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

Authors: Dorey, C. Kathleen | Gierhart, Dennis | Fitch, Karlotta A. | Crandell, Ian | Craft, Neal E.

Article Type: Review Article

Abstract: Background: Oxidative stress contributes to pathogenesis and progression of Alzheimer’s disease (AD). Higher levels of the dietary antioxidants— carotenoids and tocopherols— are associated with better cognitive functions and lower risk for AD, and lower levels of multiple carotenoids are found in serum and plasma of patients with AD. Although brains donated by individuals with mild cognitive impairment had significantly lower levels of lutein and beta-carotene, previous investigators found no significant difference in carotenoid levels of brains with AD and cognitively normal brains. Objective: This study tested the hypothesis that micronutrients are significantly lower in donor brains with AD …than in healthy elderly brains. Methods: Samples of donor brains with confirmed AD or verified health were dissected into grey and white matter, extracted with organic solvents and analyzed by HPLC. Results: AD brains had significantly lower levels of lutein, zeaxanthin, anhydrolutein, retinol, lycopene, and alpha-tocopherol, and significantly increased levels of XMiAD, an unidentified xanthophyll metabolite. No meso-zeaxanthin was detected. The overlapping protective roles of xanthophylls, carotenes, α- and γ -tocopherol are discussed. Conclusion: Brains with AD had substantially lower concentrations of some, but not all, xanthophylls, carotenes, and tocopherols, and several-fold higher concentrations of an unidentified xanthophyll metabolite increased in AD (XMiAD). Show more

Keywords: Alzheimer’s disease, antioxidants, brain, carotenoids, deficiency, lutein, lycopene, meso-zeaxanthin, oxidation, tocopherols, zeaxanthin

DOI: 10.3233/JAD-220460

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2022

Authors: Zhang, Ruxin | Song, Yanrong | Su, Xuefeng

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is considered to be the most common neurodegenerative disease, with clinical symptoms encompassing progressive memory loss and cognitive impairment. Necroptosis is a form of programmed necrosis that promotes cell death and neuroinflammation, which further mediates the pathogenesis of several neurodegenerative diseases, especially AD. Current evidence has strongly suggested that necroptosis is activated in AD brains, resulting in neuronal death and cognitive impairment. We searched the PubMed database, screening all articles published before September 28, 2022 related to necroptosis in the context of AD pathology. The keywords in the search included: “necroptosis”, “Alzheimer’s disease”, “signaling pathways”, “Aβ”, Aβo”, …“Tau”, “p-Tau”, “neuronal death”, “BBB damage”, “neuroinflammation”, “microglia”, “mitochondrial dysfunction”, “granulovacuolar degeneration”, “synaptic loss”, “axonal degeneration”, “Nec-1”, “Nec-1s”, “GSK872”, “NSA”, “OGA”, “RIPK1”, “RIPK3”, and “MLKL”. Results show that necroptosis has been involved in multiple pathological processes of AD, including amyloid-β aggregation, tau accumulation, neuronal death, and blood-brain barrier damage, etc. More importantly, existing research on AD necroptosis interventions, including drug intervention and potential gene targets, as well as its current clinical development status, was discussed. Finally, the issues pertaining to necroptosis in AD were presented. Accordingly, this review may provide further insight into clinical perspectives and challenges for the future treatment of AD by targeting the necroptosis pathway. Show more

Keywords: Alzheimer’s disease, granulovacuolar degeneration, mitochondrial dysfunction, MLKL, necroptosis, neurodegeneration, neuronal death, RIPK1, RIPK3

DOI: 10.3233/JAD-220809

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-20, 2022

Authors: Surya, Kumar | Manickam, Nivethitha | Jayachandran, Kesavan Swaminathan | Kandasamy, Mahesh | Anusuyadevi, Muthuswamy

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a major form of dementia. Abnormal amyloidogenic event-mediated degeneration of cholinergic neurons in the cognitive centers of the brain has been attributed to neuropathological sequelae and behavioral deficits in AD. Besides, impaired adult neurogenesis in the hippocampus has experimentally been realized as an underlying cause of dementia regardless of neurodegeneration. Therefore, nourishing the neurogenic process in the hippocampus has been considered an effective therapeutic strategy to mitigate memory loss. In the physiological state, the Wnt pathway has been identified as a potent mitogenic generator in the hippocampal stem cell niche. However, downstream components of Wnt signaling …have been noticed to be downregulated in AD brains. Resveratrol (RSV) is a potent Sirtuin1 (SIRT1) enhancer that facilitates neuroprotection and promotes neurogenesis in the hippocampus of the adult brain. While SIRT1 is an important positive regulator of Wnt signaling, ample reports indicate that RSV treatment strongly mediates the fate determination of stem cells through Wnt signaling. However, the possible therapeutic roles of RSV-mediated SIRT1 enhancement on the regulation of hippocampal neurogenesis and reversal of memory loss through the Wnt signaling pathway have not been addressed yet. Taken together, this review describes RSV-mediated effects on the regulation of hippocampal neurogenesis via the activation of SIRT1 in synergy with the Wnt signaling. Further, the article emphasizes a hypothesis that RSV treatment can provoke the activation of quiescent neural stem cells and prime their neurogenic capacity in the hippocampus via Wnt signaling in AD. Show more

Keywords: Adult neurogenesis, Alzheimer’s disease, cell cycle, hippocampus, resveratrol, Sirtuin1, Wnt pathway

DOI: 10.3233/JAD-220559

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2022

Authors: Shirgadwar, Shubhendu M. | Kumar, Rahul | Preeti, Kumari | Khatri, Dharmendra Kumar | Singh, Shashi Bala

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD) is an age-related progressive multifactorial, neurodegenerative disease. The autophagy and Keap1-Nrf2 axis system are both implicated in the oxidative-stress response, metabolic stress, and innate immunity, and their dysregulation is associated with pathogenic processes in PD. Phloretin (PLT) is a phenolic compound reported possessing anti-inflammatory and antioxidant activities. Objective: To evaluate the neuroprotective potential of PLT in PD via modulating the autophagy-antioxidant axis Methods: The neuroprotective effect of PLT was evaluated in vitro using rotenone (ROT) exposed SH-SY5Y cell line and in vivo using ROT administered C57BL/6 mice. Mice were administered …with PLT (50 and 100 mg/kg, p.o.) concomitantly with ROT (1 mg/kg, i.p) for 3 weeks. Locomotive activity and anxiety behaviors were assessed using rotarod and open field tests respectively. Further apoptosis (Cytochrome-C, Bax), α -Synuclein (α -SYN), tyrosine hydroxylase (TH), antioxidant proteins (nuclear factor erythroid 2-related factor 2 (NRF2), and heme oxygenase-1 (HO-1), autophagic (mTOR, Atg5,7, p62, Beclin, and LC3B-I/II), were evaluated both in in vitro and in vivo . Results: PLT improved locomotive activity and anxiety-like behavior in mice. Further PLT diminished apoptotic cell death, and α -SYN expression and improved the expression of TH, antioxidant, and autophagic regulating protein. Conclusion: Taken together, present data deciphers that the PLT effectively improves motor and non-motor symptoms via modulating the mTOR/NRF2/p62 pathway-mediated feedback loop. Hence, PLT could emerge as a prospective disease-modifying drug for PD management. Show more

Keywords: Apoptosis, autophagy, oxidative stress, Parkinson’s disease, phloretin

DOI: 10.3233/JAD-220793

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2022

Authors: Zhou, Yujia | Dong, Jingyi | Song, Jingmei | Lvy, Chaojie | Zhang, Yuyan

Article Type: Research Article

Abstract: Background: Considering the strong correlation made between Alzheimer’s disease (AD) and the pathology of glucose metabolism disorder, we sought to analyze the effects of fasting blood glucose (FBG) level, fasting plasma insulin (FINS) level, and insulin resistance index (HOMA-IR) on the risk and severity of AD. Objective: Reveal the pathological relationship between AD and insulin resistance. Methods: We searched 5 databases from inception through April 4, 2022. Meta-regression was conducted to identify if there were significant differences between groups. Shapiro-Wilk test and the Q-Q diagram were applied to evaluate the normality of variables. A multiple logistic …regression model was employed to explore the association between FBG, FINS, HOMA-IR, and Mini-Mental State Examination scale score (MMSE). Results: 47 qualified articles including 2,981 patients were enrolled in our study. FBG (p  < 0.001), FINS (p  < 0.001), and HOMA-IR (p  < 0.001) were higher in AD patients than in controls. HOMA-IR was negatively correlated with MMSE (p  = 0.001) and positively related to the sex ratio (male versus female) (p  < 0.05). HOMA-IR obeyed lognormal distribution (p  > 0.05), and the 95% bilateral boundary values were 0.73 and 10.67. FBG (p  = 0.479) was positively correlated to MMSE, while FINS (p  = 0.1657) was negatively correlated with MMSE. Conclusion: The increase in the levels of FBG, FINS, and HOMA-IR served as precise indicators of the risk of AD. HOMA-IR was found to be correlated to the increasing severity of AD, especially in male AD patients. Show more

Keywords: Alzheimer’s disease, disease degree, glucose metabolism, incidence risk, systematic analysis

DOI: 10.3233/JAD-220751

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2022

Authors: Castillo, Carolina | Bravo-Arrepol, Gastón | Wendt, Aline | Saez-Orellana, Francisco | Millar, Camila | Burgos, Carlos F. | Gavilán, Javiera | Pacheco, Carla | Ahumada-Rudolph, Ramón | Napiórkowska, Mariola | Pérez, Claudia | Becerra, José | Fuentealba, Jorge | Cabrera-Pardo, Jaime R.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive impairment and memory loss. One of the hallmarks in AD is amyloid-β peptide (Aβ) accumulation, where the soluble oligomers of Aβ (AβOs) are the most toxic species, deteriorating the synaptic function, membrane integrity, and neuronal structures, which ultimately lead to apoptosis. Currently, there are no drugs to arrest AD progression, and current scientific efforts are focused on searching for novel leads to control this disease. Lignans are compounds extracted from conifers and have several medicinal properties. Eudesmin (Eu) is an extractable lignan from the wood of Araucaria araucana …, a native tree from Chile. This metabolite has shown a range of biological properties, including the ability to control inflammation and antibacterial effects. Objective: In this study, the neuroprotective abilities of Eu on synaptic failure induced by AβOs were analyzed. Methods: Using neuronal models, PC12 cells, and in silico simulations we evaluated the neuroprotective effect of Eu (30 nM) against the toxicity induced by AβOs. Results: In primary cultures from mouse hippocampus, Eu preserved the synaptic structure against AβOs toxicity, maintaining stable levels of the presynaptic protein SV2 at the same concentration. Eu also averted synapsis failure from the AβOs toxicity by sustaining the frequencies of cytosolic Ca2+ transients. Finally, we found that Eu (30 nM) interacts with the Aβ aggregation process inducing a decrease in AβOs toxicity, suggesting an alternative mechanism to explain the neuroprotective activity of Eu. Conclusion: We believe that Eu represents a novel lead that reduces the Aβ toxicity, opening new research venues for lignans as neuroprotective agents. Show more

Keywords: Aβ interaction, Alzheimer’s disease, amyloid-β peptide, eudesmin, neuroprotection

DOI: 10.3233/JAD-220935

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2022

Authors: Yeap, Yee Jie | Kandiah, Nagaendran | Nizetic, Dean | Lim, Kah-Leong

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is the most common cause of dementia that affects millions of predominantly elderly individuals worldwide. Despite intensive research over several decades, controversies still surround the etiology of AD and the disease remains incurable. Meanwhile, new molecular players of the central amyloid cascade hypothesis have emerged and among these is a protease known as β-site APP cleavage enzyme 2 (BACE2). Unlike BACE1, BACE2 cleaves the amyloid-β protein precursor within the Aβ domain that accordingly prevents the generation of Aβ42 peptides, the aggregation of which is commonly regarded as the toxic entity that drives neurodegeneration in AD. Given …this non-amyloidogenic role of BACE2, it is attractive to position BACE2 as a therapeutic target for AD. Indeed, several groups including ours have demonstrated a neuroprotective role for BACE2 in AD. In this review, we discuss emerging evidence supporting the ability of BACE2 in mitigating AD-associated pathology in various experimental systems including human pluripotent stem cell-derived cerebral organoid disease models. Alongside this, we also provide an update on the identification of single nucleotide polymorphisms occurring in the BACE2 gene that are linked to increased risk and earlier disease onset in the general population. In particular, we highlight a recently identified point mutation on BACE2 that apparently leads to sporadic early-onset AD. We believe that a better understanding of the role of BACE2 in AD would provide new insights for the development of viable therapeutic strategies for individuals with dementia. Show more

Keywords: Alzheimer’s disease, amyloid-β protein precursor secretase, beta-secretase, neuroprotection

DOI: 10.3233/JAD-220867

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2022

Authors: Chen, Xiaokun | Jiang, Shenzhong | Wang, Renzhi | Bao, Xinjie

Article Type: Review Article

Abstract: Alzheimer’s disease (AD), a progressive dementia, is one of the world’s most dangerous and debilitating diseases. Clinical trial results of amyloid-β (Aβ) and tau regulators based on the pretext of straightforward amyloid and tau immunotherapy were disappointing. There are currently no effective strategies for slowing the progression of AD. Further understanding of the mechanisms underlying AD and the development of novel therapeutic options are critical. Neurogenesis is impaired in AD, which contributes to memory deficits. Transplanted neural stem cells (NSCs) can regenerate degraded cholinergic neurons, and new neurons derived from NSCs can form synaptic connections with neighboring neurons. In theory, …employing NSCs to replace and restore damaged cholinergic neurons and brain connections may offer new treatment options for AD. However there remain barriers to surmount before NSC-based therapy can be used clinically. The objective of this article is to describe recent advances in the treatment of AD models and clinical trials involving NSCs. In addition, we discuss the challenges and prospects associated with cell transplant therapy for AD. Show more

Keywords: Alzheimer’s disease, cell therapy, neural stem cells, neurodegenerative disease, transplantation

DOI: 10.3233/JAD-220721

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2022

Authors: Huang, Li | Lu, Zhaogang | Zhang, Hexin | Wen, Hongyong | Li, Zongji | Liu, Qibing | Wang, Rui

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases worldwide. The accumulation of amyloid-β (Aβ) protein and plaque formation in the brain are two major causes of AD. Interestingly, growing evidence demonstrates that the gut flora can alleviate AD by affecting amyloid production and metabolism. However, the underlying mechanism remains largely unknown. This review will discuss the possible association between the gut flora and Aβ in an attempt to provide novel therapeutic directions for AD treatment based on the regulatory effect of Aβ on the gut flora.

Keywords: Alzheimer’s disease, amyloid-β, colitis, insulin resistance, intestinal flora, neuroinflammation

DOI: 10.3233/JAD-220651

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2022

Authors: Itzhaki, Ruth F.

Article Type: Article Commentary

Abstract: Wang et al. found that elderly COVID-19 patients were at risk of AD. The following facts suggest a possible explanation: reactivation of herpes simplex virus type 1 (HSV1) and other herpesviruses can occur in SARS-CoV-2 patients; in cell cultures, HSV1 infection causes occurrence of many AD-like features, as does reactivation of latent HSV1 after addition of certain infectious agents; recurrent experimental reactivation of HSV1-infected mice leads to formation of the main features of AD brains, and to cognitive decline. These suggest that COVID-19 results in repeated reactivation of HSV1 in brain, with subsequent accumulation of damage and eventual development of …AD. Show more

Keywords: Alzheimer’s disease, COVID-10, herpes simplex virus type 1, infections, reactivation, vaccinations

DOI: 10.3233/JAD-220955

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-4, 2022

Authors: Krishna, Geethu | Santhoshkumar, Rashmi | Sivakumar, Palanimuthu Thangaraju | Alladi, Suvarna | Mahadevan, Anita | Dahale, Ajit B. | Arshad, Faheem | Subramanian, Sarada

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) and frontotemporal dementia (FTD) are pathologically distinct neurodegenerative disorders with certain overlap in cognitive and behavioral symptoms. Both AD and FTD are characterized by synaptic loss and accumulation of misfolded proteins, albeit, in different regions of the brain. Objective: To investigate the synaptic and organellar markers in AD and FTD through assessment of the levels of synaptic protein, neurogranin (Ng) and organellar proteins, mitofusin-2 (MFN-2), lysosomal associated membrane protein-2 (LAMP-2), and golgin A4 from neuronal exosomes. Methods: Exosomes isolated from the plasma of healthy controls (HC), AD and FTD subjects were characterized …using transmission electron microscopy. Neurodegenerative status was assessed by measurement of neurofilament light chain (NfL) using Simoa. The pooled exosomal extracts from each group were analyzed for Ng, MFN-2, LAMP-2, and golgin A4 by western blot analysis using enhanced chemiluminescence method of detection. Results: The densitometric analysis of immunoreactive bands demonstrated a 65% reduction of Ng in AD and 53% in FTD. Mitochondrial protein MFN-2 showed a significant reduction by 32% in AD and 46% in FTD. Lysosomal LAMP-2 and Golgi complex associated golgin A4 were considerably increased in both AD and FTD. Conclusion: Changes in Ng may reflect the ongoing synaptic degeneration that are linked to cognitive disturbances in AD and FTD. Importantly, the rate of synaptic degeneration was more pronounced in AD. Changes to a similar extent in both the dementia groups in organellar proteins indicates shared mechanisms of protein accumulation/degradation common to both AD and FTD. Show more

Keywords: Alzheimer’s disease, exosomes, frontotemporal dementia, golgin A4, immunoblotting, LAMP-2, MFN-2, neurogranin

DOI: 10.3233/JAD-220829

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2022

Authors: Naren, Padmashri | Cholkar, Anjali | Kamble, Suchita | Samim, Khan Sabiya | Srivastava, Saurabh | Madan, Jitender | Mehra, Neelesh | Tiwari, Vinod | Singh, Shashi Bala | Khatri, Dharmendra Kumar

Article Type: Review Article

Abstract: Parkinson’s disease (PD) is the second most common neurodegenerative illness majorly affecting the population between the ages of 55 to 65 years. Progressive dopaminergic neuronal loss and the collective assemblage of misfolded alpha-synuclein in the substantia nigra, remain notable neuro-pathological hallmarks of the disease. Multitudes of mechanistic pathways have been proposed in attempts to unravel the pathogenesis of PD but still, it remains elusive. The convergence of PD pathology is found in organelle dysfunction where mitochondria remain a major contributor. Mitochondrial processes like bioenergetics, mitochondrial dynamics, and mitophagy are under strict regulation by the mitochondrial genome and nuclear genome. These …processes aggravate neurodegenerative activities upon alteration through neuroinflammation, oxidative damage, apoptosis, and proteostatic stress. Therefore, the mitochondria have grabbed a central position in the patho-mechanistic exploration of neurodegenerative diseases like PD. The management of PD remains a challenge to physicians to date, due to the variable therapeutic response of patients and the limitation of conventional chemical agents which only offer symptomatic relief with minimal to no disease-modifying effect. This review describes the patho-mechanistic pathways involved in PD not only limited to protein dyshomeostasis and oxidative stress, but explicit attention has been drawn to exploring mechanisms like organelle dysfunction, primarily mitochondria and mitochondrial genome influence, while delineating the newer exploratory targets such as GBA1, GLP, LRRK2, and miRNAs and therapeutic agents targeting them. Show more

Keywords: Autophagy, mitochondrial dysfunction, mitogenome, neuroinflammation, Parkinson’s disease, oxidative stress

DOI: 10.3233/JAD-220682

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-30, 2022

Authors: Raghavan, Kadalraja | Dedeepiya, Vidyasagar Devaprasad | Yamamoto, Naoki | Ikewaki, Nobunao | Sonoda, Tohru | Iwasaki, Masaru | Kandaswamy, Ramesh Shankar | Senthilkumar, Rajappa | Preethy, Senthilkumar | Abraham, Samuel J.K.

Article Type: Research Article

Abstract: Background: Aureobasidium pullulans (black yeast) AFO-202 strain-produced beta glucan, Nichi Glucan, has been shown to improve the behavior and sleep pattern along with an increase in α-synuclein and melatonin in children with autism spectrum disorder (ASD). Objective: In this randomized pilot clinical study, we have evaluated the gut microbiota of subjects with ASD after consumption of Nichi Glucan. Methods: Eighteen subjects with ASD were randomly allocated: six subjects in the control group (Group 1): conventional treatment comprising remedial behavioral therapies and L-carnosine 500 mg per day, and 12 subjects (Group 2) underwent supplementation with Nichi Glucan …0.5 g twice daily along with the conventional treatment for 90 days. Results: Whole genome metagenome (WGM) sequencing of the stool samples at baseline and after intervention showed that among genera of relevance, the abundance of Enterobacteriaceae was decreased almost to zero in Group 2 after intervention, whereas it increased from 0.36% to 0.85% in Group 1. The abundance of Bacteroides increased in Group 1, whereas it decreased in Group 2. The abundance of Prevotella increased while the abundance of Lactobacillus decreased in both Group 1 and Group 2. Among species, a decrease was seen in Escherichia coli , Akkermansia muciniphila CAG:154 , Blautia spp. , Coprobacillus sp. , and Clostridium bolteae CAG:59 , with an increase of Faecalibacterium prausnitzii and Prevotella copri , which are both beneficial. Conclusion: AFO-202 beta 1,3–1,6 glucan, in addition to balancing the gut microbiome in children with ASD and its role in effective control of curli-producing Enterobacteriaceae that leads to α-synuclein misfolding and accumulation, may have a prophylactic role in Parkinson’s and Alzheimer’s diseases as well. Show more

Keywords: AFO-202, autism, beta glucans, curli protein, Enterobacteriaceae, neurodegenerative diseases

DOI: 10.3233/JAD-220388

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2022

Authors: Harrington, Karra D. | Vasan, Shradha | Kang, Jee eun | Sliwinski, Martin J. | Lim, Michelle H.

Article Type: Systematic Review

Abstract: Background: Loneliness has been highlighted as a risk factor for dementia. However, the nature of the relationship between loneliness and cognitive function prior to onset of dementia is unclear. Objective: The aim of this systematic review and meta-analysis was to examine the relationship between loneliness and cognitive function in samples screened for dementia at study commencement. Methods: Five electronic databases (PubMed, PsycNET, Web of Science, EBSCOhost, Scopus) were searched from inception to August 31, 2021. A narrative review and random-effects meta-analysis were conducted on studies meeting search criteria. PROSPERO registration number: CRD42020155539. Results: The …sixteen studies that met inclusion criteria involved 30,267 individuals, with mean age ranging from 63.0 to 84.9 years. Studies varied in dementia screening criteria, measurement of loneliness and cognitive function, and statistical modeling approach. The narrative review indicated that loneliness was associated with poorer global cognition, episodic memory, working memory, visuospatial function, processing speed, and semantic verbal fluency. Results of the meta-analysis indicated that loneliness was negatively associated with global cognitive function (overall r  = –0.08; 95% CI = –0.14, –0.02; n  = 6). Due to lack of sufficient data and heterogeneity between studies, we were unable to explore associations with other cognitive domains or longitudinal associations. Conclusion: Loneliness is associated with subtle impairment across multiple cognitive domains in older adults who were screened for dementia. Better characterization of this relationship will provide important information about how loneliness contributes to the clinical and pathological sequalae of AD and be informative for risk reduction and early detection strategies. Show more

Keywords: Alzheimer disease, cognition, dementia, loneliness

DOI: 10.3233/JAD-220832

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2022

Authors: Liu, Che | Lee, Sang H. | Loewenstein, David A. | Galvin, James E. | Levin, Bonnie E. | McKinney, Alexander | Alperin, Noam

Article Type: Research Article

Abstract: Background: Lower cerebral blood flow (CBF) and brain atrophy are linked to Alzheimer’s disease (AD). It is still undetermined whether reduced CBF precedes or follows brain tissue loss. Objective: We compared total CBF (tCBF), global cerebral perfusion (GCP), and volumes of AD-prone regions between cognitively normal (CN) and early amnestic mild cognitive impairment (aMCI) and tested their associations with cognitive performance to assess their predictive value for differentiation between CN and early aMCI. Methods: A total of 74 participants (mean age 69.9±6.2 years, 47 females) were classified into two groups: 50 CN and 24 aMCI, of …whom 88% were early aMCI. tCBF, GCP, and global and regional brain volumetry were measured using phase-contrast and T1-weighted MRI. Neuropsychological tests tapping global cognition and four cognitive domains (memory, executive function, language, and visuospatial) were administered. Comparisons and associations were investigated using analyses of covariance (ANCOVA) and linear regression analyses, respectively. Results: Women had significantly higher GCP than men. Both, tCBF and GCP were significantly reduced in aMCI compared with CN, while volume differences in volumes of cerebral gray matter, white matter, and AD-prone regions were not significant. tCBF and GCP were significantly associated with global cognition (standardized beta (stβ) = 0.324 and stβ= 0.326) and with memory scores (stβ≥0.297 and stβ≥0.264) across all participants. Associations of tCBF and GCP with memory scores were also significant in CN (stβ= 0.327 and stβ= 0.284) and in aMCI (stβ= 0.627 and stβ= 0.485). Conclusion: Reduced tCBF and GCP are sensitive biomarkers of early aMCI that likely precede brain tissue loss. Show more

Keywords: Amnestic mild cognitive impairment, cerebral blood flow, cerebral perfusion, global cognition, memory, phase-contrast MRI

DOI: 10.3233/JAD-220734

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2022

Authors: Lima, Marisa | Tábuas-Pereira, Miguel | Durães, João | Vieira, Daniela | Faustino, Pedro | Baldeiras, Inês | Santana, Isabel

Article Type: Research Article

Abstract: Background: Frontal-variant of Alzheimer’s disease (fvAD) was purposed for patients with AD pathology that, despite the typical amnestic presentation, show early and progressive deterioration of behavior and executive functions, closely resembling the behavioral-variant of frontotemporal dementia (bvFTD). This leads to a challenging differential diagnosis where neuropsychological evaluation and in vivo pathological evidence are essential. Objective: To evaluate the contribution of a comprehensive neuropsychological assessment (NP) battery in distinguishing between fvAD-dementia and bvFTD supported by cerebrospinal fluid (CSF) biomarkers. Methods: We included 40 patients with a baseline NP profile with prominent early executive and/or behavioral dysfunction, …who meet both diagnosis of bvFTD and fvAD-dementia, according to international criteria. All patients underwent comprehensive NP assessment and CSF-AD biomarker evaluation. Neuropsychological domains as well as clinical and sociodemographic features, and APOE genotype were compared between groups. Results: 21 patients (52.5%) met the biological criteria for AD (decreased Aβ42 together with increased T-tau or P-tau in CSF) and were therefore classified as fvAD (mean age was 64.57, with 47.6% female). There were no differences between groups regarding age/age-at-onset, gender, or educational level. Regarding neuropsychological profile, performances in language and memory functions were equivalent in both groups. Significant differences were found in visuo-constructional abilities (p  = 0.004), Trail Making Test A (p  < 0.001), and Raven’s Colored Progressive Matrices (p  = 0.019), with fvAD patients showing worst performances. Conclusion: In patients with an early prominent frontal profile, a higher impairment in attention and visuo-spatial functions, signaling additional right hemisphere fronto-parietal dysfunction, point towards a diagnosis of fvAD-dementia and may be useful in clinical practice. Show more

Keywords: ATN system, behavioral-variant frontotemporal dementia, cerebrospinal fluid biomarkers, frontal-variant Alzheimer’s disease, neuropsychological assessment

DOI: 10.3233/JAD-220897

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2022

Authors: Sharma, Neelam | Banerjee, Rupkatha | Davis, Ronald L.

Article Type: Research Article

Abstract: Background: Mitochondrial (MT) dysfunction is a hallmark of Alzheimer’s disease (AD). Amyloid-β protein precursor and amyloid-β peptides localize to MT and lead to MT dysfunction in familial forms of AD. This dysfunction may trigger subsequent types of pathology. Objective: To identify the MT phenotypes that occur early in order to help understand the cascade of AD pathophysiology. Methods: The 5xFAD mouse model was used to explore the time course of MT pathologies in both sexes. Protein biomarkers for MT dynamics were measured biochemically and MT function was measured using oxygen consumption and ATP assays. …Results: We discovered progressive alterations in mitochondrial dynamics (biogenesis, fission, fusion, and mitophagy) and function (O2 consumption, ATP generation, and Ca2+ import) in the hippocampus of 5xFAD mice in both sexes as early as 2 months of age. Thus, mitochondrial dynamics and function become altered at young ages, consistent with an early role for mitochondria in the AD pathological cascade. Conclusion: Our study offers the baseline information required to understand the hierarchical relationship between the multiple pathologies that develop in this mouse model and provides early biomarkers for MT dysfunction. This will aid in dissecting the temporal cascade of pathologies, understanding sex-specific differences, and in testing the efficacy of putative mitochondrial therapeutics. Show more

Keywords: Alzheimer’s disease, amyloid-β protein precursor, bioenergetics, biogenesis, fission/fusion, mitophagy, MT dysfunction

DOI: 10.3233/JAD-220884

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2022

Authors: Eiser, Arnold R. | Fulop, Tamas

Article Type: Article Commentary

Abstract: In this commentary, we offer an overview of the several environmental and metabolic factors that have been identified as contributing to the development of Alzheimer’s disease (AD). Many of these factors involve extracranial organ systems including immune system dysfunction accompanied by neuroinflammation (inflammaging), gastrointestinal dysbiosis, insulin resistance, and hepatic dysfunction. A variety of microbial factors including mouth flora, viruses, and fungi appear to play a significant role. There is a role for the colonic microbiome becoming dysbiotic and producing toxic metabolites. Declining hepatic function contributes diminished neuronal precursors and reduces toxin elimination. Environmental toxins especially metals play an important role …in impairing the blood-brain barrier and acting synergistically with biotoxins and other toxic chemicals. Prevention and treatment of AD appears to require measuring several of these biomarkers and implementing corrective actions regarding such toxicants and correcting metabolic dysfunction at early or preclinical stages of this disorder. Show more

Keywords: Alzheimer’s disease, biotoxins, dementia, dysbiosis, environmental exposure, metabolism, neuroinflammation

DOI: 10.3233/JAD-221078

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-5, 2022

Authors: Huang, Wenhao | Xia, Qing | Zheng, Feifei | Zhao, Xue | Ge, Fangliang | Xiao, Jiaying | Liu, Zijie | Shen, Yingying | Ye, Ke | Wang, Dayong | Li, Yanze

Article Type: Review Article

Abstract: The neurovascular unit (NVU) is involved in the pathological changes in Alzheimer’s disease (AD). The NVU is a structural and functional complex that maintains microenvironmental homeostasis and metabolic balance in the central nervous system. As one of the most important components of the NVU, microglia not only induce blood-brain barrier breakdown by promoting neuroinflammation, the infiltration of peripheral white blood cells and oxidative stress but also mediate neurovascular uncoupling by inducing mitochondrial dysfunction in neurons, abnormal contraction of cerebral vessels, and pericyte loss in AD. In addition, microglia-mediated dysfunction of cellular components in the NVU, such as astrocytes and pericytes, …can destroy the integrity of the NVU and lead to NVU impairment. Therefore, we review the mechanisms of microglia-mediated NVU dysfunction in AD. Furthermore, existing therapeutic advancements aimed at restoring the function of microglia and the NVU in AD are discussed. Finally, we predict the role of pericytes in microglia-mediated NVU dysfunction in AD is the hotspot in the future. Show more

Keywords: Alzheimer’s disease, blood-brain barrier, microglia, neurovascular uncoupling, neurovascular unit, pericyte

DOI: 10.3233/JAD-221064

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-20, 2023

Authors: Guo, Xiaodi | Zhang, Guoxin | Peng, Qinyu | Huang, Liqin | Zhang, Zhaohui | Zhang, Zhentao

Article Type: Review Article

Abstract: Meningeal lymphatic vessels (mLVs), the functional lymphatic system present in the meninges, are the key drainage route responsible for the clearance of molecules, immune cells, and cellular debris from the cerebrospinal fluid and interstitial fluid into deep cervical lymph nodes. Aging and ApoE4, the two most important risk factors for Alzheimer’s disease (AD), induce mLV dysfunction, decrease cerebrospinal fluid influx and outflux, and exacerbate amyloid pathology and cognitive dysfunction. Dysfunction of mLVs results in the deposition of metabolic products, accelerates neuroinflammation, and promotes the release of pro-inflammatory cytokines in the brain. Thus, mLVs represent a novel therapeutic target for treating …neurodegenerative and neuroinflammatory diseases. This review aims to summarize the structure and function of mLVs and to discuss the potential effect of aging and ApoE4 on mLV dysfunction, as well as their roles in the pathogenesis of AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, Apolipoprotein E4, meningeal lymphatic vessels, tau

DOI: 10.3233/JAD-221016

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2022

Authors: Daly, Timothy | Henry, Vincent | Bourdenx, Mathieu

Article Type: Review Article

Abstract: Background: Many putative causes and risk factors have been associated with outcomes in Alzheimer’s disease (AD) but all attempts at disease-modifying treatment have failed to be clinically significant. Efforts to address this “association—intervention” mismatch have tended to focus on the novel design of interventions. Objective: Here, we instead deal with the notion of association in depth. We introduce the concept of disease-associated process (DAP) as a flexible concept that can unite different areas of study of AD from genetics to epidemiology to identify disease-modifying targets. Methods: We sort DAPs using three properties: specificity for AD, frequency …in patients, and pathogenic intensity for dementia before using a literature review to apply these properties in three ways. Firstly, we describe and visualize known DAPs. Secondly, we exemplify qualitative specificity analysis with the DAPs of tau protein pathology and autophagy to reveal their differential implication in AD. Finally, we use DAP properties to define the terms “risk factor,” “cause,” and “biomarker.” Results: We show how DAPs fit into our collaborative disease ontology, the Alzheimer’s Disease-Associated Processes and Targets (ADAPT) ontology. We argue that our theoretical system can serve as a democratic research forum, offering a more biologically adequate view of dementia than reductionist models. Conclusion: The ADAPT ontology is a tool that could help to ground debates around priority setting using objective criteria for the identifying of targets in AD. Further efforts are needed to address issues of how biomedical research into AD is prioritized and funded. Show more

Keywords: Alzheimer’s disease, association, autophagy, biomarker, cause, disease ontology, intervention, risk factors, specificity, tau

DOI: 10.3233/JAD-221004

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2022

Authors: Ishabiyi, Felix Oluwasegun | Ogidi, James | Olukade, Baliqis Adejoke | Amorha, Chizoba Christabel | El-Sharkawy, Lina Y. | Okolo, Chukwuemeka Calistus | Adeniyi, Titilope Mary | Atasie, Nkechi Hope | Ibrahim, Abdulwasiu | Balogun, Toheeb Adewale

Article Type: Research Article

Abstract: Background: The development of therapeutic agents against Alzheimer’s disease (AD) has stalled recently. Drug candidates targeting amyloid-β (Aβ) deposition have often failed clinical trials at different stages, prompting the search for novel targets for AD therapy. The NLRP3 inflammasome is an integral part of innate immunity, contributing to neuroinflammation and AD pathophysiology. Thus, it has become a promising new target for AD therapy. Objective: The study sought to study the potential of bioactive compounds derived from Azadirachta indica to inhibit the NLRP3 protein implicated in the pathophysiology of AD. Methods: Structural bioinformatics via molecular docking …and density functional theory (DFT) analysis was utilized for the identification of novel NLRP3 inhibitors from A. indica bioactive compounds. The compounds were further subjected to pharmacokinetic and drug-likeness analysis. Results obtained from the compounds were compared against that of oridonin, a known NLRP3 inhibitor. Results: The studied compounds optimally saturated the binding site of the NLRP3 NACHT domain, forming principal interactions with the different amino acids at its binding site. The studied compounds also demonstrated better bioactivity and chemical reactivity as ascertained by DFT analysis and all the compounds except 7-desacetyl-7-benzoylazadiradione, which had two violations, conformed to Lipinski’s rule of five. Conclusion: In silico studies show that A. indica derived compounds have better inhibitory potential against NLRP3 and better pharmacokinetic profiles when compared with the reference ligand (oridonin). These compounds are thus proposed as novel NLRP3 inhibitors for the treatment of AD. Further wetlab studies are needed to confirm the potency of the studied compounds. Show more

Keywords: Alzheimer’s disease, Azadiracta indica, density functional theory, inflammasomes, molecular docking, NLRP3

DOI: 10.3233/JAD-221020

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-19, 2023

Authors: Sagaro, Getu Gamo | Traini, Enea | Amenta, Francesco

Article Type: Systematic Review

Abstract: Background: Choline alphoscerate (alpha glyceryl phosphorylcholine, α-GPC) is a choline-containing phospholipid used as a medicine or nutraceutical to improve cognitive function impairment occurring in neurological conditions including adult-onset dementia disorders. Despite its 1985 marketing authorization, there are still discrepancies between countries regarding its approval as a prescription medicine and discussions about its effectiveness. Objective: This study aimed to evaluate the efficacy of the α-GPC compound for treating cognitive impairment in patients with adult-onset neurological disorders. Methods: Relevant studies were identified by searching PubMed, Web of Science, and Embase. Studies that evaluated the effects of α-GPC alone …or in combination with other compounds on adult-onset cognitive impairment reporting cognition, function, and behavior were considered. We assessed the risk of bias of selected studies using the Cochrane risk of bias tool. Results: A total of 1,326 studies and 300 full-text articles were screened. We included seven randomized controlled trials (RCTs) and one prospective cohort study that met our eligibility criteria. We found significant effects of α-GPC in combination with donepezil on cognition [4 RCTs, mean difference (MD):1.72, 95% confidence interval (CI): 0.20 to 3.25], functional outcomes [3 RCTs, MD:0.79, 95% CI: 0.34 to 1.23], and behavioral outcomes [4 RCTs; MD: –7.61, 95% CI: –10.31 to –4.91]. We also observed that patients who received α-GPC had significantly better cognition than those who received either placebo or other medications [MD: 3.50, 95% CI: 0.36 to 6.63]. Conclusion: α-GPC alone or in combination with donepezil improved cognition, behavior, and functional outcomes among patients with neurological conditions associated with cerebrovascular injury. Show more

Keywords: Alzheimer’s disease, choline alphoscerate, cognitive function, dementia, donepezil

DOI: 10.3233/JAD-221189

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2023

Authors: Basha, SK Chand | Ramaiah, Mekala Janaki | Kosagisharaf, Jagannatha Rao

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a complex neurodegenerative disorder involving heterogenous pathophysiological characteristics, which has become a challenge to therapeutics. The major pathophysiology of AD comprises amyloid-β (Aβ), tau, oxidative stress, and apoptosis. Recent studies indicate the significance of Triggering receptor expressed on myeloid cells 2 (TREM2) and its mutant variants in AD. TREM2 are the transmembrane receptors of microglial cells that performs a broad range of physiological cell processes. Phagocytosis of Aβ is one of the physiological roles of TREM, which plays a pivotal role in AD progression. R47H, a mutant variant of TREM2, increases the risk of AD by …impairing TREM2–Aβ binding. Inconclusive evidence regarding the TREM2 signaling cascade mechanism of Aβ phagocytosis motivates the current review to propose a new hypothesis. The review systematically assesses the cross talk between TREM2 and other AD pathological domains and the influence of TREM2 on amyloid and tau seeding. Disease associated microglia (DAM), a novel state of microglia with unique transcriptional and functional signatures reported in neurodegenerative conditions, also depend on the TREM2 pathway for its differentiation. DAM is suggested to have a neuroprotective role. We hypothesize that TREM2, along with its signaling adaptors and endogenous proteins, play a key role in ameliorating Aβ clearance. We indicate that TREM2 has the potential to ameliorate the Aβ burden, though with differential clearance ability and may act as a potential therapeutic target. Show more

Keywords: Alzheimer’s disease, amyloid-β, DAP10, DAP12, disease associated microglia, microglia, neurodegeneration, PLCγ2, DAM, R47H, TREM2

DOI: 10.3233/JAD-221070

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2023

Authors: Marin-Marin, Lidón | Miró-Padilla, Anna | Costumero, Víctor

Article Type: Research Article

Abstract: Background: Malfunctioning of the default mode network (DMN) has been consistently related to mild cognitive impairment (MCI) and Alzheimer’s disease (AD). However, evidence on differences in this network between MCI converters (MCI-c) and non-converters (MCI-nc), which could mark progression to AD, is still inconsistent. Objective: To multimodally investigate the DMN in the AD continuum. Methods: We measured gray matter (GM) volume, white matter (WM) integrity, and functional connectivity (FC) at rest in healthy elderly controls, MCI-c, MCI-nc, and AD patients, matched on sociodemographic variables. Results: Significant differences between AD patients and controls were found …in the structure of most of the regions of the DMN. MCI-c only differed from MCI-nc in GM volume of the left parahippocampus and bilateral hippocampi and middle frontal gyri, as well as in WM integrity of the parahippocampal cingulum connecting the left hippocampus and precuneus. We found significant correlations between integrity in some of those regions and global neuropsychological status, as well as an excellent discrimination ability between converters and non-converters for the sum of GM volume of left parahippocampus, bilateral hippocampi, and middle frontal gyri, and WM integrity of left parahippocampal cingulum. However, we found no significant differences in FC. Conclusion: These results further support the relationship between abnormalities in the DMN and AD, and suggest that structural measures could be more accurate than resting-state estimates as markers of conversion from MCI to AD. Show more

Keywords: Atrophy, default mode network, dementia, functional MRI, mild cognitive impairment

DOI: 10.3233/JAD-220603

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2022

Authors: Mascarenhas Fonseca, Luciana | Sage Chaytor, Naomi | Olufadi, Yunusa | Buchwald, Dedra | Galvin, James E. | Schmitter-Edgecombe, Maureen | Suchy-Dicey, Astrid

Article Type: Research Article

Abstract: Background: American Indians have high prevalence of risk factors for Alzheimer’s disease and related dementias (ADRD) compared to the general population, yet dementia onset and frequency in this population are understudied. Intraindividual cognitive variability (IICV), a measure of variability in neuropsychological test performance within a person at a single timepoint, may be a novel, noninvasive biomarker of neurodegeneration and early dementia. Objective: To characterize the cross-sectional associations between IICV and hippocampal, total brain volume, and white matter disease measured by magnetic resonance imaging (MRI) among older American Indians. Methods: IICV measures for memory, executive function, and …processing speed, and multidomain cognition were calculated for 746 American Indians (aged 64–95) who underwent MRI. Regression models were used to examine the associations of IICV score with hippocampal volume, total brain volume, and graded white matter disease, adjusting for age, sex, education, body mass index, intracranial volume, diabetes, stroke, hypertension, hypercholesterolemia, alcohol use, and smoking. Results: Higher memory IICV measure was associated with lower hippocampal volume (Beta = –0.076; 95% CI –0.499, –0.023; p  = 0.031). After adjustment for Bonferroni or IICV mean scores in the same tests, the associations were no longer significant. No IICV measures were associated with white matter disease or total brain volume. Conclusion: These findings suggest that the IICV measures used in this research cannot be robustly associated with cross-sectional neuroimaging features; nonetheless, the results encourage future studies investigating the associations between IICV and other brain regions, as well as its utility in the prediction of neurodegeneration and dementia in American Indians. Show more

Keywords: Alzheimer’s disease, American Indians, cognitive variability, dementia, dispersion, indigenous, magnetic resonance imaging, Native Americans, neurodegeneration

DOI: 10.3233/JAD-220825

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2022

Authors: García-Alberca, José María | Gris, Esther | de la Guía, Paz | Mendoza, Silvia | de la Rica, María López

Article Type: Research Article

Abstract: Background: Souvenaid® is a medical food that contains nutrients that can help synapse synthesis in Alzheimer’s disease (AD). The potential effectiveness of combination therapy of Souvenaid with cholinesterase inhibitors (AChEI) is currently not well-known. Objective: To look into the effect of combination therapy with Souvenaid plus AChEI in people with mild AD in the real-world. Methods: We carried out a retrospective analysis in mild AD patients attending a memory clinic. Three groups were studied according to the treatment they received: Souvenaid alone (n  = 66), AChEI alone (n  = 84), and Souvenaid+AChEI (n  = 70). Treatment effects were …evaluated at baseline, 6 and 12 months. Cognitive functioning was assessed by Mini-Mental State Examination (MMSE), Rey Auditory Verbal Learning Test (RAVLT), Symbol Digit Modalities Test (SDMT), Boston Naming Test (BNT), Trail Making Test (TMT/A-B), Phonemic and Semantic Verbal Fluency Test (PVFT/SVFT); neuropsychiatric symptoms were evaluated by the Neuropsychiatric Inventory (NPI); functional capacity was assessed by the Bayer Activities Daily Living Scale (BAYER-S). A Mixed Model for Repeated Measures analysis was carried out to evaluate changes in outcome scores. Results: After 12 months Souvenaid+AChEI showed significant improvement in MMSE (p  < 0.001), RAVLT (p  < 0.0001), SVFT (p  = 0.002), PVFT (p  = 0.007), TMTA (p  = 0.039), TMTB (p  = 0.001), and NPI (p  < 0.0001) compared to AChEI alone. Conclusion: Souvenaid showed cognitive and behavioral benefits in mild AD patients. These effects increased when Souvenaid and AChEI were used in combination. This study can serve as a model for the design of prospective controlled trials that help to support the combined use of Souvenaid and antidementia drugs in AD. Show more

Keywords: Acetylcholinesterase inhibitors, Alzheimer’s disease, cognitive dysfunction, medical food, Souvenaid

DOI: 10.3233/JAD-221003

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2022

Authors: Sun, Ruihua | Shang, Junkui | Yan, Xi | Zhao, Jingran | Wang, Wan | Wang, Wenjing | Li, Wei | Gao, Chenhao | Wang, Fengyu | Zhang, Haohan | Wang, Yanliang | Cao, Huixia | Zhang, Jiewen

Article Type: Research Article

Abstract: Background: Chronic cerebral hypoperfusion (CCH) is associated with neuronal loss and blood-brain barrier (BBB) impairment in vascular dementia (VaD). However, the relationship and the molecular mechanisms between BBB dysfunction and neuronal loss remain elusive. Objective: We explored the reasons for neuron loss following CCH. Methods: Using permanent bilateral common carotid artery occlusion (2VO) rat model, we observed the pathological changes of cortical neurons and BBB in the sham group as well as rats 3d, 7d, 14d, and 28d post 2VO. In order to further explore the factors influencing neuron loss following CCH with regard to cortical …blood vessels, we extracted cortical brain microvessels at five time points for transcriptome sequencing. Finally, integrin receptor a4β1 (VLA-4) inhibitor was injected into the tail vein, and cortical neuron loss was detected again. Results: We found that cortical neuron loss following CCH is a continuous process, but damage to the BBB is acute and transient. Results of cortical microvessel transcriptome analysis showed that biological processes related to vascular inflammation mainly occurred in the chronic phase. Meanwhile, cell adhesion molecules, cytokine-cytokine receptor interaction were significantly changed at this phase. Among them, the adhesion molecule VCAM1 plays an important role. Using VLA-4 inhibitor to block VCAM1-VLA-4 interaction, cortical neuron damage was ameliorated at 14d post 2VO. Conclusion: Injury of the BBB may not be the main reason for persistent loss of cortical neurons following CCH. The continuous inflammatory response within blood vessels maybe an important factor in the continuous loss of cortical neurons following CCH. Show more

Keywords: Blood-brain barrier, chronic cerebral hypoperfusion, inflammation, neuron, VCAM1

DOI: 10.3233/JAD-221059

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2022

Authors: Corrigan, Rachel R. | Labrador, Luis | Grizzanti, John | Mey, Megan | Piontkivska, Helen | Casadesus-Smith, Gemma

Article Type: Research Article

Abstract: Background: Amylin, a pancreatic amyloid peptide involved in energy homeostasis, is increasingly studied in the context of Alzheimer’s disease (AD) etiology. To date, conflicting pathogenic and neuroprotective roles for this peptide and its analogs for AD pathogenesis have been described. Objective: Whether the benefits of amylin are associated with peripheral improvement of metabolic tone/function or directly through the activation of central amylin receptors is also unknown and downstream signaling mechanisms of amylin receptors are major objectives of this study. Methods: To address these questions more directly we delivered the amylin analog pramlintide systemically (IP), at previously …identified therapeutic doses, while centrally (ICV) inhibiting the receptor using an amylin receptor antagonist (AC187), at doses known to impact CNS function. Results: Here we show that pramlintide improved cognitive function independently of CNS receptor activation and provide transcriptomic data that highlights potential mechanisms. Furthermore, we show than inhibition of the amylin receptor increased amyloid-beta pathology in female APP/PS1 mice, an effect than was mitigated by peripheral delivery of pramlintide. Through transcriptomic analysis of pramlintide therapy in AD-modeled mice we found sexual dimorphic modulation of neuroprotective mechanisms: oxidative stress protection in females and membrane stability and reduced neuronal excitability markers in males. Conclusion: These data suggest an uncoupling of functional and pathology-related events and highlighting a more complex receptor system and pharmacological relationship that must be carefully studied to clarify the role of amylin in CNS function and AD. Show more

Keywords: Alzheimer’s disease, amylin, amyloid-β, metabolism, receptor antagonism, RNA sequencing

DOI: 10.3233/JAD-221057

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-20, 2022

Authors: Wang, Xin | Zhou, Xueyan | Lee, Jingyun | Furdui, Cristina M. | Ma, Tao

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the most common dementia syndrome in the elderly characterized by synaptic failure and unique brain pathology. De novo protein synthesis is required for the maintenance of memory and synaptic plasticity. Mounting evidence links impaired neuronal protein synthesis capacity and overall protein synthesis deficits to AD pathogenesis. Meanwhile, identities of AD-associated dysregulation of “newly synthesized proteome” remain elusive. Objective: To investigate de novo proteome alterations in the hippocampus of aged Tg19959 AD model mice. Methods: In this study, we combined the bioorthogonal noncanonical amino acid tagging (BONCAT) method with the unbiased large-scale …proteomic analysis in acute living brain slices (we name it “BONSPEC”) to investigate de novo proteome alterations in the hippocampus of Tg19959 AD model mice. We further applied multiple bioinformatics methods to analyze in-depth the proteomics data. Results: In total, 1,742 proteins were detected across the 10 samples with the BONSPEC method. After exclusion of those only detected in less than half of the samples in both groups, 1,362 proteins were kept for further analysis. 37 proteins were differentially expressed (based on statistical analysis) between the WT and Tg19959 groups. Among them, 19 proteins were significantly decreased while 18 proteins were significantly increased in the hippocampi of Tg19959 mice compared to WT mice. The results suggest that proteins involved in synaptic function were enriched in de novo proteome of AD mice. Conclusion: Our study could provide insights into the future investigation into the molecular signaling mechanisms underlying AD and related dementias (ADRDs). Show more

Keywords: Aging, Alzheimer’s disease, mass spectrometry, protein synthesis, proteomics

DOI: 10.3233/JAD-221044

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2022

Authors: Tang, Xingyao | Wang, Ying | Simó, Rafael | Stehouwer, Coen D.A. | Zhou, Jian-Bo

Article Type: Research Article

Abstract: Background: Diabetes is a risk factor for cognitive impairment, and disease duration is associated with geriatric decline and functional disabilities. Objective: This study aimed to examine the association of diabetes duration with domain-specific cognitive impairment in elderly. Methods: A total of 3,142 participants from the National Health and Nutrition Examination Survey (NHANES) from the period between 2011 and 2014 were included. We assessed cognitive function using the Digit Symbol Substitution Test (DSST), the CERAD Word Learning (CERAD-WL) test, the CERAD Delayed Recall (CERAD-DR) test and animal fluency (AF) test. Results: After adjusting for age, …sex, race/ethnicity, education level, and annual household income, we found that diabetes with a duration longer than 20 years were at 3.32-fold increased risk of DSST impairment (OR = 3.32, 95% CI: 1.95 to 5.67), 1.72-fold increased risk of CERAD-WL impairment (OR = 1.72, 95% CI: 1.13 to 2.62), and 1.76-fold increased risk of AF impairment (OR = 1.76, 95% CI: 1.23 to 2.53), compared with those with no diabetes. Associations were generally stronger in women than in men. Participants with diabetes, who were diagnosed at 50–59 years old were at increased risk of DSST impairment, CERAD-WL impairment, CERAD-DR impairment, and AF impairment per 5 years longer duration of diabetes. Conclusion: Longer diabetes duration was associated with the increased risk of cognitive impairment, especially in processing speed and attention. The presence of chronic kidney disease was associated with the increased risk of DSST impairment. Show more

Keywords: Age of onset, cognitive impairment, diabetes duration

DOI: 10.3233/JAD-220972

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2022

Authors: Igarashi, Ataru | Sakata, Yukinori | Azuma-Kasai, Mie | Kamiyama, Harue | Kawaguchi, Mika | Tomita, Kiyoyuki | Ishii, Mika | Ikeda, Manabu

Article Type: Research Article

Abstract: Background: The need for a cognition bolt-on version of the EQ-5D, which would capture cognitive impairment by adding a dimension to the generic instrument assessing health status, has been increasing in Japan. Objective: To develop a cognition bolt-on version of the 5-level EQ-5D (EQ-5D-5L+C), we linguistically validated a cognition dimension and psychometrically validated the EQ-5D-5L+C. Methods: Following linguistic validation of the cognition dimension, psychometric validation of the EQ-5D-5L+C proxy version utilized anonymized data collected from nursing home residents between October 2021 to April 2022. The validity, reliability, and sensitivity to change were evaluated. Results: …Data from 254 participants, including the finalized Japanese EQ-5D-5L+C proxy version, were analyzed for the psychometric validation. Mean (±standard deviation) age and Mini-Mental State Examination (MMSE) scores were 87.14±7.29 years and 15.76±8.46, respectively. The correlation was strongest between the cognition dimension and MMSE scores (r s  = –0.640). Test-retest reliability was good in the cognition dimension in both baseline and two-time points (3 months: k  = 0.644; 6 months: k  = 0.656). Although a correlation between changes in the cognition dimension and those in the MMSE score from baseline was weak (3 months: r s  = –0.191; 6 months: r s  = –0.267), a correlation with changes in the MMSE score was higher when the cognition dimension was added compared to the EQ-5D alone (3 months: r s  = –0.142 versus r s  = –0.074). Conclusion: The Japanese EQ-5D-5L+C proxy version developed is a valid tool that captures health status including cognitive function, with a consideration for an over-time assessment. The benefits in adding the cognition dimension to the EQ-5D-5L to assess health state were suggested. Show more

Keywords: Cognition, health status, quality of life, psychometrics, public health

DOI: 10.3233/JAD-221080

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2022

Authors: Jun, Yu Kyung | Lee, Seung Woo | Kim, Kwang Woo | Moon, Jung Min | Koh, Seong-Joon | Lee, Hyun Jung | Kim, Joo Sung | Han, Kyungdo | Im, Jong Pil

Article Type: Research Article

Abstract: Background: The fecal immunochemical test (FIT) is widely used in screening for colorectal cancer (CRC), but FIT results can be positive for diseases other than CRC. Objective: We investigated the association between positive results of FIT and the incidence of dementia using a nationwide database. Methods: FIT-positive participants were collected from a database provided by the Korean National Health Insurance Service. Results: The incidence of all kinds of dementia was higher in FIT-positive than FIT-negative subjects (p  < 0.0001). FIT-positive participants had a higher risk of Alzheimer’s disease (AD) (p  < 0.0001) and vascular dementia (p … = 0.0002), compared to participants with FIT negativity. The risk of all kinds of dementia or AD in FIT-positive participants was higher in younger (age < 65 years) than older participants (p  < 0.0001 for all kinds of dementia; p  = 0.0002 for AD). Conclusion: FIT positivity was correlated with an increased risk of dementia, especially in participants under 65 years of age. The study suggests that clinicians can consider dementia when FIT-positive participants fail to show any malignancies. Show more

Keywords: Alzheimer’s disease, dementia, occult blood, population surveillance, vascular dementia

DOI: 10.3233/JAD-220770

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2022

Authors: Yang, Mingming | Qi, Rongrong | Liu, Yuxiao | Shen, Xin | Zhao, Yulou | Jin, Nana | Wu, Ruozhen | Liu, Fei | Gu, Jianlan

Article Type: Research Article

Abstract: Background: Neurofibrillary tangles aggregated from anomalous hyperphosphorylated tau is a hallmark of Alzheimer’s disease (AD). Trans-active response DNA-binding protein of 43 kDa (TDP-43) enhances the instability and exon (E) 10 inclusion of tau mRNA. Cytoplasmic inclusion of hyperphosphorylated TDP-43 in the neurons constitutes the third most prevalent proteinopathy of AD. Casein kinase 1δ (CK1δ ) is elevated in AD brain and phosphorylates TDP-43 in vitro . Objective: To determine the roles of CK1δ in phosphorylation, aggregation, and function of TDP-43 in the processing of tau mRNA. Methods: The interaction and colocalization of TDP-43 and …CK1δ were analyzed by co-immunoprecipitation and immunofluorescence staining. TDP-43 phosphorylation by CK1δ was determined in vitro and in cultured cells. RIPA-insoluble TDP-43 aggregates obtained by ultracentrifugation were analyzed by immunoblots. The instability and E10 splicing of tau mRNA were studied by using a reporter of green fluorescence protein tailed with 3’-untranslational region of tau mRNA and a mini-tau gene and analyzed by real-time quantitative PCR and reverse transcriptional PCR. Results: We found that CK1δ interacted and co-localized with TDP-43. TDP-43 was phosphorylated by CK1δ at Ser379, Ser403/404, and Ser409/410 in vitro and in cultured cells, which was mutually enhanced. CK1δ overexpression promoted the aggregation of TDP-43 and suppressed its activity in enhancing the instability and E10 inclusion of tau mRNA. Conclusion: CK1δ phosphorylates TDP-43, promotes its aggregation, and inhibits its activity in promoting the instability of tau mRNA and inclusion of tau E10. Elevated CK1δ in AD brain may contribute to TDP-43 and tau pathologies directly or indirectly. Show more

Keywords: Casein kinase 1δ , mRNA processing, phosphorylation, tau, TDP-43

DOI: 10.3233/JAD-220985

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2022

Authors: Chenoweth, Lynn | Williams, Anna | McGuire, Jane | Reyes, Patricia | Maiden, Genevieve | Brodaty, Henry | Liu, Zhixin | Cook, Jacquelene | McCade, Donna | Taylor-Rubin, Cathleen | Freeman, Matilda | Burley, Claire

Article Type: Research Article

Abstract: Background: While Australian guidelines promote person-centered healthcare (PCC) for persons with dementia, healthcare systems, routines, rules, and workplace cultures can pose challenges in the provision of PCC. Objective: To present a knowledge translation protocol of the PCC model in a sub-acute rehabilitation hospital. Methods: The two-year pre/post/follow-up translation project will include (n  = 80) persons with dementia, (n  = 80) adult family/carers of patient participants, (n  = 60) healthcare staff (medical, nursing, allied health), and (n  = 8) PCC staff champions. Champions will complete six half-days’ training in PCC. Medical, nursing, and allied health staff will be provided with PCC …learning manuals, complete six hours of online PCC education and attend six face-to-face PCC education sessions. Champions will provide ongoing support to staff in PCC practice. The Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework will be used to evaluate: i) outcomes for prospective patients provided with PCC, compared with a matched sample of retrospective patients (primary outcomes agitation incidence and severity); 2) champion and staff PCC knowledge, confidence, engagement, and practice quality; 3) person, family/carer, champion, and staff satisfaction with PCC; 4) PCC costs and benefits; and 5) organizational structures, systems and policies required to implement and maintain PCC in sub-acute healthcare. Results: We will identify if PCC benefits persons with dementia, staff, and healthcare services, and we will generate evidence on the educational and organizational resources required to embed PCC in practice. Conclusion: Project findings will inform tailored PCC education applications for dissemination in healthcare and produce evidence-based PCC practice guidelines to improve healthcare for persons with dementia. Show more

Keywords: Delirium, dementia, health personnel, hospitals, patient-centered care, quality of healthcare

DOI: 10.3233/JAD-220882

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2022

Authors: Huque, Hamidul | Eramudugolla, Ranmalee | Chidiac, Benjamin | Ee, Nicole | Ehrenfeld, Lauren | Matthews, Fiona E. | Peters, Ruth | Anstey, Kaarin J.

Article Type: Systematic Review

Abstract: Background: Despite rising interest in sex differences in dementia, it is unclear whether sex differences in dementia incidence and prevalence are apparent globally. Objective: We examine sex differences in incidence and prevalence of Alzheimer’s disease (AD), Vascular dementia (VaD), and Any dementia and evaluate whether country-level indicators of gender inequality accounted for differences. Methods: Systematic review with meta-analysis was used to obtain estimates of incidence and prevalence of AD, VaD, and Any dementia using random effects meta-analysis, and population-based studies with clinical or validated dementia measures. Meta-regression was used to evaluate how country-specific factors of life-expectancy, …education, and gender differences in development, unemployment, and inequality indices influenced estimates. Results: We identified 205 eligible studies from 8,731 articles, representing 998,187 participants across 43 countries. There was no sex difference in incidence of Any dementia, AD, or VaD, except in the 90 + age-group (women higher). When examined by 5-year age bands, the only sex difference in prevalence of Any dementia was in the 85+, and there was no sex difference in VaD. AD was more prevalent in women at most ages. Globally, the overall prevalence of dementia in adults 65 + was higher for women (80.22/100, CI:62.83-97.61) than men (54.86/1000 CI:43.55-66.17). Meta-regression revealed that sex differences in Any dementia prevalence, were associated with gender differences in life expectancy and in education. Conclusion: Globally, there are no sex differences in age-specific dementia incidence, but prevalence of AD is higher in women. Country-level factors like life expectancy and gender differences in education may explain variability in sex differences. Show more

Keywords: Alzheimer’s disease, dementia, gender differences, incidence, prevalence, sex differences

DOI: 10.3233/JAD-220724

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2022

Authors: Bian, Zhihong | Yu, Haibo | Hu, Xinran | Bian, Yuting | Sun, Hongming | Tadokoro, Koh | Takemoto, Mami | Yunoki, Taijun | Nakano, Yumiko | Fukui, Yusuke | Morihara, Ryuta | Abe, Koji | Yamashita, Toru

Article Type: Research Article

Abstract: Background: NADPH oxidase 2 (NOX2) is an important source of reactive oxygen species (ROS). Activated NOX2 may contribute to Alzheimer’s disease (AD). Our previous studies showed that a novel vitamin E mixture, Tocovid, had potential neuroprotective effects in a stroke mice model and an AD cell model. Objective: The aim of this study was two-fold: to assess whether long-term Tocovid treatment can regulate NOX2, and the therapeutic effects of long-term administration of Tocovid to an AD mice model. Methods: Therapeutic effects of long-term administration of Tocovid (200 mg/kg /day) on an Aβ-overexpressed transgenic AD mice model (APP23, …n  = 8) was investigated. The therapeutic effect of Tocovid in 16-month-old mice compared with the no-treatment APP23 group (n  = 9) was assessed. Results: Tocovid treatment strongly improved motor and memory deficits of APP23 mice by attenuating NOX2 expression, oxidative stress, neuroinflammation, neurovascular unit dysfunction, synaptic alteration, and Aβ deposition after 16 months. Conclusion: These findings suggest that NOX2 is a potential target in AD pathology. Long-term administration of Tocovid may be a promising candidate for AD treatment. Show more

Keywords: Alzheimer’s disease, cerebral amyloid angiopathy, NOX2, oxidative stress, Tocovid

DOI: 10.3233/JAD-220761

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2022

Authors: Zhu, Min | Tang, Minglu | Du, Yifeng

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) brings heavy burden to society and family. There is an urgent need to find effective methods for disease diagnosis and treatment. The robust rank aggregation (RRA) approach that could aggregate the resulting gene lists has been widely utilized in genomic data analysis. Objective: To identify hub genes using RRA approach in AD. Methods: Seven microarray datasets in frontal cortex from GEO database were used to identify differential expressed genes (DEGs) in AD patients using RRA approach. STRING was performed to explore the protein-to-protein interaction (PPI). Gene Ontology enrichment and Kyoto Encyclopedia of …Genes and Genomes pathway analyses were utilized for enrichment analysis. Human Gene Connectome and Gene Set Enrichment Analysis were used for functional annotation. Finally, the expression levels of hub genes were validated in the cortex of 5xFAD mice by quantitative real-time polymerase chain reaction. Results: After RRA analysis, 473 DEGs (216 upregulated and 257 downregulated) were identified in AD samples. PPI showed that DEGs had a total of 416 nodes and 2750 edges. These genes were divided into 17 clusters, each of which contains at least three genes. After functional annotation and enrichment analysis, TAC1 is identified as the hub gene and may be related to synaptic function and inflammation. In addition, Tac1 was found downregulated in cortices of 5xFAD mice. Conclusion: In the current study, TAC1 is identified as a key gene in the frontal cortex of AD, providing insight into the possible pathogenesis and potential therapeutic targets for this disease. Show more

Keywords: Alzheimer’s disease, bioinformatics, synaptic function, tachykinins

DOI: 10.3233/JAD-220950

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2022

Authors: Janse, André | van de Rest, Ondine | de Groot, Lisette C.P.G.M. | Witkamp, Renger F.

Article Type: Research Article

Abstract: Background: Vitamin D deficiency is associated with all-cause dementia and Alzheimer’s disease (AD). At the same time, this knowledge is limited specifically for vascular dementia (VaD), while data regarding other subtypes of dementia are even more limited. Objective: To investigate the association of 25-hydroxy vitamin D (25(OH)D) status with dementia subtypes in an outpatient geriatric population. Methods: In a cross-sectional design, we analyzed data from 1,758 patients of an outpatient memory clinic in The Netherlands. Cognitive disorders were diagnosed by a multidisciplinary team according to international clinical standards. At each first-visit 25(OH)D levels were measured. Data …were analyzed using ANCOVA in four models with age, gender, BMI, education, alcohol, smoking, season, polypharmacy, calcium, eGFR, and glucose as co-variates. 25(OH)D was treated as a continuous square rooted (sqr) variable. Results: In the fully adjusted model, reduced 25(OH)D serum levels (sqr) were found in AD (estimated mean 7.77±0.11 CI95% 7.55-7.99): and in VaD (estimated mean 7.60±0.16 CI95% 7.28-7.92) patients compared to no-dementia (ND) patients (estimated mean 8.27±0.09 CI95% 8.10-8.45) (ND-AD: p  = 0.006, CI95% 0.08-0.92.; ND-VaD p  = 0.004 CI95% 0.13-1.22). We did not find differences in 25(OH)D levels of mild cognitive impairment (MCI) or other dementia patients compared to ND patients, nor differences in comparing dementia subtypes. Conclusion: We observed significantly lower 25(OH)D serum levels in both AD and VaD patients compared to no-dementia patients, but no significant differences between MCI and Lewy body and mixed dementia subtypes in this cross-sectional study of a geriatric outpatient clinic population. Show more

Keywords: 25(OH)D, Alzheimer’s disease, cognition, dementia, Lewy body dementia, mild cognitive impairment, vascular dementia, vitamin D

DOI: 10.3233/JAD-220732

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2022

Authors: Hays Weeks, Chelsea C. | Zlatar, Zvinka Z. | Meloy, M.J. | Shin, David D. | Thomas, Liu | Wierenga, Christina E.

Article Type: Research Article

Abstract: Background: The apolipoprotein E (APOE ) ɛ 4 allele confers risk for age and Alzheimer’s disease related cognitive decline but the mechanistic link remains poorly understood. Blood oxygenation level dependent (BOLD) response in the fusiform gyrus (FG) during object naming appears greater among APOE ɛ 4 carriers even in the face of equivalent cognitive performance, suggesting neural compensation. However, BOLD is susceptible to known age and APOE -related vascular changes that could confound its interpretation. Objective: To address this limitation, we used calibrated fMRI during an object naming task and a hypercapnic challenge to obtain a more …direct measure of neural function – percent change cerebral metabolic rate of oxygen consumption (%ΔCMRO2 ). Methods: Participants were 45 older adults without dementia (28 ɛ 4– , 17 ɛ 4+) between the ages of 65 and 85. We examined APOE -related differences in %ΔCMRO2 in the FG during object naming and the extent to which APOE modified associations between FG %ΔCMRO2 and object naming accuracy. Exploratory analyses also tested the hypothesis that %ΔCMRO2 is less susceptible to vascular compromise than are measures of %ΔCBF and %ΔBOLD. Results: We observed a modifying role of APOE on associations between FG %ΔCMRO2 and cognition, with ɛ 4 carriers (but not non-carriers) demonstrating a positive association between right FG %ΔCMRO2 and object naming accuracy. Conclusion: Results suggest that the relationship between neural function and cognition is altered among older adult APOE ɛ 4 carriers prior to the onset of dementia, implicating CMRO2 response as a potential mechanism to support cognition in APOE -related AD risk. Show more

Keywords: Aging, Alzheimer’s disease, APOE ɛ4, calibrated fMRI, cerebral blood flow, cognition, cognitive decline, metabolism

DOI: 10.3233/JAD-220749

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2022

Authors: Rahkonen, Atte | Taipale, Heidi | Koponen, Marjaana | Hartikainen, Sirpa | Tolppanen, Anna-Maija | Tanskanen, Antti | Tiihonen, Miia

Article Type: Research Article

Abstract: Background: Use of pharmacological treatments is one possible modifiable risk factor for cognitive disorders. Objective: To investigate if the use of muscle relaxants is associated with the risk of Alzheimer’s disease (AD). Methods: The study was performed in a nested case-control design. Altogether 70,718 community-dwelling residents of Finland who received AD diagnosis in 2005–2011 were included as cases (the MEDALZ study). Each case was matched with four controls without AD by age, sex, and region of residence (N  = 282,858). Data was extracted from Prescription register (1995–2012), Special Reimbursement register (1972–2012), and Hospital Discharge register (1972–2012). Drug …use periods were modeled with PRE2DUP-method. Defined daily dose (DDD) was used to quantify the use. Analyses were conducted for any muscle relaxant use, and drug specific analyses were done for orphenadrine and tizanidine. A five-year lag window prior to the diagnosis was used, and results analyzed with conditional logistic regression. Results: The use of any muscle relaxant was associated with the risk of AD, aOR (95% CI) 1.04 (1.02–1.07). Stronger associations were observed with longer use (>366 days, aOR 1.12 (1.03–1.21)) than shorter use (1–365 days aOR, 1.04 (1.02–1.06)) compared to non-users. Dose-response was not observed. Tizanidine was not associated with AD, whereas cumulative exposure of orphenadrine (≥101 DDDs) was associated with the risk of AD, aOR 1.19 (1.07–1.32). Conclusion: Muscle relaxant use was associated with the risk of AD and higher exposure to orphenadrine showed increased risk. Further studies on higher doses and longer durations of use are warranted. Show more

Keywords: Alzheimer’s disease, dementia, muscle relaxant, orphenadrine, tizanidine

DOI: 10.3233/JAD-220409

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2022

Authors: Sacripante, Riccardo | Girtler, Nicola | Doglione, Elisa | Nobili, Flavio | Della Sala, Sergio

Article Type: Research Article

Abstract: Background: Some authors report steeper slopes of forgetting in early Alzheimer’s disease (AD), while others do not. Contrasting findings are thought to be due to methodological inconsistencies or variety of testing methods, yet they also emerge when people are assessed on the same testing procedure. Objective: We aimed to assess if forgetting slopes of people with mild cognitive impairment due to AD (MCI-AD) are different from age-matched healthy controls (HC) by using a prose paradigm. Methods: Twenty-nine people with MCI-AD and twenty-six HC listened to a short prose passage and were asked to freely recall it …after delays of 1 h and 24 h. Results: Generalized linear mixed modelling revealed that, compared to HC, people with MCI-AD showed poorer encoding at immediate recall and steeper forgetting up to 1 h in prose memory as assessed by free recall and with repeated testing of the same material. Forgetting rates between groups did not differ from 1 h to 24 h. Conclusion: The differences observed in MCI-AD could be due to a post-encoding deficit. These findings could be accounted either by a differential benefit from retrieval practice, whereby people with MCI-AD benefit less than HC, or by a working memory deficit in people with MCI-AD, which fails to support their memory performance from immediate recall to 1 h. Show more

Keywords: Alzheimer’s disease, episodic memory, forgetting, mild cognitive impairment, repeated testing

DOI: 10.3233/JAD-220803

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2022

Authors: Wang, Jian | Yu, Neng-Wei | Wang, Duo-Zi | Guo, Lei | Yang, Shu | Zheng, Bo | Guo, Fu-Qiang | Wang, Jian-Hong

Article Type: Research Article

Abstract: Background: Previous cross-sectional studies have identified a possible link between Helicobacter pylori (H. pylori ) infection and dementia. However, the association of H. pylori infection with longitudinal cognitive decline has rarely been investigated. Objective: This cohort study aims to demonstrate the effects of H. pylori infection on longitudinal cognitive decline. Methods: This cohort study recruited 268 subjects with memory complaints. Among these subjects, 72 had a history of H. pylori infection, and the rest 196 subjects had no H. pylori infection. These subjects were followed up for 24 months and received …cognitive assessment in fixed intervals of 12 months. Results: At baseline, H. pylori infected, and uninfected participants had no difference in MMSE scores. At 2 years of follow-up, H. pylori infected participants had lower MMSE scores than uninfected participants. H. pylori infection was associated with an increased risk of longitudinal cognitive decline, as defined by a decrease of MMSE of 3 points or more during follow-up, adjusting for age, sex, education, APOE ɛ 4 genotype, hypertension, diabetes, hyperlipidemia, and smoking history (HR: 2.701; 95% CI: 1.392 to 5.242). H. pylori infection was associated with larger cognitive decline during follow-up, adjusting for the above covariates (standardized coefficient: 0.282, p  < 0.001). Furthermore, H. pylori infected subjects had significantly higher speed of cognitive decline than uninfected subjects during follow-up, adjusting for the above covariates. Conclusion: H. pylori infection increases the risk of longitudinal cognitive decline in older subjects with memory complaints. This study is helpful for further understanding the association between infection and dementia. Show more

Keywords: Alzheimer’s disease, cognitive decline, Helicobacter pylori , infection

DOI: 10.3233/JAD-221112

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2022

Authors: Fischer, Michael Hén Forbord | Zibrandtsen, Ivan Chrilles | Høgh, Peter | Musaeus, Christian Sandøe

Article Type: Systematic Review

Abstract: Background: Magnitude-squared coherence (MSCOH) is an electroencephalography (EEG) measure of functional connectivity. MSCOH has been widely applied to investigate pathological changes in patients with Alzheimer’s disease (AD). However, significant heterogeneity exists between the studies using MSOCH. Objective: We systematically reviewed the literature on MSCOH changes in AD as compared to healthy controls to investigate the clinical utility of MSCOH as a marker of AD. Methods: We searched PubMed, Embase, and Scopus to identify studies reporting EEG MSCOH used in patients with AD. The identified studies were independently screened by two researchers and the data was extracted, …which included cognitive scores, preprocessing steps, and changes in MSCOH across frequency bands. Results: A total of 35 studies investigating changes in MSCOH in patients with AD were included in the review. Alpha coherence was significantly decreased in patients with AD in 24 out of 34 studies. Differences in other frequency bands were less consistent. Some studies showed that MSCOH may serve as a diagnostic marker of AD. Conclusion: Reduced alpha MSCOH is present in patients with AD and MSCOH may serve as a diagnostic marker. However, studies validating MSCOH as a diagnostic marker are needed. Show more

Keywords: Alzheimer’s disease, coherence, electroencephalography, functional connectivity

DOI: 10.3233/JAD-220508

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2022

Authors: Nicolazzo, Jessica | Cavuoto, Marina | Rowsthorn, Ella | Cribb, Lachlan | Bransby, Lisa | Gibson, Madeline | Wall, Prudence | Velakoulis, Dennis | Eratne, Dhamidhu | Buckley, Rachel | Yassi, Nawaf | Yiallourou, Stephanie | Brodtmann, Amy | Hamilton, Garun S. | Naughton, Matthew T. | Lim, Yen Ying | Pase, Matthew P.

Article Type: Research Article

Abstract: Background: Insomnia is one of the most common sleep disorders yet its relationship to the biology of Alzheimer’s disease remains equivocal. Objective: We investigated the cross-sectional relationship between insomnia symptom severity and cerebrospinal fluid (CSF) concentrations of Alzheimer’s disease biomarkers in a cognitively unimpaired middle-aged community sample. Methods: A total of 63 participants from the Healthy Brain Project (age = 59±7 years; 67% women) completed a lumbar puncture and two weeks of actigraphy to measure two of insomnia’s core features: difficulty initiating sleep (prolonged sleep onset latency) and difficulty maintaining sleep (wake after sleep onset [WASO] and number …of awakenings). Additionally, the Insomnia Severity Index (ISI) was completed by 58 participants. Linear and Tobit regression were used to estimate the associations between each insomnia variable and CSF Aβ42 , phosphorylated tau 181 (p-tau181), total-tau, and neurofilament light chain protein (NfL), adjusting for age, sex, and APOE ɛ 4 genotype. Results: Higher ISI score was associated with greater average levels of CSF Aβ 42 (per point: 30.7 pg/mL, 95% CI: 4.17–57.3, p  = 0.023), as was higher WASO (per 10 min: 136 pg/mL, 95% CI: 48–223, p  = 0.002) and more awakenings (per 5:123 pg/mL, 95% CI = 55–192, p  < 0.001). Difficulty initiating sleep was not associated with CSF Aβ 42 , nor were insomnia features associated with p-tau181, total-tau, or NfL levels. Conclusion: Insomnia symptoms were associated with higher CSF Aβ 42 levels in this relatively young, cognitively unimpaired sample. These findings may reflect increased amyloid production due to acute sleep disruption. Show more

Keywords: Alzheimer’s disease, amyloid, dementia, insomnia, sleep

DOI: 10.3233/JAD-220924

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2022

Authors: Moebius, Hans J. | Church, Kevin J.

Article Type: Review Article

Abstract: An estimated 6.5 million Americans aged 65 years or older have Alzheimer’s disease (AD), which will grow to 13.8 million Americans by 2060. Despite the growing burden of dementia, no fundamental change in drug development for AD has been seen in >  20 years. Currently approved drugs for AD produce only modest symptomatic improvements in cognition with small effect sizes. A growing mismatch exists between the urgent need to develop effective drugs for symptomatic AD and the largely failed search for disease modification. The failure rate of clinical trials in AD is high overall, and in particular for disease-modifying therapies. Research …efforts in AD have focused predominantly on amyloid-β and tau pathologies, but limiting clinical research to these “classical hallmarks” of the disease does not address the most urgent patient, caregiver, or societal needs. Rather, clinical research should consider the complex pathophysiology of AD. Innovative approaches are needed that provide outside-the-box thinking, and re-imagine trial design, interventions, and outcomes as well as progress in proteomics and fluid biomarker analytics for both diagnostics and disease monitoring. A new approach offering a highly specific, yet multi-pronged intervention that exerts positive modulation on the HGF/MET neurotrophic system is currently being tested in mid-to-late-stage clinical trials in mild to moderate AD. Findings from such trials may provide data to support novel approaches for development of innovative drugs for treating AD at various disease stages and may offer benefits for those already symptomatic and disease alteration in AD and other neurodegenerative diseases. Show more

Keywords: Alzheimer’s disease, hepatocyte growth factor, HGF/MET, neurodegeneration, neurotrophic, pathogenesis, synaptogenesis

DOI: 10.3233/JAD-220871

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2022

Authors: Baez, Sandra | Trujillo-Llano, Catalina | de Souza, Leonardo Cruz | Lillo, Patricia | Forno, Gonzalo | Santamaría-García, Hernando | Okuma, Cecilia | Alegria, Patricio | Huepe, David | Ibáñez, Agustín | Decety, Jean | Slachevsky, Andrea

Article Type: Research Article

Abstract: Background: Although social cognition is compromised in patients with neurodegenerative disorders such as behavioral variant frontotemporal dementia (bvFTD) and Alzheimer’s disease (AD), research on moral emotions and their neural correlates in these populations is scarce. No previous study has explored the utility of moral emotions, compared to and in combination with classical general cognitive state tools, to discriminate bvFTD from AD patients. Objective: To examine self-conscious (guilt and embarrassment) and other-oriented (pity and indignation) moral emotions, their subjective experience, and their structural brain underpinnings in bvFTD (n  = 31) and AD (n  = 30) patients, compared to healthy controls (n … = 37). We also explored the potential utility of moral emotions measures to discriminate bvFTD from AD. Methods: We used a modified version of the Moral Sentiment Task measuring the participants’ accuracy scores and their emotional subjective experiences. Results: bvFTD patients exhibited greater impairments in self-conscious and other-oriented moral emotions as compared with AD patients and healthy controls. Moral emotions combined with general cognitive state tools emerged as useful measures to discriminate bvFTD from AD patients. In bvFTD patients, lower moral emotions scores were associated with lower gray matter volumes in caudate nucleus and inferior and middle temporal gyri. In AD, these scores were associated with lower gray matter volumes in superior and middle frontal gyri, middle temporal gyrus, inferior parietal lobule and supramarginal gyrus. Conclusion: These findings contribute to a better understanding of moral emotion deficits across neurodegenerative disorders, highlighting the potential benefits of integrating this domain into the clinical assessment. Show more

Keywords: Alzheimer’s disease, behavioral variant frontotemporal dementia, moral emotions, neural correlates, social cognition

DOI: 10.3233/JAD-221131

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2023

Authors: Samudra, Niyatee | Ranasinghe, Kamalini | Kirsch, Heidi | Rankin, Katherine | Miller, Bruce

Article Type: Review Article

Abstract: Cortical network hyperexcitability related to synaptic dysfunction in Alzheimer’s disease (AD) is a potential target for therapeutic intervention. In recent years, there has been increased interest in the prevalence of silent seizures and interictal epileptiform discharges (IEDs, or seizure tendency), with both entities collectively termed “subclinical epileptiform activity” (SEA), on neurophysiologic studies in AD patients. SEA has been demonstrated to be common in AD, with prevalence estimates ranging between 22-54%. Converging lines of basic and clinical evidence imply that modifying a hyperexcitable state results in an improvement in cognition. In particular, though these results require further confirmation, post-hoc findings from …a recent phase II clinical trial suggest a therapeutic effect with levetiracetam administration in patients with AD and IEDs. Here, we review key unanswered questions as well as potential clinical trial avenues. Specifically, we discuss postulated mechanisms and treatment of hyperexcitability in patients with AD, which are of interest in designing future disease-modifying therapies. Criteria to prompt screening and optimal screening methodology for hyperexcitability have yet to be defined, as does timing and personalization of therapeutic intervention. Show more

Keywords: Alzheimer’s disease, amyloid-β, epilepsy, hyperexcitability, interictal epileptiform discharge, seizure, tau

DOI: 10.3233/JAD-220983

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2023

Authors: Azami, Hamed | Moguilner, Sebastian | Penagos, Hector | Sarkis, Rani A. | Arnold, Steven E. | Gomperts, Stephen N. | Lam, Alice D.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is associated with EEG changes across the sleep-wake cycle. As the brain is a non-linear system, non-linear EEG features across behavioral states may provide an informative physiologic biomarker of AD. Multiscale fluctuation dispersion entropy (MFDE) provides a sensitive non-linear measure of EEG information content across a range of biologically relevant time-scales. Objective: To evaluate MFDE in awake and sleep EEGs as a potential biomarker for AD. Methods: We analyzed overnight scalp EEGs from 35 cognitively normal healthy controls, 23 participants with mild cognitive impairment (MCI), and 19 participants with mild dementia due …to AD. We examined measures of entropy in wake and sleep states, including a slow-to-fast-activity ratio of entropy (SFAR-entropy). We compared SFAR-entropy to linear EEG measures including a slow-to-fast-activity ratio of power spectral density (SFAR-PSD) and relative alpha power, as well as to cognitive function. Results: SFAR-entropy differentiated dementia from MCI and controls. This effect was greatest in REM sleep, a state associated with high cholinergic activity. Differentiation was evident in the whole brain EEG and was most prominent in temporal and occipital regions. Five minutes of REM sleep was sufficient to distinguish dementia from MCI and controls. Higher SFAR-entropy during REM sleep was associated with worse performance on the Montreal Cognitive Assessment. Classifiers based on REM sleep SFAR-entropy distinguished dementia from MCI and controls with high accuracy, and outperformed classifiers based on SFAR-PSD and relative alpha power. Conclusion: SFAR-entropy measured in REM sleep robustly discriminates dementia in AD from MCI and healthy controls. Show more

Keywords: Alzheimer’s disease, EEG, entropy, mild cognitive impairment, REM sleep, sleep

DOI: 10.3233/JAD-221152

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2022

Authors: Correro II, Anthony N. | Gauthreaux, Kathryn | Perales-Puchalt, Jaime | Chen, Yen-Chi | Chan, Kwun C.G. | Kukull, Walter A. | Flatt, Jason D.

Article Type: Research Article

Abstract: Background: Lesbian and gay older adults have health disparities that are risk factors for Alzheimer’s disease, yet little is known about the neurocognitive aging of sexual minority groups. Objective: To explore cross-sectional and longitudinal dementia outcomes for adults in same-sex relationships (SSR) and those in mixed-sex relationships (MSR). Methods: This prospective observational study utilized data from the National Alzheimer’s Coordinating Center Uniform Data Set (NACC UDS) collected from contributing Alzheimer’s Disease Research Centers. Participants were adults aged 55+ years at baseline with at least two visits in NACC UDS (from September 2005 to March 2021) who …had a spouse, partner, or companion as a co-participant. Outcome measures included CDR ® Dementia Staging Instrument, NACC UDS neuropsychological testing, and the Functional Activities Questionnaire. Multivariable linear mixed-effects models accounted for center clustering and repeated measures by individual. Results: Both MSR and SSR groups experienced cognitive decline regardless of baseline diagnosis. In general, MSR and SSR groups did not differ statistically on cross-sectional or longitudinal estimates of functioning, dementia severity, or neuropsychological testing, with two primary exceptions. People in SSR with mild cognitive impairment showed less functional impairment at baseline (FAQ M  = 2.61, SD = 3.18 vs. M  = 3.97, SD = 4.53, respectively; p  <  0.01). The SSR group with dementia had less steep decline in attention/working memory (β estimates = –0.10 versus –0.18; p  <  0.01). Conclusion: Participants in SSR did not show cognitive health disparities consistent with a minority stress model. Additional research into protective factors is warranted. Show more

Keywords: Cognitive aging, cognitive dysfunction, dementia, sexual minorities

DOI: 10.3233/JAD-220309

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-20, 2023