Journal of Alzheimer's Disease - Volume 93, issue 4

Authors: Balietti, Marta | Casoli, Tiziana | Giorgetti, Belinda | Colangeli, Roberto | Nicoletti, Cristina | Solazzi, Moreno | Pugliese, Arianna | Conti, Fiorenzo

Article Type: Research Article

Abstract: Background: Numerous mouse models of Alzheimer’s disease (AD) are available, but all suffer from certain limitations, thus prompting further attempts. To date, no one model exists with amyloidopathy in a BALB/c strain. Objective: To generate and characterize the C.B6/J-APPswe mouse, a model of AD with a mutated human gene for the amyloid-β protein precursor (AβPP) inserted in a BALB/c background. Methods: We analyzed five groups at different ages (3, 6, 9, 12, and 16–18 months) of C.B6/J-APPswe and wild-type mice (50% males and 50% females) for the main hallmarks of …AD by western blotting, amyloid-β (Aβ) ELISA, immunocytochemistry, electrophysiology, and behavioral tests. Results: The C.B6/J-APPswe mouse displays early AβPP and Aβ production, late amyloid plaques formation, high level of Tau phosphorylation, synaptic deficits (reduced density and functional impairment due to a reduced post-synaptic responsiveness), neurodegeneration caused by apoptosis and necroptosis/necrosis, microgliosis, astrocytic abnormalities, and sex-related differences in explorative behavior, anxiety-like behavior, and spatial long-term and working memories. Social housing is feasible despite the intra-cage aggressiveness of male animals. Conclusion: C.B6/J-APPswe mice develop most of the distinctive features of AD and is a suitable model for the study of brain atrophy mechanisms and of the differences between males and females in the onset of cognitive/non-cognitive deficits. Show more

Keywords: Alzheimer’s disease, amyloid-β protein precursor, cognitive impairment, congenic mouse, neurodegeneration, neuroinflammation, sex-related differences, synaptic alteration

DOI: 10.3233/JAD-230195

Citation: Journal of Alzheimer's Disease, vol. 93, no. 4, pp. 1485-1508, 2023

Authors: Chen, Xiao | Li, Wanlu | Huang, Yuhui | Yang, Jiaxi | Tao, Yang | Huang, Liyan | Shen, Jiadong | Ma, Yanan | Liu, Zuyun | Xu, Xin | Xu, Xiaolin | Zong, Geng | Yuan, Changzheng

Article Type: Research Article

Abstract: Background: The Cognitive role of untreated type 2 diabetes mellitus (T2DM) has been less well substantiated. Objective: We sought to explore the prospective association of T2DM and untreated T2DM with cognitive function among middle-aged and older Chinese adults. Methods: Data of 7,230 participants without baseline brain damage/mental retardation, or memory-related diseases in China Health and Retirement Longitudinal Study (CHARLS) from 2011– 2012 to 2015, were analyzed. Fasting plasma glucose and self-reported information on T2DM diagnosis and treatment were assessed. Participants were categorized into normoglycemia, impaired fasting glucose (IFG), and T2DM (including untreated and treated T2DM) groups. …Episodic memory and executive function were assessed by modified Telephone Interview for Cognitive Status every two years. We used generalized estimating equation model to examine the association of baseline T2DM status with cognitive function in succeedingyears. Results: Compared to those with normoglycemia, T2DM was associated with worse overall cognitive function after controlling for demographic variables, lifestyles, follow-up time, major clinical factors, and baseline cognitive function, although the associations were statistically non-significant (β = –0.19, 95% CI: –0.39, 0.00). However, a significant association was mainly observed for those with untreated T2DM (β = –0.26, 95% CI: –0.47, –0.04), especially in the domain of executive function (β = –0.19, 95% CI: –0.35, –0.03). In general, IFG and treated T2DM individuals had similar levels of cognitive function with normoglycemia participants. Conclusion: Our findings supported a detrimental role of untreated T2DM on cognitive function among middle-aged and older adults. Screening and early treatment for T2DM are warranted for maintaining better cognitive function in later life. Show more

Keywords: Alzheimer’s disease, cognitive function, prospective study, type 2 diabetes mellitus, untreated T2DM

DOI: 10.3233/JAD-220822

Citation: Journal of Alzheimer's Disease, vol. 93, no. 4, pp. 1509-1520, 2023

Authors: Carlos, Arenn F. | Machulda, Mary M. | Rutledge, Matthew H. | Nguyen, Aivi T. | Reichard, R. Ross | Baker, Matthew C. | Rademakers, Rosa | Dickson, Dennis W. | Petersen, Ronald C. | Josephs, Keith A.

Article Type: Research Article

Abstract: Background: Increasing evidence suggests that TAR DNA-binding protein 43 (TDP-43) pathology in Alzheimer’s disease (AD), or AD-TDP, can be diffuse or limbic-predominant. Understanding whether diffuse AD-TDP has genetic, clinical, and pathological features that differ from limbic AD-TDP could have clinical and research implications. Objective: To better characterize the clinical and pathologic features of diffuse AD-TDP and differentiate it from limbic AD-TDP. Methods: 363 participants from the Mayo Clinic Study of Aging, Alzheimer’s Disease Research Center, and Neurodegenerative Research Group with autopsy confirmed AD and TDP-43 pathology were included. All underwent genetic, clinical, neuropsychologic, and neuropathologic evaluations. …AD-TDP pathology distribution was assessed using the Josephs 6-stage scale. Stages 1–3 were classified as Limbic, those 4–6 as Diffuse. Multivariable logistic regression was used to identify clinicopathologic features that independently predicted diffuse pathology. Results: The cohort was 61% female and old at onset (median: 76 years [IQR:70–82]) and death (median: 88 years [IQR:82–92]). Fifty-four percent were Limbic and 46% Diffuse. Clinically, ∼10–20% increases in odds of being Diffuse associated with 5-year increments in age at onset (p  = 0.04), 1-year longer disease duration (p  = 0.02), and higher Neuropsychiatric Inventory scores (p  = 0.03), while 15-second longer Trailmaking Test-B times (p  = 0.02) and higher Block Design Test scores (p  = 0.02) independently decreased the odds by ~ 10–15%. There was evidence for association of APOE ɛ 4 allele with limbic AD-TDP and of TMEM106B rs3173615 C allele with diffuse AD-TDP. Pathologically, widespread amyloid-β plaques (Thal phases: 3–5) decreased the odds of diffuse TDP-43 pathology by 80–90%, while hippocampal sclerosis increased it sixfold (p  < 0.001). Conclusion: Diffuse AD-TDP shows clinicopathologic and genetic features different from limbic AD-TDP. Show more

Keywords: Alzheimer’s disease, neuropathology, neuropsychology, TDP-43 proteinopathy

DOI: 10.3233/JAD-221094

Citation: Journal of Alzheimer's Disease, vol. 93, no. 4, pp. 1521-1535, 2023

Authors: Ortner, Marion | Lanz, Korbinian | Goldhardt, Oliver | Müller-Sarnowski, Felix | Diehl-Schmid, Janine | Förstl, Hans | Hedderich, Dennis M. | Yakushev, Igor | Logan, Chad A. | Weinberger, Jan-Philipp | Simon, Maryline | Grimmer, Timo

Article Type: Research Article

Abstract: Background: Differentiating dementia due to small vessel disease (SVD) from dementia due to Alzheimer’s disease (AD) with concomitant SVD is challenging in clinical practice. Accurate and early diagnosis of AD is critical to delivering stratified patient care. Objective: We characterized the results of Elecsys® cerebrospinal fluid (CSF) immunoassays (Roche Diagnostics International Ltd) in patients with early AD, diagnosed using core clinical criteria, with varying extent of SVD. Methods: Frozen CSF samples (n  = 84) were measured using Elecsys β-Amyloid(1–42) (Aβ42 ), Phospho-Tau (181P) (pTau181), and Total-Tau (tTau) CSF immunoassays, adapted for use on the cobas® …e 411 analyzer (Roche Diagnostics International Ltd), and a robust prototype β-Amyloid(1–40) (Aβ40 ) CSF immunoassay. SVD was assessed by extent of white matter hyperintensities (WMH) using the lesion segmentation tool. Interrelations between WMH, biomarkers, fluorodeoxyglucose F18-positron emission tomography (FDG-PET), and other parameters (including age and Mini-Mental State examinations [MMSE]) were assessed using Spearman’s correlation, sensitivity/specificity, and logistic/linear regression analyses. Results: The extent of WMH showed significant correlation with Aβ42 /Aβ40 ratio (Rho=-0.250; p  = 0.040), tTau (Rho = 0.292; p  = 0.016), tTau/Aβ42 ratio (Rho = 0.247; p  = 0.042), age (Rho = 0.373; p  = 0.002), and MMSE (Rho=-0.410; p  = 0.001). Sensitivity/specificity point estimates for Elecsys CSF immunoassays versus FDG-PET positivity for underlying AD pathophysiology were mostly comparable or greater in patients with high versus low WMH. WMH were not a significant predictor and did not interact with CSF biomarker positivity but modified the association between pTau181 and tTau. Conclusion: Elecsys CSF immunoassays detect AD pathophysiology regardless of concomitant SVD and may help to identify patients with early dementia with underlying AD pathophysiology. Show more

Keywords: Alzheimer’s disease, biomarkers, cerebral small vessel diseases, cerebrospinal fluid, diagnosis, differential

DOI: 10.3233/JAD-221187

Citation: Journal of Alzheimer's Disease, vol. 93, no. 4, pp. 1537-1549, 2023

Authors: Lee, Jaegyeong | Kim, Junhyoung | Park, Ahyoung | Hong, Rak-kyeun | Ko, Myungjin | Heo, Mina | Kim, Hoowon | Chung, Ji Yeon

Article Type: Research Article

Abstract: Background: Subjective cognitive decline (SCD) is a self-reported experience of declining cognitive function showing normal performance in cognitive assessments, which is a known risk factor for dementia. Recent studies highlight the importance of nonpharmacological multidomain interventions that can target multiple risk factors of dementia in older adults. Objective: This study investigated the efficacy of the Silvia program, a mobile-based multidomain intervention, to improve cognitive function and health-related outcomes of older adults with SCD. We compare its effects to a conventional paper-based multidomain program on various health indicators related to risk factors of dementia. Methods: This prospective …randomized controlled trial involved 77 older adults with SCD recruited from the Dementia Prevention and Management Center in Gwangju, South Korea during May to October 2022. Participants were randomly assigned to either the mobile- or paper-based group. Interventions were administered for 12 weeks, where pre- and post-assessments were conducted. Results: The K-RBANS total score did not show significant differences between groups. The mobile group showed better improvement in K-PRMQ scores and PSS scores than the paper group. Differences within groups showed that mobile-based interventions significantly improved K-PRMQ, STAI-X-1, PSS, and EQ-5D-5 L scores, while paper-based interventions significantly improved PSS, and EQ-5D-5 L scores. Patient adherence rate was 76.6%. Conclusion: Overall, the Silvia program was effective for improving self-reported memory failures, stress, anxiety, and health-related quality of life in older adults with SCD. However, longer periods of administration for more than 12 weeks may be needed to achieve significant improvements in cognitive function by objective measures. Show more

Keywords: Alzheimer’s disease, clinical trial, cognitive aging, cognitive decline, cognitive training, dementia, health promotion, healthy lifestyle, online intervention, preventive health

DOI: 10.3233/JAD-221299

Citation: Journal of Alzheimer's Disease, vol. 93, no. 4, pp. 1551-1562, 2023

Authors: Vyas, Chirag M. | Sadreyev, Ruslan I. | Gatchel, Jennifer R. | Kang, Jae H. | Reynolds III, Charles F. | Mischoulon, David | Chang, Grace | Hazra, Aditi | Manson, JoAnn E. | Blacker, Deborah | De Vivo, Immaculata | Okereke, Olivia I.

Article Type: Research Article

Abstract: Background: Associations between epigenetic aging with cognitive aging and neuropsychiatric measures are not well-understood. Objective: 1) To assess cross-sectional correlations between second-generation DNA methylation (DNAm)-based clocks of healthspan and lifespan (i.e., GrimAge, PhenoAge, and DNAm-based estimator of telomere length [DNAmTL]) and cognitive and neuropsychiatric measures; 2) To examine longitudinal associations between change in DNAm markers and change in cognition over 2 years. Methods: Participants were members of VITAL-DEP (VITamin D and OmegA-3 TriaL- Depression Endpoint Prevention) study. From previously ascertained cognitive groups (i.e., cognitively normal and mild cognitive impairment), we randomly selected 45 participants, aged≥60 years, …who completed in-person neuropsychiatric assessments at baseline and 2 years. The primary outcome was global cognitive score (averaging z-scores of 9 tests). Neuropsychiatric Inventory severity scores were mapped from neuropsychiatric symptoms (NPS) from psychological scales and structured diagnostic interviews. DNAm was assayed using Illumina MethylationEPIC 850K BeadChip at baseline and 2 years. We calculated baseline partial Spearman correlations between DNAm markers and cognitive and NPS measures. We constructed multivariable linear regression models to examine longitudinal relations between DNAm markers and cognition. Results: At baseline, we observed a suggestive negative correlation between GrimAge clock markers and global cognition but no signal between DNAm markers and NPS measures. Over 2 years: each 1-year increase in DNAmGrimAge was significantly associated with faster declines in global cognition; each 100-base pair increase in DNAmTL was significantly associated with better global cognition. Conclusion: We found preliminary evidence of cross-sectional and longitudinal associations between DNAm markers and global cognition. Show more

Keywords: Alzheimer’s disease, cognition, DNA methylation, epigenetics, neuropsychiatric symptoms

DOI: 10.3233/JAD-230093

Citation: Journal of Alzheimer's Disease, vol. 93, no. 4, pp. 1563-1575, 2023