Journal of Alzheimer's Disease - Volume 82, issue 4

Authors: Elmaleh, David R. | Downey, Matthew A. | Kundakovic, Ljiljana | Wilkinson, Jeremy E. | Neeman, Ziv | Segal, Eran

Article Type: Review Article

Abstract: Progressive neurodegenerative diseases represent some of the largest growing treatment challenges for public health in modern society. These diseases mainly progress due to aging and are driven by microglial surveillance and activation in response to changes occurring in the aging brain. The lack of efficacious treatment options for Alzheimer’s disease (AD), as the focus of this review, and other neurodegenerative disorders has encouraged new approaches to address neuroinflammation for potential treatments. Here we will focus on the increasing evidence that dysbiosis of the gut microbiome is characterized by inflammation that may carry over to the central nervous system and into …the brain. Neuroinflammation is the common thread associated with neurodegenerative diseases, but it is yet unknown at what point and how innate immune function turns pathogenic for an individual. This review will address extensive efforts to identify constituents of the gut microbiome and their neuroactive metabolites as a peripheral path to treatment. This approach is still in its infancy in substantive clinical trials and requires thorough human studies to elucidate the metabolic microbiome profile to design appropriate treatment strategies for early stages of neurodegenerative disease. We view that in order to address neurodegenerative mechanisms of the gut, microbiome and metabolite profiles must be determined to pre-screen AD subjects prior to the design of specific, chronic titrations of gut microbiota with low-dose antibiotics. This represents an exciting treatment strategy designed to balance inflammatory microglial involvement in disease progression with an individual’s manifestation of AD as influenced by a coercive inflammatory gut. Show more

Keywords: Antibiotics, Alzheimer’s disease, microbiome, neurodegenerative disease, neuroinflammation

DOI: 10.3233/JAD-210198

Citation: Journal of Alzheimer's Disease, vol. 82, no. 4, pp. 1373-1401, 2021

Authors: Espay, Alberto J. | Sturchio, Andrea | Schneider, Lon S. | Ezzat, Kariem

Article Type: Research Article

Abstract: Brain proteins function in their soluble, native conformation and cease to function when transformed into insoluble aggregates, also known as amyloids. Biophysically, the soluble-to-insoluble phase transformation represents a process of polymerization, similar to crystallization, dependent on such extrinsic factors as concentration, pH, and a nucleation surface. The resulting cross-β conformation of the insoluble amyloid is markedly stable, making it an unlikely source of toxicity. The spread of brain amyloidosis can be fully explained by mechanisms of spontaneous or catalyzed polymerization and phase transformation instead of active replication, which is an enzyme- and energy-requiring process dependent on a specific nucleic acid …code for the transfer of biological information with high fidelity. Early neuronal toxicity in Alzheimer’s disease may therefore be mediated to a greater extent by a reduction in the pool of soluble, normal-functioning protein than its accumulation in the polymerized state. This alternative loss-of-function hypothesis of pathogenicity can be examined by assessing the clinical and neuroimaging effects of administering non-aggregating peptide analogs to replace soluble amyloid-β levels above the threshold below which neuronal toxicity may occur. Correcting the depletion of soluble amyloid-β, however, would only exemplify ‘rescue medicine.’ Precision medicine will necessitate identifying the pathogenic factors catalyzing the protein aggregation in each affected individual. Only then can we stratify patients for etiology-specific treatments and launch precision medicine for Alzheimer’s disease and other neurodegenerative disorders. Show more

Keywords: Alzheimer’s disease, clinico-pathologic, disease modification, precision medicine, neuroprotection

DOI: 10.3233/JAD-210415

Citation: Journal of Alzheimer's Disease, vol. 82, no. 4, pp. 1403-1415, 2021

Authors: Nara, Peter L. | Sindelar, Daniel | Penn, Marc S. | Potempa, Jan | Griffin, W. Sue T.

Article Type: Research Article

Abstract: Porphyromonas gingivalis ( Pg) is a primary oral pathogen in the widespread biofilm-induced “chronic” multi-systems inflammatory disease(s) including Alzheimer’s disease (AD). It is possibly the only second identified unique example of a biological extremophile in the human body. Having a better understanding of the key microbiological and genetic mechanisms of its pathogenesis and disease induction are central to its future diagnosis, treatment, and possible prevention. The published literature around the role of Pg in AD highlights the bacteria’s direct role within the brain to cause disease. The available evidence, although somewhat adopted, does not fully support this as the major …process. There are alternative pathogenic/virulence features associated with Pg that have been overlooked and may better explain the pathogenic processes found in the “infection hypothesis” of AD. A better explanation is offered here for the discrepancy in the relatively low amounts of “Pg bacteria” residing in the brain compared to the rather florid amounts and broad distribution of one or more of its major bacterial protein toxins. Related to this, the “Gingipains Hypothesis”, AD-related iron dyshomeostasis, and the early reduced salivary lactoferrin, along with the resurrection of the Cholinergic Hypothesis may now be integrated into one working model. The current paper suggests the highly evolved and developed Type IX secretory cargo system of Pg producing outer membrane vesicles may better explain the observed diseases. Thus it is hoped this paper can provide a unifying model for the sporadic form of AD and guide the direction of research, treatment, and possible prevention. Show more

Keywords: Alzheimer’s disease, biological extremophile, cholinergic hypothesis, dementia, outer membrane vesicles, Porphyromonas gingivalis, systemic inflammation

DOI: 10.3233/JAD-210448

Citation: Journal of Alzheimer's Disease, vol. 82, no. 4, pp. 1417-1450, 2021

Authors: Kang, Sarang | Gim, Jungsoo | Lee, Jiwoon | Gunasekaran, Tamil Iniyan | Choi, Kyu Yeong | Lee, Jang Jae | Seo, Eun Hyun | Ko, Pan-Woo | Chung, Ji Yeon | Choi, Seong-Min | Lee, Young Min | Jeong, Jee Hyang | Park, Kyung Won | Song, Min Kyung | Lee, Ho-Won | Kim, Ki Woong | Choi, Seong Hye | Lee, Dong Young | Kim, Sang Yun | Kim, Hoowon | Kim, Byeong C. | Ikeuchi, Takeshi | Lee, Kun Ho

Article Type: Short Communication

Abstract: The present study reports two novel genome-wide significant loci for late-onset Alzheimer’s disease (LOAD) identified from APOE ε4 non-carrier subjects of East Asian origin. A genome-wide association study of Alzheimer’s disease was performed in 2,291 Korean seniors in the discovery phase, from the Gwangju Alzheimer’ and Related Dementias (GARD) cohort study. The study was replicated in a Japanese cohort of 1,956 subjects that suggested two novel susceptible SNPs in two genes: LRIG1 and CACNA1A. This study demonstrates that the discovery of AD-associated variants is feasible in non-European ethnic groups using samples comprising fewer subjects from the more homogeneous genetic …background. Show more

Keywords: Alzheimer’s disease, APOE, genome-wide association study, late-onset Alzheimer’s disease, stratified genome analysis

DOI: 10.3233/JAD-210145

Citation: Journal of Alzheimer's Disease, vol. 82, no. 4, pp. 1451-1460, 2021

Authors: Solomon, Alina | Handels, Ron | Wimo, Anders | Antikainen, Riitta | Laatikainen, Tiina | Levälahti, Esko | Peltonen, Markku | Soininen, Hilkka | Strandberg, Timo | Tuomilehto, Jaakko | Kivipelto, Miia | Ngandu, Tiia

Article Type: Short Communication

Abstract: We investigated the effect of a multidomain lifestyle intervention on the risk of dementia estimated using the validated CAIDE risk score (post-hoc analysis). The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) is a 2-year randomized controlled trial among 1,260 at-risk older adults (60–77 years). Difference in the estimated mean change in CAIDE score at 2 years in the intervention compared to the control group was –0.16 (95 %CI –0.31 to 0.00) (p  = 0.013), corresponding to a relative dementia risk reduction between 6.04–6.50%. This could be interpreted as a reflection of the prevention potential of the …intervention. Show more

Keywords: Clinical trial, dementia, dementia risk score, lifestyle intervention, prevention

DOI: 10.3233/JAD-210331

Citation: Journal of Alzheimer's Disease, vol. 82, no. 4, pp. 1461-1466, 2021

Authors: Mitolo, Micaela | Stanzani-Maserati, Michelangelo | Manners, David N. | Capellari, Sabina | Testa, Claudia | Talozzi, Lia | Poda, Roberto | Oppi, Federico | Evangelisti, Stefania | Gramegna, Laura L. | Magarelli, Silvia | Pantieri, Roberta | Liguori, Rocco | Lodi, Raffaele | Tonon, Caterina

Article Type: Short Communication

Abstract: Differential diagnosis between primary progressive aphasia (PPA) and Alzheimer’s disease (AD) could be difficult if based on clinical grounds alone. We evaluated the combination of proton MR spectroscopy of posterior cingulate cortex (PCC) and quantitative structural imaging asymmetries to differentiate PPA from AD patients. A greater left-lateralized temporo-parietal atrophy (higher accuracy for the PCC, 81.4%) and metabolic neurodegenerative changes in PCC (accuracy 76.8%) was demonstrated in PPA versus AD. The combined multiparametric approach increased the accuracy to 94%in the differential diagnosis between these two neurodegenerative diseases.

Keywords: Alzheimer’s disease, 1H-MRS, magnetic resonance imaging, primary progressive aphasia

DOI: 10.3233/JAD-210211

Citation: Journal of Alzheimer's Disease, vol. 82, no. 4, pp. 1467-1473, 2021

Authors: Li, Wenwen | Wang, Shiyuan | zhang, Heng | Li, Bingqiu | Xu, Lingzhi | Li, Yan | Kong, Chaojun | Jiao, Haishan | Wang, Yan | Pang, Yana | Qin, Wei | Jia, Longfei | Jia, Jianping

Article Type: Research Article

Abstract: Background: Dysfunction of microglia has been increasingly recognized as a causative factor in Alzheimer’s disease (AD); thus, developing medicines capable of restoring microglial functions is critically important and constitutes a promising therapeutic strategy. Honokiol is a natural neuroprotective compound extracted from Magnolia officinalis, which may play roles in AD therapy. Objective: This study aimed to evaluate the role and the underlying mechanisms of honokiol in microglial phagocytosis. Methods: MTT and flow cytometry were used to assess the cell viability and apoptosis, respectively. Phagocytic capacity, mitochondrial reactive oxygen species production, and membrane potential were evaluated using fluorescence …microscopy. Seahorse XF24 extracellular flux analyzer was for cell glycolysis and oxidative phosphorylation detection. Mass spectrometry was applied for metabolites measurement. Quantitative real-time polymerase chain reaction and western blotting were performed to detect the mRNA and protein level of PPARγ and PGC1α, respectively. Results: Honokiol alleviated Aβ42 -induced BV2 neurotoxicity. Honokiol promoted phagocytic efficiency of BV2 cells through reversing a metabolic switch from oxidative phosphorylation to anaerobic glycolysis and enhancing ATP production. Meanwhile, honokiol reduced mitochondrial reactive oxygen species production and elevated mitochondrial membrane potential. Moreover, honokiol increased the expression of PPARγ and PGC1α, which might play positive roles in energy metabolism and microglial phagocytosis. Conclusion: In this study, honokiol was identified as an effect natural product capable of enhancing mitochondrial function thus promoting microglial phagocytic function. Show more

Keywords: Honokiol, metabolic reprogramming, microglial phagocytosis, mitochondria

DOI: 10.3233/JAD-210177

Citation: Journal of Alzheimer's Disease, vol. 82, no. 4, pp. 1475-1485, 2021

Authors: Chaudhary, Suman | Ashok, Ajay | McDonald, Dallas | Wise, Aaron S. | Kritikos, Alexander E. | Rana, Neil A. | Harding, Clifford V. | Singh, Neena

Article Type: Research Article

Abstract: Background: Accumulation of iron is a consistent feature of Alzheimer’s disease (AD) brains. The underlying cause, however, remains debatable. Objective: To explore whether local hepcidin synthesized by brain cells contributes to iron accumulation in AD brains. Methods: Brain tissue from the cingulate cortex of 33 cases of AD pre-assigned to Braak stage I-VI, 6 cases of non-dementia, and 15 cases of non-AD dementia were analyzed for transcriptional upregulation of hepcidin by RT-qPCR and RT-PCR. Change in the expression of ferritin, ferroportin (Fpn), microglial activation marker Iba1, IL-6, and TGFβ2 was determined by western blotting. Total tissue …iron was determined by colorimetry. Results: Significant transcriptional upregulation of hepcidin was observed in Braak stage III-VI relative to Braak stage I and II, non-AD dementia, and non-dementia samples. Ferritin was increased in Braak stage V, and a significant increase in tissue iron was evident in Braak stage III-VI. The expression of Iba1 and IL-6 was also increased in Braak stage III-VI relative to Braak stage I and II and non-AD dementia samples. Amyloid-β plaques were absent in most Braak stage I and II samples, and present in Braak stage III-VI samples with few exceptions. Conclusion: These observations suggest that upregulation of brain hepcidin is mediated by IL-6, a known transcriptional activator of hepcidin. The consequent downregulation of Fpn on neuronal and other cells results in accumulation of iron in AD brains. The increase in hepcidin is disease-specific, and increases with disease progression, implicating AD-specific pathology in the accumulation of iron. Show more

Keywords: Alzheimer’s disease, ferritin, hepcidin, IL-6, iron, oxidative stress

DOI: 10.3233/JAD-210221

Citation: Journal of Alzheimer's Disease, vol. 82, no. 4, pp. 1487-1497, 2021

Authors: Yao, Weina | Chen, Haifeng | Sheng, Xiaoning | Zhao, Hui | Xu, Yun | Bai, Feng | Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Abnormal default mode network (DMN) was associated with the progress of Alzheimer’s disease (AD). Rather than treat the DMN as a unitary network, it can be further divided into three subsystems with different functions. Objective: It remains unclear the interactions of DMN subsystems associated with the progress of cognitive impairments and AD pathological features. Methods: This study has recruited 187 participants, including test data and verification data. Firstly, an imaging analysis approach was utilized to investigate disease-related differences in the interactions of DMN subsystems in test data (n  = 149), including 42 cognitively normal subjects, 43 …early mild cognitive impairment (EMCI), 32 late mild cognitive impairment (LMCI), and 32 AD patients. Brain-behavior-pathological relationships regarding to the interactions among DMN subsystems were then further examined. Secondly, DMN subsystems abnormalities for classifying AD spectrum population in the independent verification data (n  = 38). Results: This study found that the impaired cognition relates to disturbances in the interactions between DMN subsystems but preferentially in core subsystem, and the abnormal regulatory processes of core subsystem were significantly associated with the levels of cerebrospinal fluid Aβ and tau in AD-spectrum patients. Meantime, the nonlinear relationship between dysfunctional core subsystem and impaired cognition was observed as one progresses through the stages of MCI to AD. Importantly, this classification presented a higher sensitivity and specificity dependent on the core-centered connection abnormalities. Conclusion: The abnormal interaction patterns of DMN subsystems at an early stage of AD appeared and presented as core-centered connection abnormalities, which were the potential neuroimaging features for monitoring the development of AD. Show more

Keywords: Alzheimer’s disease, classification, cognitive impairment, default mode network, regulation, subsystems

DOI: 10.3233/JAD-210481

Citation: Journal of Alzheimer's Disease, vol. 82, no. 4, pp. 1499-1511, 2021

Authors: Sakakibara, Yasufumi | Hirota, Yu | Ibaraki, Kyoko | Takei, Kimi | Chikamatsu, Sachie | Tsubokawa, Yoko | Saito, Takashi | Saido, Takaomi C. | Sekiya, Michiko | Iijima, Koichi M.

Article Type: Research Article

Abstract: Background: The locus coeruleus (LC), a brainstem nucleus comprising noradrenergic neurons, is one of the earliest regions affected by Alzheimer’s disease (AD). Amyloid-β (Aβ) pathology in the cortex in AD is thought to exacerbate the age-related loss of LC neurons, which may lead to cortical tau pathology. However, mechanisms underlying LC neurodegeneration remain elusive. Objective: Here, we aimed to examine how noradrenergic neurons are affected by cortical Aβ pathology in App NL -G -F /NL -G -F knock-in mice. Methods: The density of noradrenergic axons in LC-innervated regions and the LC neuron number were …analyzed by an immunohistochemical method. To explore the potential mechanisms for LC degeneration, we also examined the occurrence of tau pathology in LC neurons, the association of reactive gliosis with LC neurons, and impaired trophic support in the brains of App NL -G -F /NL -G -F mice. Results: We observed a significant reduction in the density of noradrenergic axons from the LC in aged App NL -G -F /NL -G -F mice without neuron loss or tau pathology, which was not limited to areas near Aβ plaques. However, none of the factors known to be related to the maintenance of LC neurons (i.e., somatostatin/somatostatin receptor 2, brain-derived neurotrophic factor, nerve growth factor, and neurotrophin-3) were significantly reduced in App NL -G -F /NL -G -F mice. Conclusion: This study demonstrates that cortical Aβ pathology induces noradrenergic neurodegeneration, and further elucidation of the underlying mechanisms will reveal effective therapeutics to halt AD progression. Show more

Keywords: Alzheimer’s disease, amyloid-β , locus coeruleus, neurotrophic factors, noradrenaline, somatostatin, tau

DOI: 10.3233/JAD-210385

Citation: Journal of Alzheimer's Disease, vol. 82, no. 4, pp. 1513-1530, 2021