Journal of Alzheimer's Disease - Volume 95, issue 3

Authors: Schork, Nicholas J. | Elman, Jeremy A.

Article Type: Research Article

Abstract: Background: APOE is the largest genetic risk factor for Alzheimer’s disease (AD), but there is a substantial polygenic component. Polygenic risk scores (PRS) can summarize small effects across the genome but may obscure differential risk across molecular processes and pathways that contribute to heterogeneity of disease presentation. Objective: We examined polygenic risk impacting specific AD-associated pathways and its relationship with clinical status and biomarkers of amyloid, tau, and neurodegeneration (A/T/N). Methods: We analyzed data from 1,411 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). We applied pathway analysis and clustering to identify AD-associated “pathway clusters” …and construct pathway-specific PRSs (excluding the APOE region). We tested associations with diagnostic status, abnormal levels of amyloid and ptau, and hippocampal volume. Results: Thirteen pathway clusters were identified, and eight pathway-specific PRSs were significantly associated with AD diagnosis. Amyloid-positivity was associated with endocytosis and fibril formation, response misfolded protein, and regulation protein tyrosine PRSs. Ptau positivity and hippocampal volume were both related to protein localization and mitophagy PRS, and ptau-positivity was also associated with an immune signaling PRS. A global AD PRS showed stronger associations with diagnosis and all biomarkers compared to pathway PRSs. Conclusions: Pathway PRS may contribute to understanding separable disease processes, but do not add significant power for predictive purposes. These findings demonstrate that AD-phenotypes may be preferentially associated with risk in specific pathways, and defining genetic risk along multiple dimensions may clarify etiological heterogeneity in AD. This approach to delineate pathway-specific PRS can be used to study other complex diseases. Show more

Keywords: Alzheimer’s disease, amyloid, dementia, genetic risk score, hippocampal volume, tau

DOI: 10.3233/JAD-230548

Citation: Journal of Alzheimer's Disease, vol. 95, no. 3, pp. 915-929, 2023

Authors: Vassilaki, Maria | Fu, Sunyang | Christenson, Luke R. | Garg, Muskan | Petersen, Ronald C. | St. Sauver, Jennifer | Sohn, Sunghwan

Article Type: Research Article

Abstract: Background: Multiple algorithms with variable performance have been developed to identify dementia using combinations of billing codes and medication data that are widely available from electronic health records (EHR). If the characteristics of misclassified patients are clearly identified, modifying existing algorithms to improve performance may be possible. Objective: To examine the performance of a code-based algorithm to identify dementia cases in the population-based Mayo Clinic Study of Aging (MCSA) where dementia diagnosis (i.e., reference standard) is actively assessed through routine follow-up and describe the characteristics of persons incorrectly categorized. Methods: There were 5,316 participants (age at …baseline (mean (SD)): 73.3 (9.68) years; 50.7% male) without dementia at baseline and available EHR data. ICD-9/10 codes and prescription medications for dementia were extracted between baseline and one year after an MCSA dementia diagnosis or last follow-up. Fisher’s exact or Kruskal-Wallis tests were used to compare characteristics between groups. Results: Algorithm sensitivity and specificity were 0.70 (95% CI: 0.67, 0.74) and 0.95 (95% CI: 0.95, 0.96). False positives (i.e., participants falsely diagnosed with dementia by the algorithm) were older, with higher Charlson comorbidity index, more likely to have mild cognitive impairment (MCI), and longer follow-up (versus true negatives). False negatives (versus true positives) were older, more likely to have MCI, or have more functional limitations. Conclusions: We observed a moderate-high performance of the code-based diagnosis method against the population-based MCSA reference standard dementia diagnosis. Older participants and those with MCI at baseline were more likely to be misclassified. Show more

Keywords: Alzheimer’s disease, dementia, electronic health records, sensitivity, specificity

DOI: 10.3233/JAD-230344

Citation: Journal of Alzheimer's Disease, vol. 95, no. 3, pp. 931-940, 2023

Authors: Chen, Shanquan | Wang, Yuqi | Mueller, Christoph

Article Type: Article Commentary

Abstract: Code-based algorithms are crucial tools in the detection of dementia using electronic health record data, with broad applications in medical research and healthcare. Vassilaki et al.’s study explores the efficacy of code-based algorithms in dementia detection using electronic health record data, achieving approximately 70% sensitivity and positive predictive value. Despite the promising results, the algorithms fail to detect around 30% of dementia cases, highlighting challenges in distinguishing cognitive decline factors. The study emphasizes the need for algorithmic improvements and further exploration across diverse healthcare systems and populations, serving as a critical step toward bridging gaps in dementia care and understanding.

Keywords: Alzheimer’s disease, code-based algorithm, dementia, electronic health record

DOI: 10.3233/JAD-230887

Citation: Journal of Alzheimer's Disease, vol. 95, no. 3, pp. 941-943, 2023

Authors: Wang, Yaqi | Yang, Kai | Fu, Pengrui | Zheng, Xiaolei | Yang, Hui | Zhou, Qingbo | Ma, Wen | Wang, Ping

Article Type: Research Article

Abstract: Background: The ability to understand and make use of object-scene relationships are critical for object and scene recognition. Objective: The current study assessed whether patients with mild cognitive impairment (MCI), possibly in the preclinical phase of Alzheimer’s disease, exhibited impairment in processing contextual information in scene and object recognition. Methods: In Experiment 1, subjects viewed images of foreground objects in either semantic consistent or inconsistent scenes under no time pressure, and they verbally reported the names of foreground objects and backgrounds. Experiment 2 replicated Experiment 1, except that subjects were required to name scene first. Experiment …3 examined object and scene recognition accuracy baselines, recognition difficulty, familiarity with objects/scenes, and object-scene consistency judgements. Results: There were contextual consistency effects on scene recognition for MCI and healthy subjects, regardless of response sequence. Scenes were recognized more accurately under the consistent condition than the inconsistent condition. Additionally, MCI patients were more susceptible to incongruent contextual information, possibly due to inhibitory deficits or over-dependence on semantic knowledge. However, no significant differences between MCI and healthy subjects were observed in consistency judgement, recognition accuracy, recognition difficulty and familiarity rating, suggesting no significant impairment in object and scene knowledge among MCI subjects. Conclusions: The study indicates that MCI patients retain relatively intact contextual processing ability but may exhibit inhibitory deficits or over-reliance on semantic knowledge. Show more

Keywords: Alzheimer’s disease, contextual consistency, inhibitory deficits, mild cognitive impairment, object and scene recognition, over-reliance on semantic knowledge

DOI: 10.3233/JAD-221132

Citation: Journal of Alzheimer's Disease, vol. 95, no. 3, pp. 945-963, 2023

Authors: de Oliveira Otto, Marcia C. | Wu, Jason H.Y. | Thacker, Evan L. | Lai, Heidi Tsz Mung | Lemaitre, Rozenn N. | Padhye, Nikhil | Song, Xiaoling | King, Irena B. | Lopez, Oscar | Siscovick, David S. | Mozaffarian, Dariush

Article Type: Research Article

Abstract: Background: Comprising nearly 35% of brain lipids, polyunsaturated fatty acids (PUFA) are essential for optimal brain function. However, the role of PUFA on cognitive health outcomes later in life is largely unknown. Objective: We investigated prospective associations of plasma phospholipid omega-3 (ALA [18 : 3], EPA [20 : 5], DPA [22 : 5], DHA [22 : 6]) and omega-6 (LA [18 : 2], AA [20 : 4]) PUFA with cognitive decline, risk of cognitive impairment and dementia among adults aged≥65 years in the Cardiovascular Health Study. Methods: Circulating fatty acid concentrations were measured serially at baseline (1992/1993), 6 years, and 13 years later. Cognitive decline …and impairment were assessed using the 100-point Modified Mini-Mental State Examination (3MSE) up to 7 times. Clinical dementia was identified using adjudicated neuropsychological tests, and ICD-9 codes. Results: Among 3,564 older adults free of stroke and dementia at baseline, cognitive function declined annually by approximately -0.5 3MSE points; 507 participants developed cognitive impairment and 499 dementia over up to 23 years of follow-up. In multivariable models, higher circulating arachidonic acid (AA) concentrations were associated with slower cognitive decline and lower dementia risk, with associations growing stronger with greater length of follow-up (hazard ratio [HR,95% CI] of dementia per interquintile range, 0.74 [0.56-0.97] at 5 years, and 0.53 [0.37-0.77] at 15 years). Circulating docosapentaenoic (DPA) concentrations were associated with slower cognitive decline and lower risk of cognitive impairment (extreme-quintile HR, 0.72 [95% CI: 0.55, 0.95]). Findings were generally null or inconsistent for other omega-3 or omega-6 PUFA. Conclusion: Circulating AA and DPA, but not other PUFA, are associated with slower rate of cognitive decline and lower risk of dementia or cognitive impairment later in life. Show more

Keywords: Aging, Alzheimer’s disease, cognition, dementia, diet, fatty acids

DOI: 10.3233/JAD-230083

Citation: Journal of Alzheimer's Disease, vol. 95, no. 3, pp. 965-979, 2023

Authors: Jiang, Jiwei | Wang, Anxin | Liu, Yaou | Yao, Zeshan | Sun, Mengfan | Jiang, Tianlin | Li, Wenyi | Jiang, Shirui | Zhang, Xiaoli | Wang, Yanli | Zhang, Yuan | Jia, Ziyan | Zou, Xinying | Xu, Jun

Article Type: Research Article

Abstract: Background: Current technology for exploring neuroimaging markers and neural circuits of neuropsychiatric symptoms (NPS) in patients with Alzheimer’s disease (AD) is expensive and usually invasive, limiting its use in clinical practice. Objective: To investigate the cerebral morphology and perfusion characteristics of NPS and identify the spatiotemporal perfusion circuits of NPS sub-symptoms. Methods: This nested case-control study included 102 AD patients with NPS and 51 age- and sex-matched AD patients without NPS. Gray matter volume, cerebral blood flow (CBF), and arterial transit time (ATT) were measured and generated using time-encoded 7-delay pseudo-continuous arterial spin …labeling (pCASL). Multiple conditional logistic regression analysis was used to identify neuroimaging markers of NPS. The associations between the CBF or ATT of affected brain areas and NPS sub-symptoms were evaluated after adjusting for confounding factors. The neural circuits of sub-symptoms were identified based on spatiotemporal perfusion sequencing. Results: Lower Mini-Mental State Examination scores (p  < 0.001), higher Caregiver Burden Inventory scores (p  < 0.001), and higher CBF (p  = 0.001) and ATT values (p  < 0.003) of the right anteroventral thalamic nucleus (ATN) were risk factors for NPS in patients with AD. Six spatiotemporal perfusion circuits were found from 12 sub-symptoms, including the anterior cingulate gyri-temporal pole/subcortical thalamus-cerebellum circuit, insula-limbic-cortex circuit, subcortical thalamus-temporal pole-cortex circuit, subcortical thalamus-cerebellum circuit, frontal cortex-cerebellum-occipital cortex circuit, and subcortical thalamus-hippocampus-dorsal raphe nucleus circuit. Conclusions: Prolonged ATT and increased CBF of the right ATN may be neuroimaging markers for detecting NPS in patients with AD. Time-encoded pCASL could be a reliable technique to explore the neural perfusional circuits of NPS. Show more

Keywords: Alzheimer’s disease, neuroimaging, neuropsychiatric symptoms, perfusion

DOI: 10.3233/JAD-230499

Citation: Journal of Alzheimer's Disease, vol. 95, no. 3, pp. 981-993, 2023

Authors: Abyadeh, Morteza | Yadav, Vijay K. | Kaya, Alaattin

Article Type: Research Article

Abstract: Background: Cognitive decline is a common consequence of COVID-19, and studies suggest a link between COVID-19 and Alzheimer’s disease (AD). However, the molecular mechanisms underlying this association remain unclear. Objective: To understand the potential molecular mechanisms underlying the association between COVID-19 and AD development, and identify the potential genetic targets for pharmaceutical approaches to reduce the risk or delay the development of COVID-19-related neurological pathologies. Methods: We analyzed transcriptome datasets of 638 brain samples using a novel Robust Rank Aggregation method, followed by functional enrichment, protein-protein, hub genes, gene-miRNA, and gene-transcription factor (TF) …interaction analyses to identify molecular markers altered in AD and COVID-19 infected brains. Results: Our analyses of frontal cortex from COVID-19 and AD patients identified commonly altered genes, miRNAs and TFs. Functional enrichment and hub gene analysis of these molecular changes revealed commonly altered pathways, including downregulation of the cyclic adenosine monophosphate (cAMP) signaling and taurine and hypotaurine metabolism, alongside upregulation of neuroinflammatory pathways. Furthermore, gene-miRNA and gene-TF network analyses provided potential up- and downstream regulators of identified pathways. Conclusion: We found that downregulation of cAMP signaling pathway, taurine metabolisms, and upregulation of neuroinflammatory related pathways are commonly altered in AD and COVID-19 pathogenesis, and may make COVID-19 patients more susceptible to cognitive decline and AD. We also identified genetic targets, regulating these pathways that can be targeted pharmaceutically to reduce the risk or delay the development of COVID-19-related neurological pathologies and AD. Show more

Keywords: Alzheimer’s disease, cAMP signaling pathway, COVID-19, inflammation, omics, taurine and hypotaurine metabolism

DOI: 10.3233/JAD-230684

Citation: Journal of Alzheimer's Disease, vol. 95, no. 3, pp. 995-1011, 2023

Authors: Daamen, Marcel | Scheef, Lukas | Li, Shumei | Grothe, Michel J. | Gaertner, Florian C. | Buchert, Ralph | Buerger, Katharina | Dobisch, Laura | Drzezga, Alexander | Essler, Markus | Ewers, Michael | Fliessbach, Klaus | Herrera Melendez, Ana Lucia | Hetzer, Stefan | Janowitz, Daniel | Kilimann, Ingo | Krause, Bernd Joachim | Lange, Catharina | Laske, Christoph | Munk, Matthias H. | Peters, Oliver | Priller, Josef | Ramirez, Alfredo | Reimold, Matthias | Rominger, Axel | Rostamzadeh, Ayda | Roeske, Sandra | Roy, Nina | Scheffler, Klaus | Schneider, Anja | Spottke, Annika | Spruth, Eike Jakob | Teipel, Stefan J. | Wagner, Michael | Düzel, Emrah | Jessen, Frank | Boecker, Henning

Article Type: Research Article

Abstract: Background: Atrophy of cholinergic basal forebrain (BF) nuclei is a frequent finding in magnetic resonance imaging (MRI) volumetry studies that examined patients with prodromal or clinical Alzheimer’s disease (AD), but less clear for individuals in earlier stages of the clinical AD continuum. Objective: To examine BF volume reductions in subjective cognitive decline (SCD) participants with AD pathologic changes. Methods: The present study compared MRI-based BF volume measurements in age- and sex-matched samples of N = 24 amyloid-positive and N = 24 amyloid-negative SCD individuals, based on binary visual ratings of Florbetaben positron emission tomography (PET) measurements. Additionally, …we assessed associations of BF volume with cortical amyloid burden, based on semiquantitative Centiloid (CL) analyses. Results: Group differences approached significance for BF total volume (p  = 0.061) and the Ch4 subregion (p  = 0.059) only, showing the expected relative volume reductions for the amyloid-positive subgroup. There were also significant inverse correlations between BF volumes and CL values, which again were most robust for BF total volume and the Ch4 subregion. Conclusions: The results are consistent with the hypothesis that amyloid-positive SCD individuals, which are considered to represent a transitional stage on the clinical AD continuum, already show incipient alterations of BF integrity. The negative association with a continuous measure of cortical amyloid burden also suggests that this may reflect an incremental process. Yet, further research is needed to evaluate whether BF changes already emerge at “grey zone” levels of amyloid accumulation, before amyloidosis is reliably detected by PET visual readings. Show more

Keywords: Acetylcholine, Alzheimer’s disease, amyloid, atrophy, basal forebrain, cognitive decline

DOI: 10.3233/JAD-230141

Citation: Journal of Alzheimer's Disease, vol. 95, no. 3, pp. 1013-1028, 2023

Authors: Camarillo, Joe | Villarreal Rizzo, Alan | Cabrero Castro, Jose Eduardo | Downer, Brian

Article Type: Research Article

Abstract: Background: The prevalence of type 2 diabetes in Mexico has nearly doubled for adults aged ≥60. Increases in education and healthcare resources to manage chronic conditions have contributed to population-level increases in the cognitive functioning of older adults. However, research has not focused on older adults with chronic conditions such as diabetes. Objective: Our objective was to compare the cognitive functioning of Mexican adults aged ≥60 with diabetes in 2001 and 2018. Methods: Data came from Mexican Health and Aging Study. Our study used a cross-sectional design and included participants aged ≥60 with …self-reported diabetes during the 2001 (n  = 1,052, mean age = 68.4, female = 59.6%) and 2018 (n  = 2,469, mean age = 70.6, female = 62.0%) observation waves. Five cognitive tests were used to create a score of global cognition. Generalized estimating equations were used to compare global cognition in 2001 to 2018. Results: Older adults in 2018 had more education and were more likely than older adults in 2001 to take oral medication for diabetes, insulin, and to check blood sugar weekly. Older adults in 2018 had higher global cognition than in 2001 when adjusting for age, gender, education, and health insurance coverage (b  = 0.38, SE = 0.02). This statistically significant difference remained after adjusting for health conditions, health behaviors, and diabetes management behaviors. Conclusions: Older adults in Mexico with self-reported diabetes in 2018 had higher cognitive function than in 2001. Future research is needed to investigate causes of the cohort differences in cognitive functioning among Mexican older adults with self-reported diabetes. Show more

Keywords: Alzheimer’s disease, cognition, diabetes mellitus, epidemiology, Mexico

DOI: 10.3233/JAD-230286

Citation: Journal of Alzheimer's Disease, vol. 95, no. 3, pp. 1029-1039, 2023

Authors: Al-Lahham, Rabab | Mendez, Nicolas

Article Type: Research Article

Abstract: Background: Several epidemiological data revealed an association between Alzheimer’s disease (AD) and type 2 diabetes. Researchers concentrated on brain insulin resistance with little emphasis on the link between systemic insulin resistance and AD, despite the fact that the incidence of type 2 diabetes is higher in AD patients and that impairment in insulin signaling is a risk factor for AD. Objective: The goal of this study is to determine the role of systemic insulin resistance in the pathogenesis of Alzheimer’s disease by evaluating the consequences of tau loss-of-function on peripheral insulin sensitivity. Methods: …Primary hepatocytes isolated from transgenic mouse models (Tau KO, P301 L) and wild type mice (C57BL/6) were evaluated for their insulin sensitivity using glucose uptake assays as well as biochemical analysis of insulin signaling markers. Results: Our data show that tau deletion or loss of function promotes peripheral insulin resistance as seen in primary hepatocytes isolated from Tau KO and P301 L mice, respectively. Furthermore, exposure of wild-type primary hepatocytes to sub-toxic concentrations of tau oligomers results in a dose-dependent inhibition of glucose uptake, associated with downregulation of insulin signaling. Tau oligomers-induced inactivation of insulin signaling proteins was rescued by inhibition of p38 MAPK, suggesting the involvement of p38 MAPK. Conclusions: This is the first study testing tau role in peripheral insulin resistance at the cellular level using multiple transgenic mouse models. Moreover, this study suggests that tau should be functional for insulin sensitivity, therefore, any loss of function by deletion or aggregation would result in insulin resistance. Show more

Keywords: Alzheimer’s disease, AKT, GLUT4, GSK3β , insulin resistance, IRS1, p38 MAPK, tau oligomers

DOI: 10.3233/JAD-230392

Citation: Journal of Alzheimer's Disease, vol. 95, no. 3, pp. 1041-1058, 2023