Journal of Alzheimer's Disease - Volume 85, issue 2

Authors: Brod, Staley A.

Article Type: Review Article

Abstract: Systemic inflammation is an organism’s response to an assault by the non-self. However, that inflammation may predispose humans to illnesses targeted to organs, including Alzheimer’s disease (AD). Lesions in AD have pro-inflammatory cytokines and activated microglial/monocyte/macrophage cells. Up to this point, clinical trials using anti-amyloid monoclonal antibodies have not shown success. Maybe it is time to look elsewhere by combating inflammation. Neuroinflammation with CNS cellular activation and excessive expression of immune cytokines is suspected as the “principal culprit” in the higher risk for sporadic AD. Microglia, the resident immune cell of the CNS, perivascular myeloid cells, and activated macrophages produce …IL-1, IL-6 at higher levels in patients with AD. Anti-inflammatory measures that target cellular/cytokine-mediated damage provide a rational therapeutic strategy. We propose a clinical trial using oral type 1 IFNs to act as such an agent; one that decreases IL-1 and IL-6 secretion by activating lamina propria lymphocytes in the gut associated lymphoid tissue with subsequent migration to the brain undergoing inflammatory responses. A clinical trial would be double-blind, parallel 1-year clinical trial randomized 1 : 1 oral active type 1 IFN versus best medical therapy to determine whether ingested type I IFN would decrease the rate of cognitive decline in mild cognitive impairment or mild AD. Using cognitive psychometrics, imaging, and fluid biomarkers (MxA for effective type I IFN activity beyond the gut), we can determine if oral type I IFN can prevent cognitive decline in AD. Show more

Keywords: Alzheimer’s disease, inflammation, innate immunity, pro-inflammatory cytokines

DOI: 10.3233/JAD-215125

Citation: Journal of Alzheimer's Disease, vol. 85, no. 2, pp. 457-472, 2022

Authors: Wang, Lai | Chen, Hongyang | Tang, Jing | Guo, Zhengwei | Wang, Yanming

Article Type: Review Article

Abstract: Peptidylarginine deiminases (PADs) are indispensable enzymes for post-translational modification of proteins, which can convert Arg residues on the surface of proteins to citrulline residues. The PAD family has five isozymes, PAD1, 2, 3, 4, and 6, which have been found in multiple tissues and organs. PAD2 and PAD4 were detected in cerebral cortex and hippocampus from human and rodent brain. In the central nervous system, abnormal expression and activation of PADs are involved in the pathological changes and pathogenesis of Alzheimer’s disease (AD). This article reviews the classification, distribution, and function of PADs, with an emphasis on the relationship between …the abnormal activation of PADs and AD pathogenesis, diagnosis, and the therapeutic potential of PADs as drug targets for AD. Show more

Keywords: Alzheimer’s disease, citrulline, PAD inhibitors, peptidylarginine deiminases

DOI: 10.3233/JAD-215302

Citation: Journal of Alzheimer's Disease, vol. 85, no. 2, pp. 473-484, 2022

Authors: Lynn, Jessica | Park, Mingi | Ogunwale, Christiana | Acquaah-Mensah, George K.

Article Type: Review Article

Abstract: Dementias, including the type associated with Alzheimer’s disease (AD), are on the rise worldwide. Similarly, type 2 diabetes mellitus (T2DM) is one of the most prevalent chronic diseases globally. Although mechanisms and treatments are well-established for T2DM, there remains much to be discovered. Recent research efforts have further investigated factors involved in the etiology of AD. Previously perceived to be unrelated diseases, commonalities between T2DM and AD have more recently been observed. As a result, AD has been labeled as “type 3 diabetes”. In this review, we detail the shared processes that contribute to these two diseases. Insulin resistance, the …main component of the pathogenesis of T2DM, is also present in AD, causing impaired brain glucose metabolism, neurodegeneration, and cognitive impairment. Dysregulation of insulin receptors and components of the insulin signaling pathway, including protein kinase B, glycogen synthase kinase 3β, and mammalian target of rapamycin are reported in both diseases. T2DM and AD also show evidence of inflammation, oxidative stress, mitochondrial dysfunction, advanced glycation end products, and amyloid deposition. The impact that changes in neurovascular structure and genetics have on the development of these conditions is also being examined. With the discovery of factors contributing to AD, innovative treatment approaches are being explored. Investigators are evaluating the efficacy of various T2DM medications for possible use in AD, including but not limited to glucagon-like peptide-1 receptor agonists and peroxisome proliferator-activated receptor-gamma agonists. Furthermore, there are 136 active trials involving 121 therapeutic agents targeting novel AD biomarkers. With these efforts, we are one step closer to alleviating the ravaging impact of AD on our communities. Show more

Keywords: Alzheimer’s disease, amyloid, blood-brain barrier, glucagon-like peptide 1, insulin resistance, microbiota, mitochondria, oxidative stress, therapeutics, type 2 diabetes mellitus

DOI: 10.3233/JAD-210612

Citation: Journal of Alzheimer's Disease, vol. 85, no. 2, pp. 485-501, 2022

Authors: Crestini, Alessio | Santilli, Francesca | Martellucci, Stefano | Carbone, Elena | Sorice, Maurizio | Piscopo, Paola | Mattei, Vincenzo

Article Type: Review Article

Abstract: Specific protein misfolding and aggregation are mechanisms underlying various neurodegenerative diseases such as prion disease and Alzheimer’s disease (AD). The misfolded proteins are involved in prions, amyloid-β (Aβ), tau, and α -synuclein disorders; they share common structural, biological, and biochemical characteristics, as well as similar mechanisms of aggregation and self-propagation. Pathological features of AD include the appearance of plaques consisting of deposition of protein Aβ and neurofibrillary tangles formed by the hyperphosphorylated tau protein. Although it is not clear how protein aggregation leads to AD, we are learning that the cellular prion protein (PrPC ) plays an important role in …the pathogenesis of AD. Herein, we first examined the pathogenesis of prion and AD with a focus on the contribution of PrPC to the development of AD. We analyzed the mechanisms that lead to the formation of a high affinity bond between Aβ oligomers (AβOs) and PrPC . Also, we studied the role of PrPC as an AβO receptor that initiates an AβO-induced signal cascade involving mGluR5, Fyn, Pyk2, and eEF2K linking Aβ and tau pathologies, resulting in the death of neurons in the central nervous system. Finally, we have described how the PrPC -AβOs interaction can be used as a new potential therapeutic target for the treatment of PrPC -dependent AD. Show more

Keywords: Alzheimer’s disease, Aβ oligomers, amyloid-β , amyloid-β protein precursor, neurodegenerative diseases, prion protein, prion protein refolding, prions, tau pathologies AβO-induced signal cascade

DOI: 10.3233/JAD-215171

Citation: Journal of Alzheimer's Disease, vol. 85, no. 2, pp. 503-518, 2022

Authors: Zdanowski, Szymon | Tieks, Alieke | Jeronimus, Bertus F. | Zuidersma, Marij

Article Type: Short Communication

Abstract: Using group-aggregated results and snapshot assessments of cognitive performance may prove problematic if the assessed construct shows substantial and rapid variation over time. To illustrate the significance of this issue, we analyzed cognitive performance data of ten older adults undergoing daily computerized cognitive assessments (CogState Brief Battery) for 36–93 days. In all cases, the day-to-day intra-individual variability was substantial when compared with group-level, between-person variability. This indicates that the results of studies using single snapshot assessments of cognitive functioning should be interpreted with caution. Additionally, group-aggregated measures of cognitive performance may not directly extrapolate to an individual.

Keywords: Attention, cognition, intra-individual variability, memory, reaction time, working memory

DOI: 10.3233/JAD-210304

Citation: Journal of Alzheimer's Disease, vol. 85, no. 2, pp. 519-525, 2022

Authors: Larner, Andrew J. | Marson, Anthony G.

Article Type: Article Commentary

Abstract: Epileptic seizures are increasingly recognized as part of the clinical phenotype of patients with Alzheimer’s disease (AD). However, the evidence base on which to make treatment decisions for such patients is slim, there being no clear recommendation based on systematic review of the few existing studies of anti-seizure drugs in AD patients. Here the authors examine the potential implications for the treatment of seizures in AD of the results of the recently published SANAD II pragmatic study, which examined the effectiveness of levetiracetam, zonisamide, or lamotrigine in newly diagnosed focal epilepsy, and of valproate and levetiracetam in generalized and unclassifiable …epilepsy. Show more

Keywords: Alzheimer’s disease, epilepsy, seizures, treatment

DOI: 10.3233/JAD-215154

Citation: Journal of Alzheimer's Disease, vol. 85, no. 2, pp. 527-529, 2022

Authors: Talan, Jamie

Article Type: Editorial

DOI: 10.3233/JAD-215436

Citation: Journal of Alzheimer's Disease, vol. 85, no. 2, pp. 531-533, 2022

Authors: Alam, Rifat B. | Singleton, Chelsea R. | Aguiñaga, Susan | Chodzko-Zajko, Wojtek | Jahan, Nilufer A. | Oke, Adeyosola | Schwingel, Andiara

Article Type: Research Article

Abstract: Background: Hispanics in the United States are disproportionately affected by Alzheimer’s disease and related dementias. Little is known about the impact of acculturation on cognitive performance. Objective: This study examined the association between acculturation and cognitive performance among older Hispanics. Methods: We analyzed cross-sectional data of 616 Hispanic participants in the National Health and Nutrition Examination Survey (NHANES) 2011–2014 [average age = 67.15 years, %Female = 51.46, %less than high-school graduate = 52.60]. Cognitive performance was measured by two neuropsychological tests: Animal Fluency Test (AFT) and Digit Symbol Substitution Test (DSST). We used two single-item proxy measures to quantify acculturation: nativity status …(non-US-born residing < 15 years in the US (low acculturation), non-US-born residing ≥15 years in the US, and US-born (high acculturation)); and language acculturation (only/mostly Spanish (low acculturation), Spanish and English, only/mostly English (high acculturation)). We used adjusted linear regression to evaluate associations between acculturation and cognitive performance. Results: Results indicated poorer cognitive performance among the low-acculturated groups for both nativity and linguistic measures. Participants who were non-US-born living ≥15 years (p  = 0.02) and speaking only/mostly Spanish or Spanish and English (p  = 0.01 and 0.006 respectively) had significantly lower AFT scores compared to US-born and only/mostly English-speaking groups. Participants who were non-US-born living < 15 years (p  < 0.0001) or non-US-born living ≥15 years (p  < 0.0001) and speaking only/mostly Spanish (p  = 0.0008) scored lower on the DSST than the US-born and only/mostly English-speaking participants. Conclusion: In summary, low acculturation is associated with poorer cognitive performance among older Hispanics. Acculturation might be an important attribute to help understand cognitive decline and dementias among Hispanics. Show more

Keywords: Acculturation, cognitive performance, dementia, Hispanic Americans

DOI: 10.3233/JAD-210502

Citation: Journal of Alzheimer's Disease, vol. 85, no. 2, pp. 535-544, 2022

Authors: Sapkota, Shraddha | McFall, G. Peggy | Masellis, Mario | Dixon, Roger A. | Black, Sandra E.

Article Type: Research Article

Abstract: Background: Differential cognitive trajectories in Alzheimer’s disease (AD) may be predicted by biomarkers from multiple domains. Objective: In a longitudinal sample of AD and AD-related dementias patients (n  = 312), we tested whether 1) change in brain morphometry (ventricular enlargement) predicts differential cognitive trajectories, 2) further risk is contributed by genetic (Apolipoprotein E [APOE ] ɛ 4+) and vascular (pulse pressure [PP]) factors separately, and 3) the genetic + vascular risk moderates this pattern. Methods: We applied a dynamic computational approach (parallel process models) to test both concurrent and change-related associations between predictor (ventricular size) and cognition (executive …function [EF]/attention). We then tested these associations as stratified by APOE (ɛ 4–/ɛ 4+), PP (low/high), and APOE + PP (low/intermediate/high) risk. Results: First, concurrently, higher ventricular size predicted lower EF/attention performance and, longitudinally, increasing ventricular size predicted steeper EF/attention decline. Second, concurrently, higher ventricular size predicted lower EF/attention performance selectively in APOE ɛ 4+ carriers, and longitudinally, increasing ventricular size predicted steeper EF/attention decline selectively in the low PP group. Third, ventricular size and EF/attention associations were absent in the high APOE + PP risk group both concurrently and longitudinally. Conclusion: As AD progresses, a threshold effect may be present in which ventricular enlargement in the context of exacerbated APOE + PP risk does not produce further cognitive decline. Show more

Keywords: Alzheimer’s disease, Apolipoprotein E, attention, brain imaging, executive control, pulse pressure , ClinicalTrials.gov, NCT01800214. Registered on 27 February 2013.

DOI: 10.3233/JAD-215068

Citation: Journal of Alzheimer's Disease, vol. 85, no. 2, pp. 545-560, 2022

Authors: Li, Lin | Cheng, Gui-Rong | Liu, Dan | Hu, Fei-Fei | Gan, Xu-Guang | Zhang, Bo | An, Lina | Chen, Cong | Zou, Ming-Jun | Xu, Lang | Ou, Yang-Ming | Chen, Yu-Shan | Li, Jin-Quan | Wei, Zhen | Wu, Qiong | Chen, Xing-Xing | Guo, Man-Qing | Wu, Qing-Ming | Wang, Ru | Zeng, Yan

Article Type: Research Article

Abstract: Background: Despite the improved access to health services in China, inadequate diagnosis and management of dementia are common issues, especially in rural regions. Objective: The Hubei Memory & Aging Cohort Study was designed as a prospective study in Central China to determine the prevalence, incidence, and risk factors for dementia and mild cognitive impairment (MCI) among urban and rural older adults. Methods: From 2018–2020, participants aged ≥65 years were screened, and data regarding their life behaviors, families, socio-economic status, physical and mental health, social and psychological factors, and cognition were collected. Diagnoses of MCI and dementia …were made via consensus diagnosis using the Diagnostic and Statistical Manual of Mental Disorders fourth edition criteria. Results: Of 8,221 individuals who completed their baseline clinical evaluation, 4,449 (54.1%) were women and 3,164 (38.4%) were from remote rural areas (average age: 71.96 years; mean education period: 7.58 years). At baseline, 25.98%(95%confidence interval [CI]: 24.99–26.96) and 7.24%(95%CI: 6.68–7.80) of the participants were diagnosed with MCI and dementia, respectively. Prevalence showed a strong relationship with age. The substantial disparities between rural and urban regions in MCI and dementia prevalence and multiple dementia-related risk factors were revealed. Especially for dementia, the prevalence rate in rural areas was 2.65 times higher than that in urban regions. Conclusion: Our results suggested that public health interventions are urgently needed to achieve equitable diagnosis and management for people living with dementia in the communities across urban and rural areas. Show more

Keywords: Community aging cohort, cognition, dementia, psychosocial factors, social connections

DOI: 10.3233/JAD-215129

Citation: Journal of Alzheimer's Disease, vol. 85, no. 2, pp. 561-571, 2022