Journal of Alzheimer's Disease - Volume Pre-press, issue Pre-press

Authors: Sohn, Bo Kyung | Byun, Min Soo | Yi, Dahyun | Jeon, So Yeon | Lee, Jun Ho | Choe, Young Min | Lee, Dong Woo | Lee, Jun-Young | Kim, Yu Kyeong | Sohn, Chul-Ho | Lee, Dong Young | for the KBASE Research Group

Article Type: Research Article

Abstract: Background: Physical activities (PA) have been suggested to reduce the risk of Alzheimer‘s disease (AD) dementia. However, information on the neuropathological links underlying the relationship is limited. Objective: We investigated the role of midlife and late-life PA with in vivo AD neuropathologies in old adults without dementia. Methods: This study included participants from the Korean Brain Aging Study for Early diagnosis and prediction of Alzheimer’s disease (KBASE). The participants underwent comprehensive clinical and neuropsychological assessment, [11 C] Pittsburgh Compound B positron emission tomography (PET), [18 F] fluorodeoxyglucose PET, and magnetic resonance imaging. Using the multi-modal …brain imaging data, in vivo AD pathologies including global amyloid deposition, AD-signature region cerebral glucose metabolism (AD-CM), and AD-signature region cortical thickness (AD-CT) were quantified. Both midlife and late-life PA of participants were measured using the Lifetime Total Physical Activity Questionnaire. Results: This study was performed on 260 participants without dementia (195 with normal cognitive function and 65 with mild cognitive impairment). PA of neither midlife nor late-life showed direct correspondence with any neuroimaging biomarker. However, late-life PA moderated the relationship of brain amyloid-β (Aβ) deposition with AD-CM and AD-CT. Aβ positivity had a significant negative effect on both AD-CM and AD-CT in individuals with lower late-life PA, but those with higher late-life PA did not show such results. Midlife PA did not have such a moderation effect. Conclusion: The findings suggest that physically active lifestyle in late-life, rather than that in midlife, may delay AD-associated cognitive decline by decreasing Aβ-induced neurodegenerative changes in old adults. Show more

Keywords: Amyloid, cortical thickness, neurodegeneration, physical activity

DOI: 10.3233/JAD-215258

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Premi, Enrico | Costa, Tommaso | Gazzina, Stefano | Benussi, Alberto | Cauda, Franco | Gasparotti, Roberto | Archetti, Silvana | Alberici, Antonella | van Swieten, John C. | Sanchez-Valle, Raquel | Moreno, Fermin | Santana, Isabel | Laforce, Robert | Ducharme, Simon | Graff, Caroline | Galimberti, Daniela | Masellis, Mario | Tartaglia, Carmela | Rowe, James B. | Finger, Elizabeth | Tagliavini, Fabrizio | de Mendonça, Alexandre | Vandenberghe, Rik | Gerhard, Alexander | Butler, Chris R. | Danek, Adrian | Synofzik, Matthis | Levin, Johannes | Otto, Markus | Ghidoni, Roberta | Frisoni, Giovanni | Sorbi, Sandro | Peakman, Georgia | Todd, Emily | Bocchetta, Martina | Rohrer, Johnathan D. | Borroni, Barbara | GENFI Consortium Members

Collaborators: Afonso, Sónia | Rosario Almeida, Maria | Anderl-Straub, Sarah | Andersson, Christin | Antonell, Anna | Arighi, Andrea | Balasa, Mircea | Barandiaran, Myriam | Bargalló, Nuria | Bartha, Robart | Bender, Benjamin | Benussi, Luisa | Bessi, Valentina | Binetti, Giuliano | Black, Sandra | Borrego-Ecija, Sergi | Bras, Jose | Bruffaerts, Rose | Caroppo, Paola | Cash, David | Castelo-Branco, Miguel | Convery, Rhian | Cope, Thomas | de Arriba, María | Di Fede, Giuseppe | Díaz, Zigor | Duro, Diana | Fenoglio, Chiara | Ferrari, Camilla | B. Ferreira, Catarina | Fox, Nick | Freedman, Morris | Fumagalli, Giorgio | Gabilondo, Alazne | Gauthier, Serge | Giaccone, Giorgio | Gorostidi, Ana | Greaves, Caroline | Guerreiro, Rita | Heller, Carolin | Hoegen, Tobias | Indakoetxea, Begoña | Jelic, Vesna | Jiskoot, Lize | Karnath, Hans-Otto | Keren, Ron | Langheinrich, Tobias | João Leitão, Maria | Lladó, Albert | Lombardi, Gemma | Loosli, Sandra | Maruta, Carolina | Mead, Simon | Meeter, Lieke | Miltenberger, Gabriel | van Minkelen, Rick | Mitchell, Sara | Moore, Katrina | Nacmias, Benedetta | Nicholas, Jennifer | Öijerstedt, Linn | Olives, Jaume | Panman, Jessica | Papma, Janne | Pievani, Michela | Pijnenburg, Yolande | Polito, Cristina | Prioni, Sara | Prix, Catharina | Rademakers [as London Ontario geneticist], Rosa | Redaelli, Veronica | Rittman, Tim | Rogaeva, Ekaterina | Rosa-Neto, Pedro | Rossi, Giacomina | Rossor, Martin | Santiago, Beatriz | Scarpini, Elio | Schönecker, Sonja | Semler, Elisa | Shafei, Rachelle | Shoesmith, Christen | Tábuas-Pereira, Miguel | Tainta, Mikel | Taipa, Ricardo | Tang-Wai, David | L Thomas, David | Thompson, Paul | Thonberg, Hakan | Timberlake, Carolyn | Tiraboschi, Pietro | Van Damme, Philip | Vandenbulcke, Mathieu | Veldsman, Michele | Verdelho, Ana | Villanua, Jorge | Warren, Jason | Wilke, Carlo | Woollacott, Ione | Wlasich, Elisabeth | Zetterberg, Henrik | Zulaica, Miren

Article Type: Research Article

Abstract: Background: Magnetic resonance imaging (MRI) measures may be used as outcome markers in frontotemporal dementia (FTD). Objectives: To predict MRI cortical thickness (CT) at follow-up at the single subject level, using brain MRI acquired at baseline in preclinical FTD. Methods: 84 presymptomatic subjects carrying Granulin mutations underwent MRI scans at baseline and at follow-up (31.2±16.5 months). Multivariate nonlinear mixed-effects model was used for estimating individualized CT at follow-up based on baseline MRI data. The automated user-friendly preGRN-MRI script was coded. Results: Prediction accuracy was high for each considered brain region (i.e., prefrontal region, …real CT at follow-up versus predicted CT at follow-up, mean error ≤1.87%). The sample size required to detect a reduction in decline in a 1-year clinical trial was equal to 52 subjects (power = 0.80, alpha = 0.05). Conclusion: The preGRN-MRI tool, using baseline MRI measures, was able to predict the expected MRI atrophy at follow-up in presymptomatic subjects carrying GRN mutations with good performances. This tool could be useful in clinical trials, where deviation of CT from the predicted model may be considered an effect of the intervention itself. Show more

Keywords: Frontotemporal dementia, granulin, magnetic resonance imaging, mutation, preclinical, presymptomatic

DOI: 10.3233/JAD-215447

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2021

Authors: Siddiqui, Fatima | Nistala, Kameswara Rishi Yeshayahu | Quek, Chrystie Wan Ning | Shi Ying Leong, Victoria | Ying Shan Tan, Amarinda | En Tan, Christopher Yu | Hilal, Saima

Article Type: Research Article

Abstract: Background: Dementia is the decline in cognitive function sufficient to impair one’s accustomed functioning. Countries with aging populations, such as Singapore, face rising rates of dementia. Dementia patients and their caregivers endure great financial and emotional stress. With the broad aim of minimizing these stresses, this study provides a cross-sectional view of the knowledge, attitudes, and perceptions (KAP) towards dementia in middle-aged Singaporean residents. Objective: We aim to examine 1) the associations between demographic correlates and KAP; and 2) the effect of dementia knowledge on attitudes and perceptions towards dementia. Methods: An online anonymous cross-sectional questionnaire …was administered to Singaporeans and Permanent Residents aged 45 to 65 years old in English, Mandarin, and Malay. Knowledge was evaluated across three domains: symptoms, risk factors, and management. Total and domain scores were dichotomized as good or poor knowledge using median cut-offs. Attitudes/perceptions across six domains were evaluated on Likert scales, and responses to each question were dichotomized into positive or negative attitudes/perceptions. Results: From 1,733 responses, 1,209 valid complete responses were accepted (mean age±SD 54.8±5.12 years old, females = 69.6%). Lower socioeconomic status was associated with poorer knowledge and greater barriers to risk-mitigating lifestyle modifications. Lack of personal experience with dementia and poor knowledge were also associated with erroneous attitudes/perceptions. Conclusion: Socioeconomic status and personal experience affect KAP towards dementia. Policy and education campaigns to address KAP towards dementia should account for baseline differences across demographics, for greater improvements in dementia incidence and support. Show more

Keywords: Attitudes, dementia, knowledge, middle age, practices

DOI: 10.3233/JAD-215262

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2021

Authors: Che, Bizhong | Chen, Haichang | Wang, Aili | Peng, Hao | Bu, Xiaoqing | Zhang, Jintao | Ju, Zhong | Xu, Tan | He, Jiang | Zhong, Chongke | Zhang, Yonghong

Article Type: Research Article

Abstract: Background: L-carnitine has been shown to exert neuroprotective effects on cerebral ischemia, mainly by improving mitochondrial function and reducing inflammation. L-carnitine supplementation has also been promoted to enhance cognitive function. However, the relationship between L-carnitine and cognitive impairment after ischemic stroke has seldom been studied. Objective: We aimed to evaluate the association between plasma L-carnitine and poststroke cognitive impairment. Methods: The study sample population was drawn from the China Antihypertensive Trial in Acute Ischemic Stroke. Plasma L-carnitine were measured at baseline in 617 patients with ischemic stroke using ultrahigh-performance liquid chromatography-tandem mass spectrometry. Cognitive function was …evaluated using the Montreal Cognitive Assessment at 3-month follow-up after ischemic stroke. Results: Plasma L-carnitine were inversely associated with cognitive impairment at 3 months after ischemic stroke, and the adjusted odds ratio (95% CI) for the highest versus lowest quartiles of L-carnitine was 0.60 (0.37, 0.98; p for trend = 0.04). Each 1-SD increase in log-transformed L-carnitine concentration was significantly associated with a 15% (95% CI: 1%, 29%) reduction in the risk of cognitive impairment after stroke. The addition of L-carnitine to the model including conventional risk factors significantly improved the risk reclassification for cognitive impairment (net reclassification improvement: 17.9%, integrated discrimination improvement: 0.8% ; both p  <  0.05). Furthermore, joint effects of L-carnitine and inflammation markers were observed, and patients with higher L-carnitine and a lower inflammatory status simultaneously had the lowest risk of poststroke cognitive impairment. Conclusion: The present study provided prospective evidence on the inverse association between plasma L-carnitine and cognitive impairment after ischemic stroke. Show more

Keywords: Acute ischemic stroke, cognitive impairment, inflammation, L-carnitine

DOI: 10.3233/JAD-215376

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Secnik, Juraj | Xu, Hong | Schwertner, Emilia | Hammar, Niklas | Alvarsson, Michael | Winblad, Bengt | Eriksdotter, Maria | Garcia-Ptacek, Sara | Religa, Dorota

Article Type: Research Article

Abstract: Background: The effectiveness of glucose-lowering drugs (GLDs) is unknown among patients with dementia. Objective: To analyze all-cause mortality among users of six GLDs in dementia and dementia-free subjects, respectively. Methods: This was a longitudinal open-cohort registry-based study using data from the Swedish Dementia Registry, Total Population Register, and four supplemental registers providing data on dementia status, drug usage, confounders, and mortality. The cohort comprised 132,402 subjects with diabetes at baseline, of which 11,401 (8.6%) had dementia and 121,001 (91.4%) were dementia-free. Subsequently, comparable dementia – dementia-free pairs were sampled. Then, as-treated and intention-to-treat exposures to metformin, …insulin, sulfonylurea, dipeptidyl-peptidase-4 inhibitors, glucagon-like peptide-1 analogues (GLP-1a), and sodium-glucose cotransporter-2 inhibitors (SGLT-2i) were analyzed in the parallel dementia and dementia-free cohorts. Confounding was addressed using inverse-probability weighting and propensity-score matching, and flexible parametric survival models were used to produce hazard ratios (HR) and 95% confidence intervals (CI) of the association between GLDs and all-cause mortality. Results: In the as-treated models, increased mortality was observed among insulin users with dementia (HR 1.34 [95%CI 1.24–1.45]) as well as in dementia-free subjects (1.54 [1.10–1.55]). Conversely, sulfonylurea was associated with higher mortality only in dementia subjects (1.19 [1.01–1.42]). GLP-1a (0.44 [0.25–0.78]) and SGLT-2i users with dementia (0.43 [0.23–0.80]) experienced lower mortality compared to non-users. Conclusion: Insulin and sulfonylurea carried higher mortality risk among dementia patients, while GLP-1a and SGLT-2i were associated with lower risk. GLD-associated mortality varied between dementia and comparable dementia-free subjects. Further studies are needed to optimize GLD use in dementia patients. Show more

Keywords: Antidiabetics, dementia, diabetes, hyperglycemia, mortality, propensity-score

DOI: 10.3233/JAD-215337

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2021

Authors: Liu, Mingjing | Guo, Shipeng | Huang, Daochao | Hu, Dongjie | Wu, Yili | Zhou, Weihui | Song, Weihong

Article Type: Research Article

Abstract: Background: Chronic alcohol consumption can alter the structure of the central nervous system and disrupt cognitive function. Alcoholics are more likely to develop neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). However, the role of alcohol in promoting neurotoxicity and neurodegeneration remains unclear. Objective: In this study, we aimed at estimating the effects of chronic binge alcohol exposure on brain transcriptome and behavior changes in a chronic “Drinking in the Dark” (DID) mouse model. Methods: The adult C57BL/6J male mice were exposed to alcohol for 4 weeks. RNA-seq was applied to assess the …effects of chronic alcohol exposure on transcriptome in brain. The open field test and novel object recognition test were used to assess the changes of anxiety level, locomotive function, and short-term memory induced by alcohol. RNA-seq analysis revealed that chronic alcohol exposure caused significant change in the brain transcriptome, especially in prefrontal cortex. Results: The gene dysregulation caused by chronic alcohol exposure includes pathways related to mitochondrial energy metabolism (such as oxidative phosphorylation) and multiple neurodegenerative diseases (such as AD and PD). Furthermore, the pathway and network analyses suggest that the genes involved in mitochondrial energy metabolism, ubiquitin-proteasome system, Wnt signaling pathway, and microtubules may attribute to the neurotoxicity and neurodegeneration caused by chronic alcohol consumption. Additionally, locomotive function was also significantly impaired. Conclusion: This work provides gene transcriptional profile data for future research on alcohol-induced neurodegenerative diseases, especially AD and PD. Show more

Keywords: Brain, chronic alcohol consumption, gene expression, neurodegeneration

DOI: 10.3233/JAD-215508

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2021

Authors: Stepler, Kaitlyn E. | Gillyard, Taneisha R. | Reed, Calla B. | Avery, Tyra M. | Davis, Jamaine S. | Robinson, Renã A.S.

Article Type: Review Article

Abstract: African American/Black adults are twice as likely to have Alzheimer’s disease (AD) compared to non-Hispanic White adults. Genetics partially contributes to this disparity in AD risk, among other factors, as there are several genetic variants associated with AD that are more prevalent in individuals of African or European ancestry. The phospholipid-transporting ATPase ABCA7 (ABCA7 ) gene has stronger associations with AD risk in individuals with African ancestry than in individuals with European ancestry. In fact, ABCA7 has been shown to have a stronger effect size than the apolipoprotein E (APOE ) ɛ 4 allele in African American/Black adults. ABCA7 …is a transmembrane protein involved in lipid homeostasis and phagocytosis. ABCA7 dysfunction is associated with increased amyloid-beta production, reduced amyloid-beta clearance, impaired microglial response to inflammation, and endoplasmic reticulum stress. This review explores the impact of ABCA7 mutations that increase AD risk in African American/Black adults on ABCA7 structure and function and their contributions to AD pathogenesis. The combination of biochemical/biophysical and ‘omics-based studies of these variants needed to elucidate their downstream impact and molecular contributions to AD pathogenesis is highlighted. Show more

Keywords: African Americans, Alzheimer’s disease, Blacks, health status disparities, human ABCA7 protein, proteomics, single nucleotide polymorphism, subfamily A of ATP binding cassette transporter

DOI: 10.3233/JAD-215306

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2021

Authors: Miron, Justin | Picard, Cynthia | Labonté, Anne | Auld, Daniel | Poirier, Judes | for the PREVENT-AD research group

Article Type: Research Article

Abstract: Background: In mouse models of amyloidosis, macrophage receptor 1 (MSR1) and neprilysin (NEP) have been shown to interact to reduce amyloid burden in the brain. Objective: The purpose of this study is to analyze these two gene products in combination with apolipoproteins and Aβ 1 - 42 in the cerebrospinal fluid (CSF) and plasma of individuals at different stages of Alzheimer’s disease (AD), as well as in autopsied brain samples from ROSMAP (Religious Orders Study and Memory and Aging Project). Methods: CSF/plasma levels of MSR1 and NEP were measured using the sensitive primer extension assay technology. …CSF Aβ 1 - 42 was assessed with ELISA, while CSF ApoE and ApoJ were measured with the Luminex’s multiplex technology. Brain MSR1 , APOE , and CLU (ApoJ) mRNA levels were measured with RNA-Seq and contrasted to amyloid plaques pathology using CERAD staging. Results: While plasma and CSF MSR1 levels are significantly correlated, this correlation was not observed for NEP. In addition to be highly correlated to one another, CSF levels of both MSR1 and NEP are strongly correlated with AD status and CSF Aβ 1 - 42 , ApoE, and ApoJ levels. In the cortical tissues of subjects from ROSMAP, MSR1 mRNA levels are correlated with CLU mRNA levels and the CERAD scores but not with APOE mRNA levels. Conclusion: The discrepancies observed between CSF/plasma levels of MSR1 and NEP with CSF Aβ 1 - 42 and ApoE concentrations can be explained by many factors, such as the disease stage or the involvement of the blood-brain barrier breakdown that leads to the infiltration of peripheral monocytes or macrophages. Show more

Keywords: Alzheimer’s disease, amyloid, biomarkers, inflammation, MSR1, NEP

DOI: 10.3233/JAD-215410

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2021

Authors: Bakker, Els D. | van Maurik, Ingrid S. | Mank, Arenda | Zwan, Marissa D. | Waterink, Lisa | van den Buuse, Susanne | van den Broeke, Jennifer R. | Gillissen, Freek | van de Beek, Marleen | Lemstra, Evelien | van den Bosch, Karlijn A. | van Leeuwenstijn, Mardou | Bouwman, Femke H. | Scheltens, Philip | van der Flier, Wiesje M.

Article Type: Research Article

Abstract: Background: The COVID-19 pandemic poses enormous social challenges, especially during lockdown. People with cognitive decline and their caregivers are particularly at risk of lockdown consequences. Objective: To investigate psychosocial effects in (pre-)dementia patients and caregivers during second lockdown and compare effects between first and second lockdown. Methods: We included n  = 511 (pre-)dementia patients and n  = 826 caregivers from the Amsterdam Dementia Cohort and via Alzheimer Nederland. All respondents completed a self-designed survey on psychosocial effects of COVID-19. We examined relations between experienced support and psychosocial and behavioral symptoms using logistic regression. In a subset of patients …and caregivers we compared responses between first and second lockdown using generalized estimating equation. Results: The majority of patients (≥58%) and caregivers (≥60%) reported that family and friends, hobbies, and music helped them cope. Support from family and friends was strongly related to less negative feelings in patients (loneliness: OR = 0.3[0.1–0.6]) and caregivers (loneliness: OR = 0.2[0.1–0.3]; depression: OR = 0.4[0.2–0.5]; anxiety: OR = 0.4[0.3–0.6]; uncertainty: OR = 0.3[0.2–0.5]; fatigue: OR = 0.3[0.2–0.4]; stress: OR = 0.3[0.2–0.5]). In second lockdown, less psychosocial and behavioral symptoms were reported compared to first lockdown (patients; e.g., anxiety: 22% versus 13%, p  = 0.007; apathy: 27% versus 8%, p  < 0.001, caregivers; e.g., anxiety: 23% versus 16%, p  = 0.033; patient’s behavioral problems: 50% versus 35%, p  < 0.001). Patients experienced more support (e.g., family and friends: 52% versus 93%, p  < 0.001; neighbors: 28% versus 66%, p  < 0.001). Conclusion: During second lockdown, patients and caregivers adapted to challenges posed by lockdown, as psychosocial and behavioral effects decreased, while patients experienced more social support compared to first lockdown. Support from family and friends is a major protective factor for negative outcomes in patients and caregivers. Show more

Keywords: Behavioral effects, caregiver, COVID-19, dementia, experienced support, lockdown, mild cognitive impairment, psychosocial effects, subjective cognitive decline

DOI: 10.3233/JAD-215342

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2021

Authors: Schaffert, Jeff | LoBue, Christian | Hynan, Linda S. | Hart Jr., John | Rossetti, Heidi | Carlew, Anne R. | Lacritz, Laura | White III, Charles L. | Cullum, C. Munro

Article Type: Research Article

Abstract: Background: Life expectancy (LE) following Alzheimer’s disease (AD) is highly variable. The literature to date is limited by smaller sample sizes and clinical diagnoses. Objective: No study to date has evaluated predictors of AD LE in a retrospective large autopsy-confirmed sample, which was the primary objective of this study. Methods: Participants (≥50 years old) clinically and neuropathologically diagnosed with AD were evaluated using National Alzheimer’s Coordinating Center (N = 1,401) data. Analyses focused on 21 demographic, medical, neuropsychiatric, neurological, functional, and global cognitive predictors of LE at AD dementia diagnosis. These 21 predictors were evaluated in univariate analyses. …Variables found to be significant were then entered into a forward multiple regression. LE was defined as months between AD diagnosis and death. Results: Fourteen predictors were significant in univariate analyses and entered into the regression. Seven predictors explained 27% of LE variance in 764 total participants. Mini-Mental State Examination (MMSE) score was the strongest predictor of LE, followed by sex, age, race/ethnicity, neuropsychiatric symptoms, abnormal neurological exam results, and functional impairment ratings. Post-hoc analyses revealed correlations of LE were strongest with MMSE ≤12. Conclusion: Global cognitive functioning was the strongest predictor of LE following diagnosis, and AD patients with severe impairment had the shortest LE. AD patients who are older, male, white, and have more motor symptoms, functional impairment, and neuropsychiatric symptoms were also more likely have shorter LE. While this model cannot provide individual prognoses, additional studies may focus on these variables to enhance predictions of LE in patients with AD. Show more

Keywords: Alzheimer’s disease, autopsy-confirmed, dementia, life expectancy, mortality

DOI: 10.3233/JAD-215200

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021