improved (p  < 0.001), and this effect was found in CRs who were Asian (p  = 0.017), White (p  = 0.040), community-dwelling (p  < 0.001), lived alone (p  = 0.045), or with others (p  = 0.002). Conclusion: This study demonstrated that the C-PLR can be successfully taught to CGs virtually and is effective in reducing CR’s depressive symptoms. C-PLR could be implemented more broadly to improve symptoms among CRs in community and residential settings, as well as among a diverse population of CRs. Show more

Keywords: Alzheimer’s disease, caregiver education, dementia, depressive symptoms, internet-based intervention, program evaluation

DOI: 10.3233/JAD-230371

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 573-583, 2023

Authors: Silva, Jacqueline D. | Taglialatela, Giulio | Jupiter, Daniel C.

Article Type: Research Article

Abstract: Background: Evidence suggests patients prescribed calcineurin inhibitors (CNIs) have a reduced prevalence of dementia, including Alzheimer’s disease (AD); however, this result has never been replicated in a large cohort and the involved mechanism(s) and site of action (central versus periphery) remain unclear. Objective: We aim to determine if prescription of CNIs is associated with reduced prevalence of dementia, including AD, in a large, diverse patient population. Furthermore, we aim to gain insight into the mechanism(s) and site of action for CNIs to reduce dementia prevalence. Methods: Electronic health records (EHRs) from patients prescribed tacrolimus, cyclosporine, or …sirolimus were analyzed to compare prevalence, odds, and hazard ratios related to dementia diagnoses among cohorts. EHRs from a random, heterogeneous population from the same network were obtained to generate a general population-like control. Results: All drugs examined reduced dementia prevalence compared to the general population-like control. There were no differences in dementia diagnoses upon comparing tacrolimus and sirolimus; however, patients prescribed tacrolimus had a reduced dementia prevalence relative to cyclosporine. Conclusion: Converging mechanisms of action between tacrolimus and sirolimus likely explain the similar dementia prevalence between the cohorts. Calcineurin inhibition within the brain has a greater probability of reducing dementia relative to peripherally-restricted calcineurin inhibition. Overall, immunosuppressants provide a promising therapeutic avenue for dementia, with emphasis on the brain-penetrant CNI tacrolimus. Show more

Keywords: Alzheimer’s disease, calcineurin, cyclosporine, dementia prevalence, drug repurposing, electronic health records, sirolimus, tacrolimus, TriNetX

DOI: 10.3233/JAD-230526

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 585-597, 2023

Authors: Norris, Christopher M.

Article Type: Article Commentary

Abstract: Numerous preclinical and human tissue studies implicate the protein phosphatase calcineurin (CN) as a pathophysiologic mechanism in Alzheimer’s disease (AD) and other neurodegenerative conditions. Using public electronic records of tens of thousands of individuals across the United States, Silva et al. (2023) show that use of the FDA-approved CN inhibitor, tacrolimus (for purposes of immunosuppression) is also associated with reduced prevalence of dementia-related symptoms. Notably, the study controls for age, sex, and race as well as multiple risk factors for AD. The results suggest that tacrolimus, and possibly other immunosuppressants could be repurposed for the treatment of AD-related dementia.

Keywords: Alzheimer’s disease, Ca2+ dysregulation, calcineurin, dementia, immunosuppressant

DOI: 10.3233/JAD-230780

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 599-602, 2023

Authors: Yang, Yi | Lv, Jiaxi | Bai, Huimin | Ren, Liang | Yang, Jing | Ding, Yi | Liu, Chengcheng | Chen, Xueping

Article Type: Research Article

Abstract: Background: Characterizing the periodontal status of patients with Alzheimer’s disease (AD), investigating differences in salivary metabolism between patients with and without AD under the same periodontal conditions, and understanding how it is related to oral flora are critical. Objective: We aimed to examine the periodontal condition of patients with AD and to screen salivary metabolic biomarkers from the saliva of individuals with and without AD with matched periodontal conditions. Furthermore, we aimed to explore the possible relationship between salivary metabolic changes and oral flora. Methods: In total, 79 individuals were recruited into the experiment for periodontal …analysis. Especially, 30 saliva samples from the AD group and 30 from healthy controls (HCs) with matched periodontal conditions were selected for metabolomic analysis. The random-forest algorithm was used to detect candidate biomarkers. Among these, 19 AD saliva and 19 HC samples were selected to investigate the microbiological factors influencing the alterations in saliva metabolism in patients with AD. Results: The plaque index and bleeding on probing were considerably higher in the AD group. Further, Cis-3-(1-carboxy-ethyl)-3,5-cyclohexadiene-1,2-diol, dodecanoic acid, genipic acid, and N, N-dimethylthanolamine N-oxide were determined as candidate biomarkers, based on the area under the curve (AUC) value (AUC = 0.95). The results of oral-flora sequencing showed that dysbacteriosis may be a reason for the differences in AD saliva metabolism. Conclusion: Dysregulation of the proportion of specific bacterial flora in saliva plays a vital role in metabolic changes in AD. These results will contribute to further improving the AD saliva biomarker system. Show more

Keywords: Alzheimer’s disease, metabolomics, microbiota, periodontitis, saliva

DOI: 10.3233/JAD-230291

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 603-613, 2023

Authors: Wang, Xin | Sundermann, Erin E. | Buckley, Rachel F. | Reas, Emilie T. | McEvoy, Linda K. | Banks, Sarah J.

Article Type: Research Article

Abstract: Background: The association between obesity and Alzheimer’s disease (AD) is complex. Recent studies indicated the relationships between obesity and AD may differ by sex, and women may benefit from being overweight in terms of AD risk. Objective: We investigated whether sex modifies the associations of obesity with tau positron emission tomography (PET), amyloid PET, and cognition in preclinical AD. Methods: We included 387 cognitively-unimpaired amyloid-positive participants (221 women, 166 men, 87.6% non-Hispanic White) with available 18 F-flortaucipir PET, 18 F-florbetapir PET, and completed the Preclinical Alzheimer Cognitive Composite (PACC) tests from the Anti-Amyloid Treatment in Asymptomatic …Alzheimer’s Disease (A4) study. Participants were categorized based on body mass index (BMI: kg/m2 ): normal-weight (BMI: 18.5-25), overweight (BMI: 25-30), and obese (BMI≥30). Results: Significant sex by BMI category interactions on PACC and its components: Mini-Mental State Examination (MMSE) and Reminding Test–Free+Total Recall (FCSRT96) revealed that overweight and obese women outperformed normal-weight women on FCSRT96, while obese men showed poorer MMSE performance than normal-weight men. These interactions were independent of APOE4 . There were no significant interactions of sex by BMI category on tau and amyloid PET. However, sex-stratified analyses observed obesity was associated with less regional tau and mean cortical amyloid in women, not in men. Conclusion: This study found that in preclinical AD, overweight and obesity were associated with better verbal memory in women, whereas obesity was associated with worse global cognition among men. Future studies focusing on the mechanism for this relationship may inform sex-specific interventions for AD prevention. Show more

Keywords: Alzheimer’s disease, cognition, obesity, overweight, sex differences

DOI: 10.3233/JAD-230466

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 615-624, 2023

Authors: Huan, Sheng | Liu, Mengling | Liu, Ziqiu | Gao, Jing | Yin, Guoping

Article Type: Research Article

Abstract: Background: The association between dietary or serum cholesterol and cognitive performance in older adults has not been well-established. Objective: This study aimed to investigate the potential association between dietary or serum cholesterol and cognitive performance in the elderly population. Methods: A cross-sectional analysis was conducted using data from the National Health and Nutrition Examination Survey (NHANES) 2011-2012 and 2013-2014. Diet and supplement cholesterol was estimated based on two non-consecutive 24-hour dietary recalls. Cognitive function was assessed using various statistical tests. Poor cognitive performance was defined as scores below the lowest quartile within age groups. Regression models …were adjusted for demographic factors, and subgroup analyses were performed for non-Hispanic White (NHW) and non-Hispanic Black (NHB) individuals. Results: Among 759 participants aged 60 years and above, dietary cholesterol was only associated with dietary saturated fatty acids and serum high-density lipoprotein cholesterol. There was no evidence of an association between dietary cholesterol and cognitive function, except for NHB individuals, where dietary cholesterol showed a positive correlation with cognitive function. In the overall sample and NHW participants, there were consistent positive associations between serum total cholesterol and cognitive performance across statistical tests, while such associations were rare among NHB individuals. Although not statistically significant, NHB individuals had higher dietary/supplementary/total cholesterol intake compared with NHW individuals. Conclusion: Within the normal range, increasing serum cholesterol may be a potential factor to prevent or relieve cognitive dysfunction. However, ethnic differences should be taken into account when considering the association between cholesterol and cognitive performance. Show more

Keywords: Alzheimer’s disease, cholesterol, cognitive function, dietary, NHANES

DOI: 10.3233/JAD-230422

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 625-640, 2023

Authors: Kenkpen, Angel K. | Storey, Joshua J. | Olson, Emma R. | Guden, Ty E. | Card, Tate T. | Jensen, Ashley S. | Ahrens, Jordyn L. | Hellmann Whitaker, Rachel A.

Article Type: Research Article

Abstract: Background: Long non-coding RNAs are ubiquitous throughout the human system, yet many of their biological functions remain unknown. LINC00298 RNA, a long intergenic non-coding RNA, has been shown to have preferential expression in the central nervous system where it contributes to neuronal differentiation and development. Furthermore, previous research has indicated that LINC00298 RNA is known to be a genetic risk factor for the development of Alzheimer’s disease. Objective: To biochemically characterize LINC00298 RNA and to elucidate its biological function within hippocampal neuronal cells, thereby providing a greater understanding of its role in Alzheimer’s disease pathogenesis. Methods: …LINC00298 RNA was in vitro transcribed and then subjected to structural analysis using circular dichroism, and UV-Vis spectroscopy. Additionally, affinity column chromatography was used to capture LINC00298 RNA’s protein binding partners from hippocampal neuronal cells, which were then identified using liquid chromatography and mass spectrometry (LC/MS). Results: LINC00298 RNA is comprised of stem-loop secondary structural elements, with a cylindrical tertiary structure that has highly dynamic regions, which result in high positional entropy. LC/MS identified 24 proteins within the interactome of LINC00298 RNA. Conclusion: Through analysis of LINC00298 RNA’s 24 protein binding partners, it was determined that LINC00298 RNA may play significant roles in neuronal development, proliferation, and cellular organization. Furthermore, analysis of LINC00298 RNA’s interactome indicated that LINC00298 RNA is capable of intracellular motility with dual localization in the nucleus and the cytosol. This biochemical characterization of LINC00298 RNA has shed light on its role in Alzheimer’s disease pathogenesis. Show more

Keywords: Alzheimer’s disease, genetic risk factors, long non-coding RNA, transcriptome

DOI: 10.3233/JAD-230057

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 641-661, 2023

Authors: Passmore, Susan Racine | Longhurst, Colin | Gerbitz, Abigail | Green-Harris, Gina | Norris, Nia | Edwards, Dorothy Farrar

Article Type: Research Article

Abstract: Background: Although African Americans experience the highest risk of Alzheimer’s disease (AD), they are dramatically underrepresented in preclinical biomarker research. This is especially true for studies involving lumbar puncture as it may involve more perceived risk even for those participants who are otherwise supportive of research. Objective: To understand the unique concerns of African American participants regarding biomarker studies involving lumbar puncture who demonstrate support for AD research. Methods: Study participants were African American adults contacted through an AD research registry. We employed a novel method used to create hypothetical research studies varying on a set …number of factors. The method is designed to collect potential patterns in decision making regarding research participation but differs from experimental vignette design in that the survey is administered with an accompanying qualitive interview to determine the meaning participants ascribe to factors independently and in conjunction with one another. Results: Sixty-one participants each reviewed three randomly selected research scenarios and created their “ideal” study involving lumbar puncture. Scenario variables included: disclosure of research results, racial and ethnic identity of the researcher, recruitment method, and amount of incentive. Conclusion: Findings indicate that transparency in the return of AD research results to be the strongest driver of participation, followed by race of the researcher and amount of incentive. Recruitment method had limited impact on hypothetical decision making. Show more

Keywords: Alzheimer’s disease, Black or African American, ethics, health, health equity

DOI: 10.3233/JAD-230275

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 663-675, 2023

Authors: Katisko, Kasper | Krüger, Johanna | Soppela, Helmi | Hartikainen, Päivi | Haapasalo, Annakaisa | Remes, Anne M. | Solje, Eino

Article Type: Research Article

Abstract: Background: Due to the significant presence of neuropsychiatric symptoms in patients with frontotemporal dementia (FTD) spectrum disorders, psychiatric misdiagnoses, diagnostic delay, and use of psychiatric treatments are common prior to the FTD diagnosis. Furthermore, treatment of diagnosed FTD patients mainly relies on off-label psychopharmacological approaches. Currently, limited real-world data are available regarding the actual use of psychopharmacological medications in FTD. Objective: To evaluate psychopharmacological medication use at the time of FTD diagnosis. Methods: Psychopharmacological medication use was evaluated in a Finnish FTD cohort containing 222 FTD patients, including the major clinical disease phenotypes (behavioral, language, and …motor variants) and genetic patients carrying the C9orf72 repeat expansion. A cohort of 214 Alzheimer’s disease (AD) patients was used as a neurodegenerative disease reference group. Results: Active use of psychopharmacological medications at the time of diagnosis was significantly more common in FTD compared to AD, especially in the case of antidepressants (26.1% versus 15.0%, OR = 2.01, p  = 0.008), antipsychotics (23.9% versus 9.3%, OR = 3.15, p  < 0.001), and mood-stabilizers (6.3% versus 1.9%, OR = 2.93, p  = 0.085; not statistically significant), whereas the use of cholinesterase inhibitors or memantine was nearly nonexistent in FTD patients. Female gender and behavioral variant of FTD phenotype alongside with depressive and psychotic symptoms were the most prominent factors associating with the use of these medications among the FTD spectrum patients. Conclusion: Use of off-label psychopharmacological medication and polypharmacy is substantially common at the time of FTD diagnosis. This likely reflects the challenges in using symptom-driven treatment approaches, especially prior to the eventual diagnosis. Show more

Keywords: Alzheimer’s disease, frontotemporal dementia, pharmacology, psychiatry, psychopharmacology, therapeutics

DOI: 10.3233/JAD-230494

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 677-685, 2023

Authors: Bruffaerts, Rose | Crosiers, David

Article Type: Article Commentary

Abstract: Although neuropsychiatric symptoms are a hallmark of the behavioral variant of frontotemporal degeneration (FTD), there is limited evidence on the optimal therapeutic management of these symptoms. In this issue, Katisko et al. report real-world multicentric data on the use of psychopharmacological medication in newly diagnosed patients with FTD. Such reports contribute to knowledge sharing between clinicians caring for patients with FTD. Here, we outline how improved collection of clinical data can assure more robust evidence for future therapies in FTD and other rare neurological diseases.

Keywords: Alzheimer’s disease, frontotemporal dementia, pharmacology, psychiatry, psychopharmacology, therapeutics

DOI: 10.3233/JAD-230788

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 687-689, 2023

Authors: Yin, Grace S. | van der Heide, Frank | Littlejohns, Thomas J. | Kuźma, Elżbieta | Hayat, Shabina | Brayne, Carol | Foster, Paul J. | Luben, Robert | Khawaja, Anthony P.

Article Type: Research Article

Abstract: Background: Retinal nerve fiber layer (RNFL) thickness may reflect cerebral status. Objective: This study assessed the relationship between RNFL thickness and incident all-cause dementia in the European Prospective Investigation into Cancer in Norfolk (EPIC-Norfolk) Eye Study. Methods: Glaucoma detection with variable corneal compensation (GDx-VCC) and Heidelberg Retinal Tomograph II (HRT II) derived global mean RNFL thickness from dementia-free participants at baseline within the EPIC-Norfolk Eye Study were analyzed. Incident dementia was identified through linkage to electronic medical records. Cox proportional hazard mixed-effects regression models adjusted for key confounders were used to examine the associations between RNFL …thickness and incident dementia in four separate models. Results: 6,239 participants were included with 322 cases of incident dementia and mean age of 67.5-years old, with 49.7% women (median follow-up 13.2-years, interquartile range (11.7 to 14.6 years). Greater RNFL thickness (GDx-VCC) was not significantly associated with a lower risk of incident dementia in the full adjusted model [HR per quartile increase 0.95; 95% CI 0.82–1.10]. Similarly, RNFL thickness assessed with HRT II was also not associated with incident dementia in any model (full adjusted model; HR per quartile increase: 1.06; [95% CI 0.93–1.19]. Gender did not modify any associations under study. Conclusion: GDx-VCC and HRT II derived RNFL thickness are unlikely to be useful predictors of incident dementia. Higher resolution optical imaging technologies may clarify whether there are useful relationships between neuro-retinal morphology and brain measures. Show more

Keywords: Alzheimer’s disease, dementia, retinal ganglion cells, retinal nerve fiber layer, scanning laser polarimetry

DOI: 10.3233/JAD-230073

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 691-702, 2023

Authors: Harris, Kristofer | Ling, Yaobin | Bukhbinder, Avram S. | Chen, Luyao | Phelps, Kamal N. | Cruz, Gabriela | Thomas, Jenna | Kim, Yejin | Jiang, Xiaoqian | Schulz, Paul E.

Article Type: Research Article

Abstract: Background: Accumulating evidence suggests that adult vaccinations can reduce the risk of developing Alzheimer’s disease (AD) and Alzheimer’s disease related dementias. Objective: To compare the risk for developing AD between adults with and without prior vaccination against tetanus and diphtheria, with or without pertussis (Tdap/Td); herpes zoster (HZ); or pneumococcus. Methods: A retrospective cohort study was performed using Optum’s de-identified Clinformatics® Data Mart Database. Included patients were free of dementia during a 2-year look-back period and were≥65 years old by the start of the 8-year follow-up period. We compared two similar cohorts identified using propensity score …matching (PSM), one vaccinated and another unvaccinated, with Tdap/Td, HZ, or pneumococcal vaccines. We calculated the relative risk (RR) and absolute risk reduction (ARR) for developing AD. Results: For the Tdap/Td vaccine, 7.2% (n  = 8,370) of vaccinated patients and 10.2% (n  = 11,857) of unvaccinated patients developed AD during follow-up; the RR was 0.70 (95% CI, 0.68–0.72) and ARR was 0.03 (95% CI, 0.02–0.03). For the HZ vaccine, 8.1% (n  = 16,106) of vaccinated patients and 10.7% (n  = 21,417) of unvaccinated patients developed AD during follow-up; the RR was 0.75 (95% CI, 0.73–0.76) and ARR was 0.02 (95% CI, 0.02–0.02). For the pneumococcal vaccine, 7.92% (n  = 20,583) of vaccinated patients and 10.9% (n  = 28,558) of unvaccinated patients developed AD during follow-up; the RR was 0.73 (95% CI, 0.71–0.74) and ARR was 0.02 (95% CI, 0.02–0.03). Conclusion: Several vaccinations, including Tdap/Td, HZ, and pneumococcal, are associated with a reduced risk for developing AD. Show more

Keywords: Alzheimer’s disease, cohort, dementia, diphtheria, epidemiology, herpes zoster, pertussis, pneumococcus, tetanus, vaccine

DOI: 10.3233/JAD-221231

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 703-718, 2023

Authors: Kobro-Flatmoen, Asgeir | Hormann, Thea Meier | Gouras, Gunnar

Article Type: Research Article

Abstract: Background: Amyloid-β (Aβ) is a normal product of neuronal activity, including that of the aggregation-prone Aβ42 variant that is thought to cause Alzheimer’s disease (AD). Much knowledge about AD comes from studies of transgenic rodents expressing mutated human amyloid-β protein precursor (AβPP) to increase Aβ production or the Aβ42/40 ratio. Yet, little is known about the normal expression of Aβ42 in rodent brains. Objective: To characterize the brain-wide expression of Aβ42 throughout the life span of outbred Wistar rats, and to relate these findings to brains of human subjects without neurological disease. …Methods: Aβ42 immunolabeling of 12 Wistar rat brains (3–18 months of age) and brain sections from six human subjects aged 20–88 years. Results: In healthy Wistar rats, we find intracellular Aβ42 (iAβ42 ) in neurons throughout the brain at all ages, but levels vary greatly between brain regions. The highest levels are in neurons of entorhinal cortex layer II, alongside hippocampal neurons at the CA1/subiculum border. Concerning entorhinal cortex layer II, we find similarly high levels of iAβ42 in the human subjects. Conclusion: Expression of iAβ42 in healthy Wistar rats predominates in the same structures where iAβ accumulates and Aβ plaques initially form in the much used, Wistar based McGill-R-Thy1-APP rat model for AD. The difference between wild-type Wistar rats and these AD model rats, with respect to Aβ42 , is therefore quantitative rather that qualitative. This, taken together with our human results, indicate that the McGill rat model in fact models the underlying wild-type neuronal population-specific vulnerability to Aβ42 accumulation. Show more

Keywords: Alzheimer’s disease, animal model, disease onset, entorhinal cortex

DOI: 10.3233/JAD-230349

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 719-733, 2023

Authors: Panikkar, Daniel | Vivek, Sithara | Crimmins, Eileen | Faul, Jessica | Langa, Kenneth M. | Thyagarajan, Bharat

Article Type: Research Article

Abstract: Background: Sample collection and preanalytical protocols may significantly impact the results of large-scale epidemiological studies incorporating blood-based biomarkers of neuropathology. Objective: To evaluate the stability and assay variability of several blood-based biomarkers of neuropathology for common preanalytical conditions. Methods: We collected serum and plasma samples from 41 participants and evaluated the effect of processing delay of up to 72 h when stored at 4∘C, three freeze-thaw cycles, and a combination of 48-h processing delay when stored at 4∘C and three freeze-thaw cycles on biomarker stability. Using the Simoa assay (Quanterix Inc.), we measured amyloid-β 40 (Aβ40 ), …amyloid-β 42 (Aβ42 ), neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and phosphorylated tau 181 (p-tau-181). Results: We found that Aβ40 and Aβ42 levels significantly decreased after a 24-h processing delay in both plasma and serum samples, and a single freeze-thaw cycle (p  < 0.0001). Nevertheless, serum Aβ42/40 ratio remained stable with a processing delay up to 48 h while plasma Aβ42/40 ratio showed only small but significant increase with a delay up to 72 h. Both plasma and serum GFAP and NfL levels were only modestly affected by processing delay and freeze-thaw cycles. Plasma p-tau-181 levels notably increased with a 24-, 48-, and 72-h processing delay, but remained stable in serum. Intra-individual variation over two weeks was minimal for all biomarkers and their levels were substantially lower in serum when compared with plasma. Conclusion: These results suggest that standardizing preanalytical variables will allow robust measurements of biomarkers of neuropathology in population studies. Show more

Keywords: Alzheimer’s disease, amyloid-β , blood-based biomarkers, pre-analytical variables, Simoa assay, stability

DOI: 10.3233/JAD-230384

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 735-748, 2023

Authors: Perry, George

Article Type: Book Review

DOI: 10.3233/JAD-239008

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 749-749, 2023

Article Type: Retraction

DOI: 10.3233/JAD-239009

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 751-751, 2023