Journal of Alzheimer's Disease - Volume 79, issue 3

Authors: Darst, Burcu F. | Huo, Zhiguang | Jonaitis, Erin M. | Koscik, Rebecca L. | Clark, Lindsay R. | Lu, Qiongshi | Kremen, William S. | Franz, Carol E. | Rana, Brinda | Lyons, Michael J. | Hogan, Kirk J. | Zhao, Jinying | Johnson, Sterling C. | Engelman, Corinne D.

Article Type: Research Article

Abstract: Background: Understanding metabolic mechanisms associated with cognitive changes preceding an Alzheimer’s disease (AD) diagnosis could advance our understanding of AD progression and inform preventive methods. Objective: We investigated the metabolomics of the early changes in executive function and delayed recall, the earliest aspects of cognitive function to change in the course of AD development, in order to better understand mechanisms that could contribute to early stages and progression of this disease. Methods: This investigation used longitudinal plasma samples from the Wisconsin Registry for Alzheimer’s Prevention (WRAP), a cohort of participants who were dementia free at enrollment …and enriched with a parental history of AD. Metabolomic profiles were quantified for 2,324 fasting plasma samples among 1,200 participants, each with up to three study visits, which occurred every two years. Metabolites were individually tested for association with executive function and delayed recall trajectories across age. Results: Of 1,097 metabolites tested, levels of seven were associated with executive function trajectories, including an amino acid cysteine S-sulfate and three fatty acids, including erucate (22 : 1n9), while none were associated with delayed recall trajectories. Replication was attempted for four of these metabolites that were present in the Vietnam Era Twin Study of Aging (VETSA). Although none reached statistical significance, three of these associations showed consistent effectdirections. Conclusion: Our results suggest potential metabolomic mechanisms that could contribute to the earliest signs of cognitive decline. In particular, fatty acids may be associated with cognition in a manner that is more complex than previously suspected. Show more

Keywords: Alzheimer’s disease, amino acids, cognition, executive function, fatty acids, longitudinal analysis, metabolomics

DOI: 10.3233/JAD-200176

Citation: Journal of Alzheimer's Disease, vol. 79, no. 3, pp. 1041-1054, 2021

Authors: Kumon, Hiroshi | Yoshino, Yuta | Funahashi, Yu | Mori, Hiroaki | Ueno, Mariko | Ozaki, Yuki | Yamazaki, Kiyohiro | Ochi, Shinichiro | Mori, Takaaki | Iga, Jun-ichi | Nagai, Masahiro | Nomoto, Masahiro | Ueno, Shu-ichi

Article Type: Research Article

Abstract: Background: Phosphatidylinositol-binding clathrin assembly protein (PICALM) is a validated genetic risk factor for late-onset Alzheimer’s disease (AD) and is associated with other neurodegenerative diseases. However, PICALM expression in the blood of neurodegenerative diseases remains elusive. Objective: This study aimed to assess the usefulness of PICALM expression levels in the blood of patients with AD, Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and geriatric major depressive disorder (MDD) as a diagnostic biomarker. …Methods: In total, 45, 20, 21, and 19 patients with AD, PD, DLB, and geriatric MDD, respectively, and 54 healthy controls (HCs) were enrolled in the study. Expression data from Gene Expression Omnibus database (GSE97760), (GSE133347) and (GSE98793), (GSE48350), and (GSE144459) were used to validate the ability of biomarkers in the blood of patients with AD, PD, geriatric MDD, and a postmortem human AD brain and animal model of AD (3xTg-AD mouse), respectively. Results: PICALM mRNA expression in human blood was significantly increased in patients with AD compared with that in HCs. PICALM mRNA expression and age were negatively correlated only in patients with AD. PICALM mRNA expression in human blood was significantly lower in patients with PD than in HCs. No changes in PICALM mRNA expression were found in patients with DLB and geriatric MDD. Conclusion: PICALM mRNA expression in blood was higher in patients with AD, but lower in patients with PD, which suggests that PICALM mRNA expression in human blood may be a useful biomarker for differentiating neurodegenerative diseases and geriatric MDD. Show more

Keywords: Alzheimer’s disease, blood, gene expression, major depressive disorder, phosphatidylinositol-binding clathrin assembly protein

DOI: 10.3233/JAD-201046

Citation: Journal of Alzheimer's Disease, vol. 79, no. 3, pp. 1055-1062, 2021

Authors: Russ, Tom C. | Cherrie, Mark P.C. | Dibben, Chris | Tomlinson, Sam | Reis, Stefan | Dragosits, Ulrike | Vieno, Massimo | Beck, Rachel | Carnell, Ed | Shortt, Niamh K. | Muniz-Terrera, Graciela | Redmond, Paul | Taylor, Adele M. | Clemens, Tom | van Tongeren, Martie | Agius, Raymond M. | Starr, John M. | Deary, Ian J. | Pearce, Jamie R.

Article Type: Research Article

Abstract: Background: Air pollution has been consistently linked with dementia and cognitive decline. However, it is unclear whether risk is accumulated through long-term exposure or whether there are sensitive/critical periods. A key barrier to clarifying this relationship is the dearth of historical air pollution data. Objective: To demonstrate the feasibility of modelling historical air pollution data and using them in epidemiologicalmodels. Methods: Using the EMEP4UK atmospheric chemistry transport model, we modelled historical fine particulate matter (PM2.5 ) concentrations for the years 1935, 1950, 1970, 1980, and 1990 and combined these with contemporary modelled data from 2001 to …estimate life course exposure in 572 participants in the Lothian Birth Cohort 1936 with lifetime residential history recorded. Linear regression and latent growth models were constructed using cognitive ability (IQ) measured by the Moray House Test at the ages of 11, 70, 76, and 79 years to explore the effects of historical air pollution exposure. Covariates included sex, IQ at age 11 years, social class, and smoking. Results: Higher air pollution modelled for 1935 (when participants would have been in utero ) was associated with worse change in IQ from age 11–70 years (β = –0.006, SE = 0.002, p  = 0.03) but not cognitive trajectories from age 70–79 years (p  > 0.05). There was no support for other critical/sensitive periods of exposure or an accumulation of risk (all p  > 0.05). Conclusion: The life course paradigm is essential in understanding cognitive decline and this is the first study to examine life course air pollution exposure in relation to cognitive health. Show more

Keywords: Aging, air pollution, Alzheimer’s disease, atmosphere, cognition, dementia, epidemiologic methods

DOI: 10.3233/JAD-200910

Citation: Journal of Alzheimer's Disease, vol. 79, no. 3, pp. 1063-1074, 2021

Authors: Ryan, Margaret | Tan, Valerie T.Y. | Thompson, Nasya | Guévremont, Diane | Mockett, Bruce G. | Tate, Warren P. | Abraham, Wickliffe C. | Hughes, Stephanie M. | Williams, Joanna

Article Type: Research Article

Abstract: Background: Secreted amyloid precursor protein-alpha (sAPPα) can enhance memory and is neurotrophic and neuroprotective across a range of disease-associated insults, including amyloid-β toxicity. In a significant step toward validating sAPPα as a therapeutic for Alzheimer’s disease (AD), we demonstrated that long-term overexpression of human sAPPα (for 8 months) in a mouse model of amyloidosis (APP/PS1) could prevent the behavioral and electrophysiological deficits that develop in these mice. Objective: To explore the underlying molecular mechanisms responsible for the significant physiological and behavioral improvements observed in sAPPα-treated APP/PS1 mice. Methods: We assessed the long-term effects on the hippocampal …transcriptome following continuous lentiviral delivery of sAPPα or empty-vector to male APP/PS1 mice and wild-type controls using Affymetrix Mouse Transcriptome Assays. Data analysis was carried out within the Affymetrix Transcriptome Analysis Console and an integrated analysis of the resulting transcriptomic data was performed with Ingenuity Pathway analysis (IPA). Results: Mouse transcriptome assays revealed expected AD-associated gene expression changes in empty-vector APP/PS1 mice, providing validation of the assays used for the analysis. By contrast, there were specific sAPPα-associated gene expression profiles which included increases in key neuroprotective genes such as Decorin, betaine-GABA transporter and protocadherin beta-5, subsequently validated by qRT-PCR. An integrated biological pathways analysis highlighted regulation of GABA receptor signaling, cell survival and inflammatory responses. Furthermore, upstream gene regulatory analysis implicated sAPPα activation of Interleukin-4, which can counteract inflammatory changes in AD. Conclusion: This study identified key molecular processes that likely underpin the long-term neuroprotective and therapeutic effects of increasing sAPPα levels in vivo Show more

Keywords: Alzheimer’s disease, drug development, oligonucleotide array, real-time polymerase chain reaction, transcriptome, transgenic mouse

DOI: 10.3233/JAD-200757

Citation: Journal of Alzheimer's Disease, vol. 79, no. 3, pp. 1075-1090, 2021

Authors: Nozaki, Shoko | Sawada, Norie | Matsuoka, Yutaka J. | Shikimoto, Ryo | Mimura, Masaru | Tsugane, Shoichiro

Article Type: Research Article

Abstract: Background: The relationship between midlife dietary habits and risk of dementia remains unclear. Objective: To investigate the association between dietary fish and n-3 polyunsaturated fatty acid (PUFA) consumption in midlife and risk of dementia in later life. Methods: This population-based cohort study assessed food frequency (average intake in 1995 and 2000) and cognition (2014-2015) in 1,127 participants (aged 45–64 in 1995). We used logistic regression analyses to calculate odds ratios (ORs) for dementia and mild cognitive impairment (MCI) diagnoses for consumption quartiles of fish, PUFA-rich fish, total n-3 PUFAs, total n-6 PUFAs, types of PUFAs, and …n-3/n-6 PUFA ratio. Estimated ORs were adjusted for age; sex; education; smoking status; alcohol consumption frequency; physical activity; histories of cancer, myocardial infarction, and diabetes mellitus; and depression. Results: Significantly reduced risks of dementia over non-dementia (MCI plus cognitively normal) were observed in the second (OR = 0.43 (95% CI = 0.20–0.93)), third (OR = 0.22 (95% CI = 0.09–0.54)), and highest quartiles (OR = 0.39 (95% CI = 0.18–0.86)) for fish; the third (OR = 0.39 (95% CI = 0.16–0.92)) and highest quartiles (OR = 0.44 (95% CI = 0.19–0.98)) for eicosapentaenoic acid (EPA); the second (OR = 0.39 (95% CI = 0.18–0.84)), third (OR = 0.30 (95% CI = 0.13–0.70)), and highest quartiles (OR = 0.28 (95% CI = 0.12–0.66)) for docosahexaenoic acid (DHA); and the third (OR = 0.36 (95% CI = 0.16–0.85)) and highest quartiles (OR = 0.42 (95% CI = 0.19–0.95)) for docosapentaenoic acid (DPA). Conclusion: High intake of fish in midlife might aid in preventing dementia. Show more

Keywords: Cognitive dysfunction, dementia, diet, epidemiology, habits, longitudinal studies, observational study, risk factors, unsaturated fatty acids

DOI: 10.3233/JAD-191313

Citation: Journal of Alzheimer's Disease, vol. 79, no. 3, pp. 1091-1104, 2021

Authors: Barthelson, Karissa | Pederson, Stephen Martin | Newman, Morgan | Lardelli, Michael

Article Type: Research Article

Abstract: Background: The early cellular stresses leading to Alzheimer’s disease (AD) remain poorly understood because we cannot access living, asymptomatic human AD brains for detailed molecular analyses. Sortilin-related receptor 1 (SORL1 ) encodes a multi-domain receptor protein genetically associated with both rare, early-onset familial AD (EOfAD) and common, sporadic, late-onset AD (LOAD). SORL1 protein has been shown to act in the trafficking of the amyloid β A4 precursor protein (AβPP) that is proteolysed to form one of the pathological hallmarks of AD, amyloid-β (Aβ) peptide. However, other functions of SORL1 in AD are less well understood. Objective: To investigate …the effects of heterozygosity for an EOfAD-like mutation in SORL1 on the brain transcriptome of young-adult mutation carriers using zebrafish as a model organism. Methods: We performed targeted mutagenesis to generate an EOfAD-like mutation in the zebrafish orthologue of SORL1 and performed RNA-sequencing on mRNA isolated from the young adult brains of siblings in a family of fish either wild type (non-mutant) or heterozygous for the EOfAD-like mutation. Results: We identified subtle differences in gene expression indicating changes in mitochondrial and ribosomal function in the mutant fish. These changes appear to be independent of changes in mitochondrial content or the expression of AβPP-related proteins in zebrafish. Conclusion: These findings provided evidence supporting that EOfAD mutations in SORL1 affect mitochondrial and ribosomal function and provide the basis for future investigation elucidating the nature of these effects. Show more

Keywords: Alzheimer’s disease, mitochondria, ribosome, RNA-seq, sorl1, zebrafish

DOI: 10.3233/JAD-201383

Citation: Journal of Alzheimer's Disease, vol. 79, no. 3, pp. 1105-1119, 2021

Authors: Fu, Zhenrong | Zhao, Mingyan | Wang, Xuetong | He, Yirong | Tian, Yuan | Yang, Yujing | Han, Ying | Li, Shuyu

Article Type: Research Article

Abstract: Background: Individuals with subjective cognitive decline (SCD), defined by self-reported memory complaints but normal performance in objective neuropsychological tests, may be at higher risk of worsening or more frequent memory loss until conversion to Alzheimer’s disease (AD) or related dementia. Asymmetry in two hemispheres is a cardinal character of human brain’s structure and function, and altered brain asymmetry has also been connected with AD. Objective: This study aimed to determine whether the asymmetry of subcortical structures in individuals with SCD and amnestic mild cognitive impairment (aMCI) and AD patients are altered compared with normal controls (NC). …Methods: We investigated neuroanatomical alterations in 35 SCD, 43 aMCI, and 41 AD subjects compared with 42 NC, focusing on asymmetrical changes in subcortical structures based on structural magnetic resonance images (sMRI). General linear model was conducted to test group differences, and partial correlation was used to model the interaction between asymmetry measurements and cognitive tests. Results: Individuals with SCD (lateral ventricle and cerebellum-WM), aMCI patients (lateral ventricle, pallidum, hippocampus, amygdala, accumbens, and ventral DC), and AD patients (lateral-ventricle, cerebellum-cortical pallidum, thalamus, hippocampus, amygdala, accumbens, and ventral DC) exhibited significant altered neuroanatomical asymmetries of volume, surface area, and shape compared with NC. Significant associations between shape asymmetry and neuropsychological examinations were found in the hippocampus and accumbens. Conclusion: Altered neuroanatomical asymmetries of subcortical structures were significantly detected in SCD individuals and aMCI patients as well AD patients, and these specific asymmetry alterations are potential to be used as neuroimaging markers and for monitoring disease progression. Show more

Keywords: Brainprint, brain asymmetry, early diagnosis, subjective cognitive decline

DOI: 10.3233/JAD-201116

Citation: Journal of Alzheimer's Disease, vol. 79, no. 3, pp. 1121-1132, 2021

Authors: Gonzalez, Christopher | Tommasi, Nicole S. | Briggs, Danielle | Properzi, Michael J. | Amariglio, Rebecca E. | Marshall, Gad A. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Financial capacity is often one of the first instrumental activities of daily living to be affected in cognitively normal (CN) older adults who later progress to amnestic mild cognitive impairment (MCI) and Alzheimer’s disease (AD) dementia. Objective: The objective of this study was to investigate the association between financial capacity and regional cerebral tau. Methods: Cross-sectional financial capacity was assessed using the Financial Capacity Instrument –Short Form (FCI-SF) in 410 CN, 199 MCI, and 61 AD dementia participants who underwent flortaucipir tau positron emission tomography from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Linear regression models …with backward elimination were used with FCI-SF total score as the dependent variable and regional tau and tau-amyloid interaction as predictors of interest in separate analyses. Education, age, sex, Rey Auditory Verbal Learning Test Total Learning, and Trail Making Test B were used as covariates. Results: Significant associations were found between FCI-SF and tau regions (entorhinal: p  < 0.001; inferior temporal: p  < 0.001; dorsolateral prefrontal: p  = 0.01; posterior cingulate: p  = 0.03; precuneus: p  < 0.001; and supramarginal gyrus: p  = 0.005) across all participants. For the tau-amyloid interaction, significant associations were found in four regions (amyloid and dorsolateral prefrontal tau interaction: p  = 0.005; amyloid and posterior cingulate tau interaction: p  = 0.005; amyloid and precuneus tau interaction: p  < 0.001; and amyloid and supramarginal tau interaction: p  = 0.002). Conclusion: Greater regional tau burden was modestly associated with financial capacity impairment in early-stage AD. Extending this work with longitudinal analyses will further illustrate the utility of such assessments in detecting clinically meaningful decline, which may aid clinical trials of early-stage AD. Show more

Keywords: Alzheimer’s disease, amyloid, financial capacity, instrumental activities of daily living, mild cognitive impairment, positron emission tomography, tau

DOI: 10.3233/JAD-201122

Citation: Journal of Alzheimer's Disease, vol. 79, no. 3, pp. 1133-1142, 2021

Authors: Benítez, María J. | Cuadros, Raquel | Jiménez, Juan S.

Article Type: Research Article

Abstract: Background: Tau is a microtubule associated protein that regulates the stability of microtubules and the microtubule-dependent axonal transport. Its hyperphosphorylated form is one of the hallmarks of Alzheimer’s disease and other tauopathies and the major component of the paired helical filaments that form the abnormal proteinaceous tangles found in these neurodegenerative diseases. It is generally accepted that the phosphorylation extent of tau is the result of an equilibrium in the activity of protein kinases and phosphatases. Disruption of the balance between both types of enzyme activities has been assumed to be at the origin of tau hyperphosphorylation and the subsequent …toxicity and progress of the disease. Objective: We explore the possibility that, beside the phosphatase action on phosphorylated tau, the catalytic subunit of PKA catalyzes both tau phosphorylation and also tau dephosphorylation, depending on the ATP/ADP ratio. Methods: We use the shift in the relative electrophoretic mobility suffered by different phosphorylated forms of tau, as a sensor of the catalytic action of the enzyme. Results: The results are in agreement with the long-known thermodynamic reversibility of the phosphorylation reaction (ATP + Protein = ADP+Phospho-Protein) catalyzed by PKA and many other protein kinases. Conclusion: The results contribute to put the compartmentalized energy state of the neuron and the mitochondrial-functions disruption upstream of tau-related pathologies. Show more

Keywords: Dephosphorylation, electrophoretic mobility, phosphorylation, PKA, tau protein, thermodynamic reversibility

DOI: 10.3233/JAD-201077

Citation: Journal of Alzheimer's Disease, vol. 79, no. 3, pp. 1143-1156, 2021

Authors: Gruters, Angélique A.A. | Ramakers, Inez H.G.B. | Stiekema, Annemarie P.M. | Verhey, Frans R.J. | Kessels, Roy P.C. | de Vugt, Marjolein E.

Article Type: Research Article

Abstract: Background: Neuropsychological feedback is an important part of the neuropsychological assessment process. However, patients have difficulties remembering this information. Objective: The aim of this study was to develop a web-based visual tool to improve the understanding of neuropsychological results, information retention, and psychologist-patient communication. Methods: The visual tool was developed and optimized using an iterative three-phase stepwise approach to determine its usability, technology acceptance, and feasibility in a memory clinic population. Feedback from different user perspectives (patients, family members, and psychologists) was obtained in each phase using a multimethod approach (e.g. a multidisciplinary brainstorm session, think-aloud …sessions, focus groups). The prototype was subsequently tested in a pilot study. Results: The first phases offered insights that led to optimization of the prototype. On a scale ranging from 0 to 100, psychologists evaluated the usability as high [88.1±7.6,70–87]. During the pilot study, both patients and significant others gave positive feedback, but information retention in patients remained low. All participants thought the benefits of the visual tool included seeing cognitive strengths and weaknesses with a translation to daily life all at one glance and receiving feedback on paper to take home. Important barriers were mentioned by psychologists, such as a limited set of tests included and no integration with hospital systems. Conclusion: Overall, patients, family members, and psychologists reported that a visual display of the cognitive profile with insights into daily life had added value to clinical practice. Feedback from the pilot study was adopted in the tool for future implementation purposes. Show more

Keywords: Communication, dementia, neuropsychological tests, neuropsychology, visual aids

DOI: 10.3233/JAD-201128

Citation: Journal of Alzheimer's Disease, vol. 79, no. 3, pp. 1157-1170, 2021