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: Meysami, Somayeh | Raji, Cyrus A. | Glatt, Ryan M. | Popa, Emily S. | Ganapathi, Aarthi S. | Bookheimer, Tess | Slyapich, Colby B. | Pierce, Kyron P. | Richards, Casey J. | Lampa, Melanie G. | Gill, Jaya M. | Rapozo, Molly K. | Hodes, John F. | Tongson, Ynez M. | Wong, Claudia L. | Kim, Mihae | Porter, Verna R. | Kaiser, Scott A. | Panos, Stella E. | Dye, Richelin V. | Miller, Karen J. | Bookheimer, Susan Y. | Martin, Neil A. | Kesari, Santosh | Kelly, Daniel F. | Bramen, Jennifer E. | Siddarth, Prabha | Merrill, David A.

Article Type: Research Article

Abstract: Background: Strength and mobility are essential for activities of daily living. With aging, weaker handgrip strength, mobility, and asymmetry predict poorer cognition. We therefore sought to quantify the relationship between handgrip metrics and volumes quantified on brain magnetic resonance imaging (MRI). Objective: To model the relationships between handgrip strength, mobility, and MRI volumetry. Methods: We selected 38 participants with Alzheimer’s disease dementia: biomarker evidence of amyloidosis and impaired cognition. Handgrip strength on dominant and non-dominant hands was measured with a hand dynamometer. Handgrip asymmetry was calculated. Two-minute walk test (2MWT) mobility evaluation was combined with handgrip …strength to identify non-frail versus frail persons. Brain MRI volumes were quantified with Neuroreader. Multiple regression adjusting for age, sex, education, handedness, body mass index, and head size modeled handgrip strength, asymmetry and 2MWT with brain volumes. We modeled non-frail versus frail status relationships with brain structures by analysis of covariance. Results: Higher non-dominant handgrip strength was associated with larger volumes in the hippocampus (p  = 0.02). Dominant handgrip strength was related to higher frontal lobe volumes (p  = 0.02). Higher 2MWT scores were associated with larger hippocampal (p  = 0.04), frontal (p  = 0.01), temporal (p  = 0.03), parietal (p  = 0.009), and occipital lobe (p  = 0.005) volumes. Frailty was associated with reduced frontal, temporal, and parietal lobe volumes. Conclusion: Greater handgrip strength and mobility were related to larger hippocampal and lobar brain volumes. Interventions focused on improving handgrip strength and mobility may seek to include quantified brain volumes on MR imaging as endpoints. Show more

Keywords: Brain volumes, handgrip, mobility, prevention

DOI: 10.3233/JAD-220886

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

Authors: Reeve, Emily | Chenoweth, Lynn | Sawan, Mouna | Nguyen, Tuan Anh | Kalisch Ellett, Lisa | Gilmartin-Thomas, Julia | Tan, Edwin | Sluggett, Janet K. | Quirke, Lyntara S. | Tran, Kham | Ailabouni, Nagham | Cowan, Katherine | Sinclair, Ron | de la Perrelle, Lenore | Deimel, Judy | To, Josephine | Daly, Stephanie | Whitehead, Craig | Hilmer, Sarah N.

Article Type: Research Article

Abstract: Background: Historically, research questions have been posed by the pharmaceutical industry or researchers, with little involvement of consumers and healthcare professionals. Objective: To determine what questions about medicine use are important to people living with dementia and their care team and whether they have been previously answered by research. Methods: The James Lind Alliance Priority Setting Partnership process was followed. A national Australian qualitative survey on medicine use in people living with dementia was conducted with consumers (people living with dementia and their carers including family, and friends) and healthcare professionals. Survey findings were supplemented with …key informant interviews and relevant published documents (identified by the research team). Conventional content analysis was used to generate summary questions. Finally, evidence checking was conducted to determine if the summary questions were ‘unanswered’. Results: A total of 545 questions were submitted by 228 survey participants (151 consumers and 77 healthcare professionals). Eight interviews were conducted with key informants and four relevant published documents were identified and reviewed. Overall, analysis resulted in 68 research questions, grouped into 13 themes. Themes with the greatest number of questions were related to co-morbidities, adverse drug reactions, treatment of dementia, and polypharmacy. Evidence checking resulted in 67 unanswered questions. Conclusion: A wide variety of unanswered research questions were identified. Addressing unanswered research questions identified by consumers and healthcare professionals through this process will ensure that areas of priority are targeted in future research to achieve optimal health outcomes through quality use of medicines. Show more

Keywords: Caregivers, clinical decision-making, dementia, deprescription, health services research, multiple chronic conditions, pharmacy research, polypharmacy

DOI: 10.3233/JAD-220827

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-28, 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: Caselli, Richard J. | Chen, Yinghua | Chen, Kewei | Bauer III, Robert J. | Locke, Dona E.C. | Woodruff, Bryan K.

Article Type: Research Article

Abstract: Background: Older age is a major risk factor for severe COVID-19 disease which has been associated with a variety of neurologic complications, both acutely and chronically. Objective: We sought to determine whether milder COVID-19 disease in older vulnerable individuals is also associated with cognitive and behavioral sequelae. Methods: Neuropsychological, behavioral, and clinical outcomes before and after contracting COVID-19 disease, were compared in members of two ongoing longitudinal studies, the Arizona APOE Cohort and the national Alzheimer’s Disease Research Center (ADRC). Results: 152 APOE and 852 ADRC cohort members, mean age overall roughly 70 years, …responded to a survey that indicated 21 APOE and 57 ADRC members had contracted COVID-19 before their ensuing (post-COVID) study visit. The mean interval between test sessions that preceded and followed COVID was 2.2 years and 1.2 years respectively for the APOE and ADRC cohorts. The magnitude of change between the pre and post COVID test sessions did not differ on any neuropsychological measure in either cohort. There was, however, a greater increase in informant (but not self) reported cognitive change in the APOE cohort (p  = 0.018), but this became nonsignificant after correcting for multiple comparisons. Conclusion: Overall members of both cohorts recovered well despite their greater age-related vulnerability to more severe disease. Show more

Keywords: Alzheimer’s disease, APOE, cognitive aging, COVID-19, mild cognitive impairment

DOI: 10.3233/JAD-220435

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

Authors: Gong, Hong-Jian | Tang, Xingyao | Chai, Yin-He | Qiao, Yu-Shun | Xu, Hui | Patel, Ikramulhaq | Zhang, Jin-Yan | Simó, Rafael | Zhou, Jian-Bo

Article Type: Research Article

Abstract: Background: Obesity has been linked to cognitive impairment. However, how changes in body mass index (BMI) over the life course influence cognitive function remains unclear. Objective: The influence of distinct weight-change patterns from young adulthood to midlife and late adulthood on cognitive function in older adults was explored. Methods: A total of 5,809 individuals aged≥60 years were included and categorized into four groups on the basis of BMI change patterns. Cognitive function was assessed using four cognition tests in the baseline survey. The relationship between the weight-change patterns and cognition was evaluated using regression models. …Results: In comparison with participants who remained at non-obese, those moving from the non-obese to obese weight-change pattern from young (25 years of age) to middle adulthood showed lower Digit Symbol Substitution Test (DSST) scores (β= –1.28; 95% confidence interval [CI]: –2.24 to –0.32). A non-obese to obese change pattern from age 25 years of age to 10 years before baseline was associated with a higher risk of DSST impairment (odds ratio = 1.40; 95% CI: 1.09 to 1.79). In comparison with participants whose heaviest weight was recorded after 60 years of age, those with the heaviest weight between 18 and 40 years of age had lower DSST scores (β= –1.46; 95% CI: –2.77 to –1.52). Conclusion: Our results suggest that the transition from the non-obese to obese category in early adulthood and appearance of the heaviest weight between 18 and 40 years of age are associated with lower cognitive function in later life. Show more

Keywords: Body mass index, body weight changes, cognition, overweight

DOI: 10.3233/JAD-220788

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

Authors: Morys, Filip | Potvin, Olivier | Zeighami, Yashar | Vogel, Jacob | Lamontagne-Caron, Rémi | Duchesne, Simon | Dagher, Alain

Article Type: Research Article

Abstract: Background: Excess weight in adulthood leads to health complications such as diabetes, hypertension, or dyslipidemia. Recently, excess weight has also been related to brain atrophy and cognitive decline. Reports show that obesity is linked with Alzheimer’s disease (AD)-related changes, such as cerebrovascular damage or amyloid-β accumulation. However, to date no research has conducted a direct comparison between brain atrophy patterns in AD and obesity. Objective: Here, we compared patterns of brain atrophy and amyloid-β/tau protein accumulation in obesity and AD using a sample of over 1,300 individuals from four groups: AD patients, healthy controls, obese otherwise healthy individuals, …and lean individuals. Methods: We age- and sex-matched all groups to the AD-patients group and created cortical thickness maps of AD and obesity. This was done by comparing AD patients with healthy controls, and obese individuals with lean individuals. We then compared the AD and obesity maps using correlation analyses and permutation-based tests that account for spatial autocorrelation. Similarly, we compared obesity and AD brain maps with amyloid-β and tau protein maps from other studies. Results: Obesity maps were highly correlated with AD maps but were not correlated with amyloid-β/tau protein maps. This effect was not accounted for by the presence of obesity in the AD group. Conclusion: Our research confirms that obesity-related grey matter atrophy resembles that of AD. Excess weight management could lead to improved health outcomes, slow down cognitive decline in aging, and lower the risk for AD. Show more

Keywords: Alzheimer’s disease, grey matter, neurodegeneration, obesity

DOI: 10.3233/JAD-220535

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

Authors: Sakai, Kenji | Noguchi-Shinohara, Moeko | Tanaka, Hidetomo | Ikeda, Tokuhei | Hamaguchi, Tsuyoshi | Kakita, Akiyoshi | Yamada, Masahito | Ono, Kenjiro

Article Type: Research Article

Abstract: Background: Cerebrospinal fluid (CSF) biomarkers in patients with cerebral amyloid angiopathy-related inflammation (CAA-ri) have demonstrated inconsistent results. Objective: We investigated the relationship between CSF amyloid-β protein (Aβ) and vascular pathological findings to elucidate the mechanisms of Aβ elimination from the brain in CAA-ri. Methods: We examined Aβ 40 and Aβ 42 levels in CSF samples in 15 patients with CAA-ri and 15 patients with Alzheimer’s disease and cerebral amyloid angiopathy (AD-CAA) using ELISA as a cross-sectional study. Furthermore, we pathologically examined Aβ 40 and Aβ 42 depositions on the leptomeningeal blood vessels …(arteries, arterioles, and veins) using brain biopsy samples from six patients with acute CAA-ri and brain tissues of two autopsied patients with CAA-ri. Results: The median Aβ40 and Aβ42 levels in the CSF showed no significant difference between pre-treatment CAA-ri (Aβ40, 6837 pg/ml; Aβ42 , 324 pg/ml) and AD-CAA (Aβ40 , 7669 pg/ml, p  = 0.345; Aβ42 , 355 pg/ml, p  = 0.760). Aβ40 and Aβ42 levels in patients with post-treatment CAA-ri (Aβ40, 1770 pg/ml, p  = 0.056; Aβ42 , 167 pg/ml, p  = 0.006) were lower than those in patients with pre-treatment CAA-ri. Regarding Aβ40 and Aβ42 positive arteries, acute CAA-ri cases showed a higher frequency of partially Aβ-deposited blood vessels than postmortem CAA-ri cases (Aβ40 , 20.8% versus 3.9%, p  = 0.0714; Aβ42 , 27.4% versus 2.0%, p  = 0.0714, respectively). Conclusion: Lower levels of CSF Aβ40 and Aβ42 could be biomarkers for the cessation of inflammation in CAA-ri reflecting the recovery of the intramural periarterial drainage pathway and vascular function. Show more

Keywords: Amyloid-β protein-related angiitis, amyloid-related imaging abnormalities, biomarker, cerebral amyloid angiopathy-related inflammation, cerebrospinal fluid, diagnosis, elimination, pathology, vasculitis

DOI: 10.3233/JAD-220838

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

Authors: Fleming, Victoria | Helsel, Brian C. | Ptomey, Lauren T. | Rosas, H. Diana | Handen, Benjamin | Laymon, Charles | Christian, Bradley T. | Head, Elizabeth | Mapstone, Mark | Lai, Florence | Krinsky-McHale, Sharon | Zaman, Shahid | Ances, Beau M. | Lee, Joseph H. | Hartley, Sigan L.

Article Type: Research Article

Abstract: Background: Virtually all adults with Down syndrome (DS) develop Alzheimer’s disease (AD) pathology, but research gaps remain in understanding early signs of AD in DS. Objective: The goal of the present study was to determine if unintentional weight loss is part of AD in DS. The specific aims were to: 1) examine relation between chronological age, weight, AD pathology, and AD-related cognitive decline were assessed in a large cohort of adults with DS, and 2) determine if baseline PET amyloid-β (Aβ) and tau PET status (–versus+) and/or decline in memory and mental status were associated with weight loss …prior to AD progression. Methods: Analyses included 261 adults with DS. PET data were acquired using [11 C] PiB for Aβ and [18 F] AV-1451 for tau. Body mass index (BMI) was calculated from weight and height. Direct measures assessed dementia and memory. Clinical AD status was determined using a case consensus process. Percent weight decline across 16–20 months was assessed in a subset of participants (n  = 77). Results: Polynomial regressions indicated an 0.23 kg/m2 decrease in BMI per year beginning at age 36.5 years, which occurs alongside the period during which Aβ and tau increase and memory and mental status decline. At a within-person level, elevated Aβ, decline in memory and mental status were associated with higher percent weight loss across 16–20 months. Conclusion: Unintentional weight loss occurs alongside Aβ deposition and prior to onset of AD dementia, and thus may be a useful sign of AD in DS. Show more

Keywords: Alzheimer’s disease, amyloid, biomarkers, body mass index, tau, weight

DOI: 10.3233/JAD-220865

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

Authors: Downer, Brian | Li, Chih-Ying | Al Snih, Soham

Article Type: Research Article

Abstract: Background: Evidence from predominately non-Hispanic White populations indicates that emergency room (ER) admissions and hospitalizations by older adults with and without dementia are associated with caregiver stress and depressive symptoms. These results may not generalize to Hispanic populations because of cultural differences in caregiving roles, responsibilities, and perspectives about care burden. Objective: Investigate the association between ER admissions and hospitalizations by Mexican American older adults with and without dementia and symptoms of depression and stress among family caregivers. Methods: Data came from the 2010/11 wave of the Hispanic Established Populations for the Epidemiologic Study of the …Elderly and Medicare claims files. The final sample included 326 older adults and their caregivers. Negative binomial regression was used to model the association between hospitalizations and ER admissions by older adults in the previous two years and caregivers’ depressive symptoms and stress in 2010/11. Results: The number of older adult ER admissions and hospitalizations was not associated with caregiver depressive symptoms. Two or more ER admissions (incident rate ratio [IRR] = 1.26, 95% CI = 1.05–1.51) and two or more hospitalizations (IRR = 1.32, 95% CI = 1.07–1.61) were associated with significantly higher caregiver stress. Additionally, ER admissions and hospitalizations for a circulatory disease or injury and poisoning were associated with significantly higher caregiver stress. These associations were not modified by the care recipient’s dementia status. Conclusion: Hospitalizations and ER admissions by older Mexican Americans were associated with greater caregiver stress but not depressive symptoms. These associations were similar for caregivers to older adults with and without dementia. Show more

Keywords: Caregivers, dementia, health services, Mexican Americans

DOI: 10.3233/JAD-220997

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

Authors: Deng, Xiaoli | Geng, Zhao | Yu, Juan | Dai, Xiaoyan | Kuang, Xunjie | Chen, Xia | Li, Ruifeng | Liu, Ting | Li, Chongyi

Article Type: Research Article

Abstract: Background: The association between cataracts and cognitive functions has been reported in several studies. However, the dynamic trajectories of cognitive changes in patients with cataracts remain unelucidated. Objective: The aim of the study was to evaluate the dynamic trajectories of cognitive changes in patients with cataracts. Methods: This observational cohort study recruited 1,146 patients with age-related cataracts (ARC) from the Department of Ophthalmology, Daping Hospital, from September 2020 to November 2021. The cognitive functions of the patients were assessed using a Chinese version of the Telephone Interview of Cognitive Status-40 (TICS-40) test at baseline and 6 …months of follow-up. The trajectories and the associated risk factors for the longitudinal cognitive decline during the 6-month follow-up were investigated. Results: Patients with severe ARC [median (IQR): 0 month, 24 (22, 25); 6 months, 23 (21,25)] had lower TICS-40 scores than those with non-severe ARC [0 month, 31 (24, 33), p  <  0.001; 6 months, 31 (23,33), p  <  0.001] and controls [0 month, 32 (28, 35), p  <  0.001; 6 months, 32 (28, 35), p  <  0.001] at both baseline and 6 months of follow-up. Age (OR: 1.311, 95% CI: 1.229 to 1.398) and cataract grade (OR: 5.569, 95% CI: 2.337 to 13.273) were found to be the risk factors of cognitive decline as indicated by a decrease in the TICS-40 scores. Conclusion: ARC is associated with an increased risk of longitudinal cognitive decline; however, the reversibility of such declines needs to be investigated further. Show more

Keywords: Age, cataract, cataract grade, cognitive decline, risk factor

DOI: 10.3233/JAD-220963

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2022

Authors: Jia, Jianping | Zhang, Yue | Shi, Yuqing | Yin, Xuping | Wang, Shiyuan | Li, Yan | Zhao, Tan | Liu, Wenying | Zhou, Aihong | Jia, Longfei

Article Type: Short Communication

Abstract: Alzheimer’s disease (AD) primarily affects older adults. In this report, we present the case of a 19-year-old male with gradual memory decline for 2 years and World Health Organization-University of California Los Angeles Auditory Verbal Learning Test (WHO-UCLA AVLT) results also showing memory impairment. Positron emission tomography-magnetic resonance imaging with 18 F fluorodeoxyglucose revealed atrophy of the bilateral hippocampus and hypometabolism in the bilateral temporal lobe. Examination of the patient’s cerebrospinal fluid showed an increased concentration of p-tau181 and a decreased amyloid-β 42/40 ratio. However, through whole-genome sequencing, no known gene mutations were identified. Considering the above, the patient was …diagnosed with probable AD. Show more

Keywords: Case report, early-onset Alzheimer’s disease, gene mutation, hippocampal atrophy, memory impairment

DOI: 10.3233/JAD-221065

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

Authors: Zhào, Hóngyi | Wei, Wei | Xie, Hongyang | Huang, Yonghua

Article Type: Short Communication

Abstract: Brain aging is characterized by the declines in motor and cognitive features. The present study is to detect motor cognitive risk syndrome (MCRS) in older adults with white matter lesions (WML). 134 WML aged patients were recruited and diagnosed with the criteria for MCRS. Numerous cognitive function tests and walking tests were performed. The frequency of MCRS is 28.35% . Verbal fluency test, Mini-Mental State Examination, and dual-task walking speed were independent risk factor of MCRS. These findings indicated that MCRS was common in WML seniors. MCRS was associated with the pathologies of WML in older adults.

Keywords: Aging, cerebral small vessel disease, dual-task walking, magnetic resonance imaging, motoric cognitive risk syndrome, white matter lesions

DOI: 10.3233/JAD-220712

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2022

Authors: Schäfer, Simona | Mallick, Elisa | Schwed, Louisa | König, Alexandra | Zhao, Jian | Linz, Nicklas | Bodin, Timothy Hadarsson | Skoog, Johan | Possemis, Nina | ter Huurne, Daphne | Zettergren, Anna | Kern, Silke | Sacuiu, Simona | Ramakers, Inez | Skoog, Ingmar | Tröger, Johannes

Article Type: Research Article

Abstract: Background: Modern prodromal Alzheimer’s disease (AD) clinical trials might extend outreach to a general population, causing high screen-out rates and thereby increasing study time and costs. Thus, screening tools that cost-effectively detect mild cognitive impairment (MCI) at scale are needed. Objective: Develop a screening algorithm that can differentiate between healthy and MCI participants in different clinically relevant populations. Methods: Two screening algorithms based on the remote ki:e speech biomarker for cognition (ki:e SB-C) were designed on a Dutch memory clinic cohort (N  = 121) and a Swedish birth cohort (N  = 404). MCI classification was each evaluated on …the training cohort as well as across on the unrelated validation cohort. Results: The algorithms achieved a performance of AUC  0.73 and AUC  0.77 in the respective training cohorts and AUC  0.81 in the unseen validation cohort. Conclusion: The results indicate that a ki:e SB-C based algorithm robustly detects MCI across different cohorts and languages, which has the potential to make current trials more efficient and improve future primary health care. Show more

Keywords: Alzheimer’s disease, biomarker, clinical trial, machine learning, mild cognitive impairment, screening

DOI: 10.3233/JAD-220762

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2022

Authors: Parker, Daniel C. | Kraus, William E. | Whitson, Heather E. | Kraus, Virginia B. | Smith, Patrick J. | Cohen, Harvey Jay | Pieper, Carl F. | Faldowski, Richard A. | Hall, Katherine S. | Huebner, Janet L. | Ilkayeva, Olga R. | Bain, James R. | Newby, L. Kristin | Huffman, Kim M.

Article Type: Research Article

Abstract: Background: The kynurenine pathway (KP) comprises a family of tryptophan-derived metabolites that some studies have reported are associated with poorer cognitive performance and an increased risk of Alzheimer’s disease and related dementias (ADRD). Objective: The objective of this study was to determine the associations of plasma KP metabolites (kynurenine [KYN], kynurenic acid [KA], and tryptophan [TRP]) with a panel of plasma ADRD biomarkers (Aβ42 / β40 ratio, pTau-181, glial fibrillary acidic protein [GFAP], and neurofilament light [NfL]) and cognitive performance in a subset of older adults drawn from the Duke Physical Performance Across the LifeSpan (PALS) study. …Methods: The Montreal Cognitive Assessment (MoCA) was used to assess cognitive performance. We used multivariate multiple regression to evaluate associations of the KYN/TRP and KA/KYN ratios with MoCA score and plasma ADRD biomarkers at baseline and over two years (n  = 301; Age = 74.8±8.7). Results: Over two years, an increasing KYN/TRP ratio was associated with increasing plasma concentrations of plasma p-Tau181 (β= 6.151; 95% CI [0.29, 12.01]; p  = 0.040), GFAP (β= 11.12; 95% CI [1.73, 20.51 ]; p  = 0.020), and NfL (β= 11.13; 95% CI [2.745, 19.52 ]; p  = 0.009), but not MoCA score or the Aβ42 /Aβ40 ratio. There were no significant associations of KA/KYN with MoCA score or plasma ADRD biomarkers. Conclusion: Our findings provide evidence that greater concentrations of KP metabolites are associated longitudinally over two years with greater biomarker evidence of neurofibrillary tau pathology (pTau-181), neuroinflammation (GFAP), and neurodegeneration (NfL), suggesting that dysregulated KP metabolism may play a role in ADRD pathogenesis. Show more

Keywords: Alzheimer’s disease and related dementias, biomarkers, cognition, kynurenines, tryptophan

DOI: 10.3233/JAD-220906

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

Authors: Leng, Yue | Stone, Katie L. | Yaffe, Kristine

Article Type: Research Article

Abstract: Background: The effect of sleep medications on cognition in older adults is controversial, possibly dependent upon sleep quality, and may differ by race. Objective: To determine the longitudinal association between sleep medication use and incident dementia over 15 years, and to explore whether the association is independent of nighttime sleep disturbances and if it differs by race. Methods: We examined 3,068 community-dwelling older adults (aged 74.1±2.9 years, 41.7% Black, 51.5% female) without dementia. Sleep medication use was recorded three times by asking “Do you take sleeping pills or other medications to help you sleep?” with the …response options: “Never (0)”, “Rarely (≤1/month)”, “Sometimes (2–4/month)”, “Often (5–15/month)”, or “Almost Always (16–30/month)”. Incident dementia was defined using hospitalization records, dementia medication prescription or clinically significant decline in global cognition. Results: 138 (7.71%) of Whites and 34 (2.66%) of Blacks reported taking sleep medications “often or almost always”. Whites were almost twice as likely to take all prescription hypnotics. 617 participants developed dementia over the follow-up. After adjustment for all covariates, participants who reported taking sleep medications ≥ 5/month versus ≤1/month were significantly more likely to develop dementia, and the association was only observed among Whites (HR = 1.79,1.21–2.66) but not Blacks (HR = 0.84,0.38–1.83); p for interaction = 0.048. Further adjustment for nighttime sleep did not appreciably alter the results. The association was similar for the cumulative frequency of sleep medication use and remained after introducing a time lag of 3 years. Conclusion: Frequent sleep medication use was associated with an increased risk of dementia in White older adults. Further research is needed to determine underlying mechanisms. Show more

Keywords: Dementia, epidemiology, medication, race, sleep

DOI: 10.3233/JAD-221006

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2022

Authors: Liu, Jia-Yao | Ma, Ling-Zhi | Wang, Jun | Cui, Xin-Jing | Sheng, Ze-Hu | Fu, Yan | Li, Meng | Ou, Ya-Nan | Yu, Jin-Tai | Tan, Lan | Lian, Yan

Article Type: Research Article

Abstract: Background: APOE ɛ4 genotype was correlated with exacerbation of pathology and higher risk of dementia in Parkinson’s disease (PD). Meanwhile, the differential influence of APOE ɛ4 on cognition in young and old individuals interpreted as antagonistic pleiotropy. Objective: To examine whether the effect of APOE ɛ4 on cognitive progression in de novo PD is age dependent. Methods: In this study, 613 de novo PD patients were recruited from Parkinson’s Progression Markers Initiative (PPMI). To examine the age-dependent relationship between APOE ɛ 4 and cognitive changes, we added 3-way interaction of …APOE ɛ4*baseline age*time to the linear mixed-effect (LME) models and evaluated the specific roles of APOE ɛ4 in the middle age group and elderly group separately. Cox regression was utilized to examine the progression of cognition in age-stratified PD participants. Results: Age significantly modified relationship between APOE ɛ4 and cognitive changes in most cognitive domains (pinteraction <0.05). In the elderly group, APOE ɛ4 carriers showed steeper decline in global cognition (p  = 0.001) as well as in most cognitive domains, and they had a greater risk of cognitive progression (adjusted HR 1.625, 95% CI 1.143–2.310, p  = 0.007), compared with non-carriers. However, in the middle age group, no significant relationships between APOE ɛ4 and cognitive decline can be detected. Conclusion: Our results indicated that the APOE ɛ4 allele has an age-dependent effect on cognitive decline in PD patients. The underlying mechanisms need to be investigated in the future. Show more

Keywords: Age, APOE ɛ4, cognition, Parkinson’s disease

DOI: 10.3233/JAD-220976

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

Authors: Posis, Alexander Ivan B. | Yarish, Natalie M. | McEvoy, Linda K. | Jain, Purva | Kroenke, Candyce H. | Saquib, Nazmus | Ikramuddin, Farha | Schnatz, Peter F. | Bellettiere, John | Rapp, Stephen R. | Espeland, Mark A. | Shadyab, Aladdin H.

Article Type: Research Article

Abstract: Background: Social support may be a modifiable risk factor for cognitive impairment. However, few long-term, large prospective studies have examined associations of various forms of social support with incident mild cognitive impairment (MCI) and dementia. Objective: To examine associations of perceived social support with incident MCI and dementia among community-dwelling older women. Methods: This prospective cohort study included 6,670 women from the Women’s Health Initiative Memory Study who were cognitively unimpaired at enrollment. We used Cox proportional hazards models to assess associations between perceived social support with incident MCI, dementia, or either MCI/dementia during an average …10.7 (SD = 6.1)-year follow-up. Modelling was repeated for emotional/information support, affection support, tangible support, and positive social interaction subscales of social support. Results: Among 6,670 women (average age = 70 years [SD = 3.8]; 97.0% non-Hispanic/Latina; 89.8% White), greater perceived social support was associated with lower risk of MCI/dementia after adjustment for age, ethnicity, race, hormone therapy, education, income, diabetes, hypertension, and body mass index (Tertile [T]3 versus T1: HR = 0.85, 95% CI 0.74–0.99; p trend  = 0.08). Associations were significant for emotional/information support (T3 versus T1: HR = 0.84, 95% CI 0.72–0.97; p trend  = 0.04) and positive social interaction (T3 versus T1: HR = 0.85, 95% CI 0.72–0.99; p trend  = 0.06) subscales. Associations were attenuated and not significant after adjustment for depressive symptom severity. Objective: Perceived social support, emotional/information support, and positive social interaction were associated with incident MCI/dementia among older women. Results were not significant after adjustment for depressive symptom severity. Improving social support may reduce risk of MCI and dementia in older women. Show more

Keywords: Cognitive aging, epidemiology, psychosocial, women’s health

DOI: 10.3233/JAD-220967

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

Authors: Eruysal, Emily | Ravdin, Lisa | Zhang, Cenai | Kamel, Hooman | Iadecola, Costantino | Ishii, Makoto

Article Type: Research Article

Abstract: Background: Plasminogen activator inhibitor-1 (PAI-1), an inhibitor of fibrinolysis that is associated with adiposity, has been implicated in Alzheimer’s disease (AD) pathogenesis. However, whether circulating PAI-1 levels are altered during preclinical AD remains unclear. Objective: To measure plasma PAI-1 levels in cognitively normal cerebrospinal fluid (CSF) AD biomarker positive and biomarker negative participants and to examine the association of plasma PAI-1 levels with CSF AD biomarkers and Mini-Mental State Examination (MMSE) scores. Methods: In this cross-sectional study, plasma PAI-1 levels were measured in 155 cognitively normal (Clinical Dementia Rating, CDR 0) non-obese older adults. 29 men …and 26 women were classified as preclinical AD by previously established CSF tau/Aβ42 criteria. All analyses were sex stratified due to reported sex differences in PAI-1 expression. Results: Plasma PAI-1 levels were associated with body mass index (BMI) but not age in men and women. In men, plasma PAI-1 levels and BMI were lower in preclinical AD compared to control. Plasma PAI-1 levels were positively associated with CSF amyloid-β42 (Aβ42) and CSF Aβ42/Aβ40 and negatively associated with CSF tau/Aβ42, while BMI was positively associated with CSF Aβ42 and negatively associated with CSF p-tau181 and CSF tau/Aβ42. In women, plasma PAI-1 levels and BMI were similar between preclinical AD and control and were not associated with CSF AD biomarkers. For men and women, plasma PAI-1 levels and BMI were not associated with MMSE scores. Conclusion: These findings suggest that there are significant sex differences in the systemic metabolic changes seen in the preclinical stage of AD. Show more

Keywords: Adipokines, Alzheimer’s disease, amyloid beta-peptides, body weight, body mass index, biomarker, immunoassay, PAI-1, sexual dimorphism, tau proteins

DOI: 10.3233/JAD-220686

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

Authors: Chen, Yuzhao | Zhang, Yilin | Chen, Qiuxuan | Liu, Yuxiang | Wei, Xuemin | Wu, Meijian | Zhang, Keke | Liu, Yinghua | Wei, Wei

Article Type: Research Article

Abstract: Background: The metabotropic glutamate receptor 5 (mGluR5) is widely expressed in postsynaptic neurons and plays a vital role in the synaptic plasticity of the central nervous system. mGluR5 is a coreceptor for amyloid-β (Aβ) oligomer, and downregulation or pharmacological blockade of mGluR5 presents the therapeutic potential of Alzheimer’s disease (AD). However, the abnormality of mGluR5 in the pathogenesis of AD and its mechanism of pathology is not clear. Objective: In this study, we would like to investigate the expression of mGluR5 in the process of AD and explore the effects and the underlying mechanisms of antagonizing mGluR5 on …cognitive function, synaptic structure, and inflammation in 5xFAD mice. Methods: mGluR5 expression and interactions with PrPc in 5XFAD mice were detected using western blot and co-immunoprecipitation. The selective mGluR5 antagonist MPEP was infused into 4-month-old 5XFAD mice for 60 consecutive days. Then, cognitive function, AD-like pathology and synaptic structure were measured. Further observations were made in mGluR5 knockdown 5XFAD mice. Results: mGluR5 expression was increased with Aβ levels at 6 months in 5XFAD mice. mGluR5 antagonist rescued cognitive disorders, promoted synaptic recovery, and alleviated both the Aβ plaque load and abnormal hyperphosphorylation in 6-month-old 5XFAD mice. Meanwhile, the results were validated in mGluR5 knockdown mice. Blockade of mGluR5 efficiently alleviates AD-like pathologies by inhibiting the PI3K/AKT/mTOR pathway and activates autophagy in 5XFAD mice. Furthermore, antagonism of mGluR5 attenuated neuroinflammation by inactivating the IKK/NF-κ B pathway. Conclusion: These findings suggest that mGluR5 may be an effective drug target for AD treatment, and inhibition of the mGluR5/PI3K-AKT pathway alleviates AD-like pathology by activating autophagy and anti-neuroinflammation in 5XFAD mice. Show more

Keywords: Alzheimer’s disease, autophagy, mGluR5, MPEP, neuroinflammation

DOI: 10.3233/JAD-221058

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2022

Authors: Chai, Yuek Ling | Liang, Nathan Hao Ping | Chong, Joyce R. | Venketasubramanian, Narayanaswamy | Tan, Boon Yeow | Hilal, Saima | Chen, Christopher P. | Lai, Mitchell K. P.

Article Type: Research Article

Abstract: Background: The lysosomal protease cathepsin D (catD) has been reported to be upregulated in postmortem Alzheimer’s disease (AD) cortex, where it colocalized with neurofibrillary tangles and correlated with levels of phosphorylated tau, suggesting pathophysiological links between catD and neurodegeneration. In contrast, studies of serum catD in AD have yielded conflicting results, and potential associations between baseline serum catD and functional outcomes of patients are at present unknown. Objective: We aimed to examine the status of serum catD in a Singapore-based longitudinal study of dementia and investigate catD associations with functional and cognitive decline. Methods: 35 subjects …with no cognitive impairment, 40 patients with cognitive impairment no dementia and 34 with AD dementia underwent annual neuropsychological assessments (mean follow-up=4.3 years), as well as collection of baseline serum for catD measurements by ELISA. Results: Higher serum catD at baseline was associated with AD clinical diagnosis (odds ratios [OR]: 10.0; 95% confidence interval [CI]: 1.02–97.95) as well as with cortical atrophy. Furthermore, higher catD was associated with global cognitive and functional decline (OR: 9.94; 95% CI: 1.02–97.34). Conclusion: The associations of serum catD with AD dementia as well as atrophy provide further support for the proposed links between catD and neurodegeneration, as well as for the assessment of serum catD as a prognostic biomarker predicting global cognitive and functional decline in larger studies. Show more

Keywords: Alzheimer’s disease, brain atrophy, cathepsin D, cognitive decline, lysosomal protease, neurodegeneration

DOI: 10.3233/JAD-220852

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 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: Li, Huiyue | Liu, Hongliang | Lutz, Michael W. | Luo, Sheng

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a common neurodegenerative disease and mild cognitive impairment (MCI) is considered as the prodromal stage of AD. Previous studies showed that changes in the neurotrophin signaling pathway could lead to cognitive decline in AD. However, the association of single nucleotide polymorphisms (SNPs) in genes that are involved in this pathway with AD progression from MCI remains unclear. Objective: We investigated the associations between SNPs involved in the neurotrophin signaling pathway with AD progression. Methods: We performed single-locus analysis to identify neurotrophin-signaling-related SNPs associated with the AD progression using 767 patients from …the Alzheimer’s Disease Neuroimaging Initiative study and 1,373 patients from the National Alzheimer’s Coordinating Center study. We constructed polygenic risk scores (PRSs) using the identified independent non-APOE SNPs and evaluated its prediction performance on AD progression. Results: We identified 25 SNPs significantly associated with AD progression with Bayesian false-discovery probability ≤0.8. Based on the linkage disequilibrium-clumping and expression quantitative trait loci analysis, we found 6 potentially functional SNPs that were associated with AD progression independently. The PRS analysis quantified the combined effects of these SNPs on longitudinal cognitive assessments and biomarkers from cerebrospinal fluid and neuroimaging. The addition of PRSs to the prediction model for 3-year survival in absence of AD-progression significantly increased the predictive accuracy. Conclusion: Genetic variants in the specific genes of the neurotrophin signaling pathway are predictors of AD progression. eQTL analysis supports that these SNPs regulate expression of key genes involved in the neurotrophin signaling pathway. Show more

Keywords: Mild cognitive impairment, neurotrophins, single nucleotide polymorphism, survival analysis

DOI: 10.3233/JAD-220680

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

Authors: Dai, Wen-Zhuo | Liu, Lu | Zhu, Meng-Zhuo | Lu, Jing | Ni, Jian-Ming | Li, Rong | Ma, Tao | Zhu, Xi-Chen

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is an increasingly common type of dementia. Apolipoprotein E (APOE ) gene is a strong risk factor for AD. Objective: Here, we explored alterations in grey matter structure (GMV) and networks in AD, as well as the effects of the APOE ɛ 4 allele on neuroimaging regions based on structural magnetic resonance imaging (sMRI). Methods: All subjects underwent an sMRI scan. GMV and cortical thickness were calculated using voxel-based morphological analysis, and structural networks were constructed based on graph theory analysis to compare differences between AD and normal controls. …Results: The volumes of grey matter in the bilateral inferior temporal gyrus, right middle temporal gyrus, right inferior parietal lobule, right limbic lobe, right frontal lobe, left anterior cingulate gyrus, and bilateral olfactory cortex of patients with AD were significantly decreased. The cortical thickness in patients with AD was significantly reduced in the left lateral occipital lobe, inferior parietal lobe, orbitofrontal region, precuneus, superior parietal gyrus, right precentral gyrus, middle temporal gyrus, pars opercularis gyrus, insular gyrus, superior marginal gyrus, bilateral fusiform gyrus, and superior frontal gyrus. In terms of local properties, there were significant differences between the AD and control groups in these areas, including the right bank, right temporalis pole, bilateral middle temporal gyrus, right transverse temporal gyrus, left postcentral gyrus, and left parahippocampal gyrus. Conclusion: There were significant differences in the morphological and structural covariate networks between AD patients and healthy controls under APOE ɛ 4 allele effects. Show more

Keywords: Alzheimer’s disease, apolipoprotein E, cortical thickness, grey matter volume, structural covariate network, structural magnetic resonance imaging

DOI: 10.3233/JAD-220877

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

Authors: Cao, Ke | Bay, Allison A. | Hajjar, Ihab | Wharton, Whitney | Goldstein, Felicia | Qiu, Deqiang | Prusin, Todd | McKay, J. Lucas | Perkins, Molly M. | Hackney, Madeleine E.

Article Type: Research Article

Abstract: Background: Functional decline in Alzheimer’s disease (AD) is impacted by impaired ability to integrate and modulate complex cognitive and motor abilities, commonly known as motor-cognitive integration. Impaired motor-cognitive integration occurs in the early stages of AD, prodromal AD (pAD), and may precede other symptoms. Combined motor and cognitive training have been recommended for people with pAD and need to be better researched. Our data suggest that partnered rhythmic rehabilitation (PRR) improves motor-cognitive integration in older adults with cognitive impairment. PRR is an ideal intervention to simultaneously target cardiovascular, social, and motor-cognitive domains important to AD. Objective/Methods: We propose …to conduct a 1-year Phase II, single-blind randomized controlled trial using PRR in 66 patients with pAD. Participants will be assigned to three months of biweekly sessions, followed by nine months of weekly sessions of PRR or group walking (WALK) with 1 : 1 allocation. Group walking in the control group will allow us to compare physical exercise alone versus the added benefit of the cognitively engaging elements of PRR. Results/Conclusion: Using an intent-to-treat approach, this innovative pilot study will 1) Determine acceptability, safety, tolerability, and satisfaction with PRR; 2) Compare efficacy of PRR versus WALK for improving motor-cognitive integration and identify the most sensitive endpoint for a Phase III trial from a set of motor-cognitive, volumetric MRI, and cognitive measures. The study will additionally explore potential neural, vascular, and inflammatory mechanisms by which PRR affects pAD to derive effect size of these intermediary measures and aid us in estimating sample size for a future trial. Show more

Keywords: Dance therapy, exercise, multitasking behavior, neuroprotection

DOI: 10.3233/JAD-220783

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

Authors: Glover, Crystal M. | Arfanakis, Konstantinos | Aggarwal, Neelum T. | Bennett, David A. | Marquez, David X. | Barnes, Lisa L.

Article Type: Research Article

Abstract: Background: Biological biomarkers yielded from positron emission tomography (PET) brain scans serve as a pathway to understanding Alzheimer’s disease pathology. PET brain scan data remain limited for populations traditionally under-included in aging research. Objective: The purpose of this qualitative study was to examine participant-identified barriers to PET brain scan consent and characterize participant-informed elements of educational materials needed to facilitate PET brain scan participation among older Black and Latino adults. Methods: Participants (N = 31) were older adults (mean age = 71 years) who self-identified as either non-Latino Black (n  = 15) or Latino (n  = 16). Each participant took part in …a one-time, in-depth individual interview. Researchers analyzed data guided by a Grounded Theory Approach with both Open Coding and Constant Comparative Coding. Results: Four overarching themes emerged across all participants: 1) knowledge limitations; 2) requirements for consent; 3) motivators for participation; and 4) social networks. Within the four themes, there were differences based on participant ethnoracial group. For example, for Theme Three, older Black adults indicated that they would expect compensation for PET brain scan participation. Conversely, older Latinos stated that they would appreciate, but not anticipate, a financial incentive. All participants stressed the importance of written educational materials with subsequent verbal discussions with studystaff. Conclusion: Findings inform the development and implementation of scientifically-relevant and culturally-cognizant engagement approaches, educational materials, and recruitment strategies to increase PET brain scan participation by diverse older adults. Show more

Keywords: Older adults, PET brain scan, qualitative interviews, recruitment science, study design

DOI: 10.3233/JAD-220861

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

Authors: Chen, Qianyun | Abrigo, Jill | Deng, Min | Shi, Lin | Wang, Yi-Xiang | Chu, Winnie Chiu Wing

Article Type: Research Article

Abstract: Background: Diagnosis of Alzheimer’s disease (AD) was recently shifted from clinical to biological construct to reflect underlying neuropathological status, where amyloid deposition designated patients to the AD continuum, and additional tau positivity represented AD. Objective: To investigate white matter (WM) alteration in the brain of patients in the AD continuum. Methods: A total of 236 subjects across the clinical and biological spectra of AD were included and stratified by normal/abnormal (–/+) amyloid (A) and tau (T) status based on positron emission tomography results, yielding five groups: A–T–cognitively normal (CN), A+T–CN, A+T+ CN, A+T+ mild cognitive impairment, …and A+T+ AD. WM alteration was measured by diffusion tensor imaging (DTI). Group differences, correlation of DTI measures with amyloid and tau, and diagnostic performance of such measures were evaluated. Results: Compared with A–T–CN, widespread WM alteration was observed in the AD continuum, including hippocampal cingulum (CGH), cingulum of the cingulate gyrus, and uncinate fasciculus. Diffusion changes measured by regional mean fractional anisotropy (FA) in the bilateral CGH were first detected in the A+T+ CN group and associated with tau burden in the AD continuum (p  <  0.001). For discrimination between A+T+ CN and A–T–CN groups, CGH FA achieved accuracy, sensitivity, and specificity of 74%, 58%, and 78% for right CGH and 57%, 83%, and 47% respectively for left CGH. Conclusion: WM alteration is widespread in the AD continuum. Diffusion alteration in CGH occurred early and was correlated with tau pathology, thus may be a promising biomarker in preclinical AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, diffusion tensor imaging, hippocampal cingulum, tau

DOI: 10.3233/JAD-220671

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

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