Volume 88, Number 1, IN PRESS

Hypothesis
Pravat K. Mandal, Divya Dwivedi, Deepika Shukla, Avantika Samkaria, Rimil Guha Roy, Yashika Arora, Komal Jindal
Interplay Between Hippocampal Glutathione Depletion and pH Increment in Alzheimer’s Disease
Abstract: Oxidative stress (OS) is a critical factor in the pathogenesis of Alzheimer’s disease (AD). Elevated OS in AD lowers the level of glutathione (GSH), a brain antioxidant. Currently, GSH is under examination in the clinical population for understanding its association with oxidative load in AD research. Significant depletion in hippocampal GSH, as observed using in vivo magnetic resonance spectroscopy (MRS), reportedly correlates with cognitive impairment in AD. Alterations in cellular-energy metabolism and increased hippocampal pH have also been reported in AD. Hence, this combined molecular interplay between hippocampal GSH and pH must be studied longitudinally for advancing AD research. Herein, we propose a schematic model depicting the molecular events in AD pathogenesis and provide a possible link between OS, GSH depletion, and pH alterations in the hippocampus. The model would further potentiate the need for in vivo longitudinal studies to confirm the interlinked mechanism between OS, hippocampal GSH depletion, and pH increment in an AD patient brain.

Short Communication
Alison E. Fohner, Colleen M. Sitlani, Petra Buzkova, Margaret F. Doyle, Xiaojuan Liu, Joshua C. Bis , Annette Fitzpatrick, Susan R. Heckbert, Sally A. Huber, Lewis Kuller, William T. Longstreth, Matthew J. Feinstein, Matthew Freiberg, Nels C. Olson, Sudha Seshadri, Oscar Lopez, Michelle C. Odden, Russell P. Tracy, Bruce M. Psaty, Joseph A. Delaney, James S. Floyd
Association of Peripheral Lymphocyte Subsets with Cognitive Decline and Dementia: The Cardiovascular Health Study
Abstract: Inflammatory biomarkers in plasma are associated with dementia. Thus, we examined the association of 18 types of peripheral immune cells, measured as proportions of their immune cell type, with cross-sectional measures of cognitive function, change in cognitive function over seven years, prevalent dementia, and time to death from dementia in 1,928 participants of the Cardiovascular Health Study, with mean age 80 years and 62% female. We did not identify any associations after accounting for multiple comparisons, though we identified marginal associations of peripheral regulatory T cells with cognitive decline and dementia.

Short Communication
Wendy Wang, Rebecca F. Gottesman, Michelle L. Meyer, Timothy M. Hughes, Kevin J. Sullivan, Dean F. Wong, Kamakshi Lakshminarayan, Pamela L. Lutsey
Carotid Intima-Media Thickness and Amyloid-β Deposition: The ARIC-PET Study
Abstract: We assessed whether carotid intima-media thickness (cIMT) is prospectively associated with amyloid-β (Aβ). 332 nondemented Atherosclerosis Risk in Communities Study participants with carotid ultrasounds (1990-1992) and PET scans (2012-2014) were studied. Participants in the highest (versus lowest) cIMT tertile had 2.17 times the odds of elevated Aβ (95% CI: 1.15-4.11), after demographic and APOE ɛ4 adjustments. An interaction with APOE ɛ4 was observed (p=0.02). Greater cIMT was associated with elevated Aβ independent of vascular risk factors among those with ≥1 APOE ɛ4 allele, but not in noncarriers. In this cohort, higher cIMT was associated with Aβ deposition 22 years later, particularly among APOE ɛ4 carriers.

Short Communication
Hiroyuki Umegaki, Yusuke Suzuki, Hitoshi Komiya, Kazuhisa Watanabe, Masaaki Nagae, Yosuke Yamada
Impact of Sarcopenia on Decline in Quality of Life in Older People with Mild Cognitive Impairment
Abstract: Quality of life (QOL) was assessed using the EQ-5D twice in 1 year in 57 older community-dwelling people (age 79.1 ± 5.9 years) with mild cognitive impairment in a memory clinic. Screening for sarcopenia at the initial assessment revealed 40.1% of participants (23/57) were sarcopenic. QOL declined in 33.3% of participants (19/57) after around 1 year. Multiple logistic regression analysis showed that sarcopenia was associated with a decline in QOL around 1 year after initial assessment. Sarcopenia may be a risk factor for decline in QOL in older people with mild cognitive impairment.

Short Communication
Masataka Narukawa, Yuko Mori, Riko Nishida, Suzuka Takahashi, Takashi Saito, Takaomi C. Saido, Takumi Misaka
Expression of Olfactory-Related Genes in the Olfactory Epithelium of an Alzheimer’s Disease Mouse Model
Abstract: Using an amyloid precursor protein (App) gene knock-in (KI) mouse of Alzheimer’s disease (AD), we investigated the expression of olfactory-related genes in olfactory impairment caused by AD. We observed the change in olfactory behavior in the App-KI mice. There was no significant difference, however, in the mRNA expression levels of olfactory-related genes between the olfactory epithelia of wild-type (WT) and App-KI mice. Amyloid-β deposition was confirmed throughout the olfactory pathway in App-KI mice, but not in WT mice. These show that the change in olfactory behavior in the App-KI mice might cause by the impairment of the olfactory pathway.

Short Communication
Kyle M. Roddick, Emre Fertan, Heather M. Schellinck, Richard E. Brown
A Signal Detection Analysis of Olfactory Learning in 12-Month-Old 5xFAD Mice
Abstract:Although Alzheimer’s disease is most often studied in terms of memory impairments, olfactory dysfunction begins in the early stages. We tested olfactory learning, sensitivity, and response bias using signal detection methods in 12-month-old male and female 5xFAD mice and their wildtype controls in the operant olfactometer. Odor detection was not reduced in the 5xFAD mice, but learning was, which was worse in female 5xFAD mice than in males. Female mice were more conservative in their response strategy. Signal detection analysis allows us to discriminate between cognitive and sensory deficits of male and female mouse models of AD.

Priscilla M. Vásquez, Wassim Tarraf, Yuyi Li, Derek Jenkins, Jose Soria-Lopez, Zvinka Z. Zlatar, Maria J. Marquine, Ariana M. Stickel, Mayra L. Estrella, Linda C. Gallo, Richard B. Lipton, Carmen R. Isasi, Jianwei Cai, Dongling Zeng, Martha L. Daviglus, Neil Schneiderman, Hector M. González
Concordance Between Self-Reported Medical Diagnosis of Mild Cognitive Impairment/Dementia and Neurocognitive Function Among Middle-Aged and Older Hispanic/Latino Adults: Results from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) and the Study of Latinos-Investigation of Neurocognitive Aging (SOL-INCA)
Abstract: Background: Population-based studies typically rely on self-reported medical diagnosis (SRMD) of mild cognitive impairment (MCI)/dementia; however, links to objective neurocognitive function have not been established. Objective: Examine the association between SRMD of MCI/dementia and objective neurocognitive function among Hispanic/Latino adults. Methods: We conducted a case-control study using the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) baseline data and its ancillary SOL-Investigation of Neurocognitive Aging (SOL-INCA) at visit 2. Hispanic/Latino adults aged 50 years and older (n=593) were administered neurocognitive tests: the Six-Item Screener (SIS), Brief-Spanish English Verbal Learning Test (B-SVELT Sum), B-SVELT Recall, Word Fluency Test (WF), Digit Symbol Substitution Test (DSS), and Trail Making Test A and B. Individual and global neurocognitive function scores were used for analyses. Propensity matching techniques and survey generalized linear regression models were used to compare SRMD of MCI/dementia with demographic, psychological, and cardiovascular risk matched controls. Complex survey design methods were applied. Results: There were 121 cases of SRMD of MCI/dementia and 472 propensity matched controls. At baseline, compared to matched controls, cases showed no differences in neurocognitive function (p>0.05). At SOL-INCA visit 2, cases had poorer scores in global neurocognitive function (p<0.05), B-SEVLT Sum, B-SEVLT Recall, WF, DSS, and Trail A (p<0.01). Conclusion: Observed differences in neurocognitive test scores between SRMD of MCI/dementia cases and matched controls were present at visit 2, but not at baseline in middle-aged and older Hispanic/Latino adults. These findings present initial evidence of the potential utility of SRMD of MCI/dementia in epidemiologic studies, where obtaining confirmation of diagnosis may not be feasible.

Lian Duan, Xueshen Qian, Qin Wang, Lan Huang, Song Ge
Experimental Periodontitis Deteriorates Cognitive Function and Impairs Insulin Signaling in a Streptozotocin-Induced Alzheimer’s Disease Rat Model
Abstract: Background: With advancements in periodontal medicine, the relationship between periodontitis and systemic diseases has garnered increasing attention. Recently, emerging evidence has indicated that periodontitis may be involved in the pathogenesis of Alzheimer’s disease (AD). Objective: To assess the impact of experimental periodontitis on cognitive function deficits in a rat model of streptozotocin-induced AD and determine the mechanisms underlying these effects. Methods: Rats were randomly assigned to the control (C), experimental periodontitis (P), Alzheimer’s disease (AD), and experimental periodontitis with streptozotocin-induced AD (AD-P) groups. Experimental periodontitis was induced using ligation and coating with Porphyromonas gingivalis. In the AD-P group, AD was induced by intracerebroventricular injection of streptozotocin after 6 weeks of experimental periodontitis induction. Results: Compared with the group C rats, those in group P exhibited alveolar bone resorption, learning and memory function impairment, and decreased insulin sensitivity and insulin signaling-related protein expression. Glial cell activation and cognitive impairment in streptozotocin-induced groups with significantly increased phosphorylated tau levels were more pronounced relative to the C group. The number of neurons and insulin sensitivity and insulin signaling-related protein expression in group AD-P rats were lower than those in the AD alone group, while the expressions of glial fibrillary acidic protein, tau phosphorylation, interleukin-6, and cyclooxygenase-2 were significantly increased. Conclusion: Periodontitis may be a risk factor exacerbating cognitive deficits in an AD-like neurodegenerative context, possibly by impairing the insulin signaling pathway and stimulating gliosis and neuroinflammation.

Daisuke Asaoka, Jinzhong Xiao, Tsutomu Takeda, Naotake Yanagisawa, Takahiro Yamazaki, Yoichiro Matsubara, Hideki Sugiyama, Noemi Endo, Motoyuki Higa, Koji Kasanuki, Yosuke Ichimiya, Shigeo Koido, Kazuya Ohno, Francois Bernier, Noriko Katsumata, Akihito Nagahara, Heii Arai, Toshifumi Ohkusa, Nobuhiro Sato
Effect of Probiotic Bifidobacterium breve in Improving Cognitive Function and Preventing Brain Atrophy in Older Patients with Suspected Mild Cognitive Impairment: Results of a 24-Week Randomized, Double-Blind, Placebo-Controlled Trial
Abstract: Background: Probiotics have been reported to ameliorate cognitive impairment. Objective: We investigated the effect of the probiotic strain Bifidobacterium breve MCC1274 (A1) in enhancing cognition and preventing brain atrophy of older patients with mild cognitive impairment (MCI). Methods: In this RCT, 130 patients aged from 65 to 88 years old with suspected MCI received once daily either probiotic (B. breve MCC1274, 2 × 1010 CFU) or placebo for 24 weeks. Cognitive functions were assessed by ADAS-Jcog and MMSE tests. Participants underwent MRI to determine brain atrophy changes using Voxel-based Specific Regional Analysis System for Alzheimer's disease (VSRAD). Fecal samples were collected for the analysis of gut microbiota composition. Results: Analysis was performed on 115 participants as the full analysis set (probiotic 55, placebo 60). ADAS-Jcog subscale “orientation” was significantly improved compared to placebo at 24 weeks. MMSE subscales “orientation in time” and “writing” were significantly improved compared to placebo in the lower baseline MMSE (<25) subgroup at 24 weeks. VSRAD scores worsened in the placebo group; probiotic supplementation tended to suppress the progression, in particular among those subjects with progressed brain atrophy (VOI Z-score 1.0). There were no marked changes in the overall composition of the gut microbiota by the probiotic supplementation. Conclusion: Improvement of cognitive function was observed on some subscales scores only likely due to the lower sensitiveness of these tests for MCI subjects. Probiotics consumption for 24 weeks suppressed brain atrophy progression, suggesting that B. breve MCC1274 helps prevent cognitive impairment of MCI subjects.

Shannon M. Drouin, G. Peggy McFall, Olivier Potvin, Pierre Bellec, Mario Masellis, Simon Duchesne, Roger A. Dixon for the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Susan Resnick)
Data-Driven Analyses of Longitudinal Hippocampal Imaging Trajectories: Discrimination and Biomarker Prediction of Change Classes
Abstract: Background: Hippocampal atrophy is a well-known biomarker of neurodegeneration, such as that observed in Alzheimer’s disease (AD). Although distributions of hippocampal volume trajectories for asymptomatic individuals often reveal substantial heterogeneity, it is unclear whether interpretable trajectory classes can be objectively detected and used for prediction analyses. Objective: To detect and predict hippocampal trajectory classes in a computationally competitive context using established AD-related risk factors/biomarkers. Methods: We used biomarker/risk factor and longitudinal MRI data in asymptomatic adults from the AD Neuroimaging Initiative (n=351; Mean=75 years; 48.7% female). First, we applied latent class growth analyses to left (LHC) and right (RHC) hippocampal trajectory distributions to identify distinct classes. Second, using random forest analyses, we tested 38 multi-modal biomarkers/risk factors for their relative importance in discriminating the lower (potentially elevated atrophy risk) from the higher (potentially reduced risk) class. Results: For both LHC and RHC trajectory distribution analyses, we observed three distinct trajectory classes. Three biomarkers/risk factors predicted membership in LHC and RHC lower classes: male sex, higher education, and lower plasma Aβ1-42. Four additional factors selectively predicted membership in the lower LHC class: lower plasma tau and Aβ1-40, higher depressive symptomology, and lower body mass index. Conclusion: Data-driven analyses of LHC and RHC trajectories detected three classes underlying the heterogeneous distributions. Machine learning analyses determined three common and four unique biomarkers/risk factors discriminating the higher and lower LHC/RHC classes. Our sequential analytic approach produced evidence that the dynamics of preclinical hippocampal trajectories can be predicted by AD-related biomarkers/risk factors from multiple modalities.

Fangda Leng*, Zhenying Zhan*, Yunchuang Sun, Fang Liu, Paul Edison, Yongan Sun, Zhaoxia Wang, on behalf of Alzheimer’s Disease Neuroimaging Initiative *These authors contributed equally to this work.
Cerebrospinal Fluid sTREM2 Has Paradoxical Association with Brain Structural Damage Rate in Early- and Late-Stage Alzheimer’s Disease
Abstract: Background: Recently it has been proposed that microglial response has a stage-dependent effect on the progression of Alzheimer’s disease (AD). Cerebrospinal fluid (CSF) sTREM2 has emerged as a promising microglial activation marker. Objective: To test the stage-dependent role of microglia by studying the association between baseline sTREM2 and dynamic brain structural changes in AD and mild cognitive impairment (MCI) patients. Methods: 22 amyloid-β-positive (A+) and tau-positive (T+) AD and 24 A+T+ MCI patients were identified from the Alzheimer's Disease Neuroimaging Initiative. The patients had baseline CSF amyloid-β, phosphorylated-tau, and sTREM2, and were followed up for at least one year by T1-weighted and diffusion tensor imaging scans. Gray matter volumes and white matter microstructural integrity were evaluated. Linear mixed models were applied to analyze how baseline sTREM2 may influence the rate of brain structural changes while adjusting for the effects of age, APOE4 status, and the CSF core markers. Results: In A+T+AD patients, baseline CSF sTREM2 was associated with faster mean diffusivity increase in the bilateral posterior corona radiata and right superior longitudinal fasciculus. In A+T+ MCI patients, baseline CSF sTREM2 was associated slower gray matter volumetric loss in parahippocampal gyrus, left fusiform cortex, left middle temporal gyrus, and left lateral occipital cortex. Baseline CSF sTREM2 also had a protective effect against mean diffusivity increase in right inferior fronto-occipital fasciculus, left superior longitudinal fasciculus, left forceps minor, and left uncinate fasciculus. Conclusion: Microglial activation at early stage might have a protective effect against neurodegeneration, while at late stage it might facilitate AD. Future efforts on modulating microglial activation could be promising, given a carefully selected time window for intervention.

Mariana Fernandes, Agostino Chiaravalloti, Natalia Manfredi, Fabio Placidi, Marzia Nuccetelli, Francesca Izzi, Riccardo Camedda, Sergio Bernardini, Orazio Schillaci, Nicola Biagio Mercuri, Claudio Liguori
Nocturnal Hypoxia and Sleep Fragmentation May Drive Neurodegenerative Processes: The Compared Effects of Obstructive Sleep Apnea Syndrome and Periodic Limb Movement Disorder on Alzheimer’s Disease Biomarkers
Abstract: Background: Sleep disorders may cause dysregulation of cerebral glucose metabolism and synaptic functions, as well as alterations in cerebrospinal fluid (CSF) biomarker levels. Objective: This study aimed at measuring sleep, CSF Alzheimer’s disease (AD) biomarkers, and cerebral glucose consumption in patients with obstructive sleep apnea syndrome (OSAS) and patients with periodic limb movement disorder (PLMD), compared to controls. Methods: OSAS and PLMD patients underwent 18F-fluoro-2-deoxy-D-glucose positron emission tomography (18F-FDG PET), polysomnographic monitoring, and lumbar puncture to quantify CSF levels of amyloid-β42 (Aβ42), total tau, and phosphorylated tau. All patients were compared to controls, who were not affected by sleep or neurodegenerative disorders. Results: Twenty OSAS patients, 12 PLMD patients, and 15 controls were included. Sleep quality and sleep structure were altered in both OSAS and PLMD patients when compared to controls. OSAS and PLMD patients showed lower CSF Aβ42 levels than controls. OSAS patients showed a significant increase in glucose uptake in a wide cluster of temporal-frontal areas and cerebellum, as well as a reduced glucose consumption in temporal-parietal regions compared to controls. PLMD patients showed increased brain glucose consumption in the left parahippocampal gyrus and left caudate than controls. Conclusion: Sleep dysregulation and nocturnal hypoxia present in OSAS patients, more than sleep fragmentation in PLMD patients, were associated with the alteration in CSF and 18F-FDG PET AD biomarkers, namely reduction of CSF Aβ42 levels and cerebral glucose metabolism dysregulation mainly in temporal areas, thus highlighting the possible role of sleep disorders in driving neurodegenerative processes typical of AD pathology.

Yinghan Zhang*, Yazhuo Hu*, Zhitao Han, Yan Geng, Zheng Xia , Yongsheng Zhou , Zhenfu Wang, Yuanyuan Wang, Eryan Kong, Xiaoning Wang, Jianjun Jia, Honghong Zhang (Handling Associate Editor: Ling-Qiang Zhu) *These authors contributed equally to this work.
Cattle Encephalon Glycoside and Ignotin Ameliorate Palmitoylation of PSD-95 and Enhance Expression of Synaptic Proteins in the Frontal Cortex of a APPswe/PS1dE9 Mouse Model of Alzheimer’s Disease
Abstract: Background: Synaptic abnormalities in synaptic proteins are the initial hallmarks of Alzheimer’s disease (AD). The higher level of palmitoylation of synaptic proteins was closely associated with amyloid-β (Aβ) in AD. Cattle encephalon glycoside and ignotin (CEGI) have been shown to act as multitarget neurotrophic agents in APPswe/PS1dE9 (APP/PS1) transgenic AD mice. However, it is not clear whether CEGI can influence Aβ deposition or whether it does so by the regulation of protein palmitoylation and expression of synaptic proteins in transgenic AD mice. Objective: In this study, we investigated the roles of CEGI in modulating postsynaptic density protein 95 (PSD-95) palmitoylation, Aβ pathologies, and expression of synaptic-associated proteins in APP/PS1 mice. Methods: Five-month-old APP/PS1 mice were treated intraperitoneally with 6.6 mL/kg of CEGI for 6 weeks. At the end of the treatment period, APP/PS1 mice were subjected to Morris water maze to test their cognitive functions. Acyl-biotinyl exchange (ABE) for PSD-95 palmitoylation, immunofluorescent staining for expression of PSD-95, N-methyl-D-aspartic acid receptor subunit 2B (NR2B), and synaptotagmin 1 (SYT1) were assessed in mouse brain sections. Results: CEGI treatment in APP/PS1 mice significantly reduced Aβ deposition, relieved memory deficits, and decreased PSD-95 palmitoylation while markedly increasing the expression of PSD-95, NR2B, and SYT1 in the frontal cortex. There was a significant correlation between Aβ expression and PSD-95 palmitoylation in APP/PS1 mice. Conclusion: Our findings demonstrate that CEGI improved AD-like neuropathology, possibly by inhibiting PSD-95 palmitoylation, improving learning memory, and enhancing expression of synaptic-associated proteins, representing a potential therapy for AD treatment.

Lyubka Tancheva, Maria Lazarova, Lyudmila Velkova, Alexander Dolashki, Diamara Uzunova, Borislav Minchev, Polina Petkova-Kirova, Yozljam Hassanova, Petja Gavrilova, Krasimira Tasheva, Teodora Taseva, Yordan Hodzhev, Atanas G. Atanasov, Miroslava Stefanova, Albena Alexandrova, Elina Tzvetanova, Ventseslav Atanasov, Reni Kalfin, Pavlina Dolashka (Handling Associate Editor: Illana Gozes)
Beneficial Effects of Snail Helix aspersa Extract in an Experimental Model of Alzheimer’s Type Dementia
Abstract: Background: Alzheimer’s disease (AD) is a complex neurodegenerative disease with multifactorial etiology, unsatisfactory treatment, and a necessity for broad-spectrum active substances for cure. The mucus from Helix aspersa snail is a mixture of bioactive molecules with antimicrobial, anti-inflammatory, antioxidant, and anti-apoptotic effects. So far there are no data concerning the capacity of snail extract (SE) to affect neurodegenerative disorders. Objective: The effects of SE from Helix aspersa on learning and memory deficits in Alzheimer’s type dementia (ATD) induced by scopolamine (Sco) in male Wistar rats were examined and some mechanisms of action underlying these effects were evaluated. Methods: SE (0.5 mL/100 g) was applied orally through a food tube for 16 consecutive days: 5 days before and 11 days simultaneously with Sco (2 mg/kg, intraperitoneally). At the end of Sco treatment, using behavioral methods, we evaluated memory performance. Additionally, in cortex and hippocampus the acetylcholinesterase (AChE) activity, acetylcholine and monoamines (dopamine, noradrenaline, and serotonin) content, levels of main oxidative stress markers, and expression of brain-derived neurotrophic factor (BDNF) and cAMP response element-binding protein (CREB) were determined. Results: We demonstrated that, according to all behavioral tests used, SE significantly improved the cognitive deficits induced by Sco. Furthermore, SE possessed AChE inhibitory activity, moderate antioxidant properties and the ability to modulate monoamines content in two brain structures. Moreover, multiple SE applications not only restored the depressed by Sco expression of CREB and BDNF, but significantly upregulated it. Conclusion: Summarizing results, we conclude that complex mechanisms underlie the beneficial effects of SE on impaired memory in Alzheimer’s type dementia.

Starr Welty, Amantha Thathiah, Arthur Samuel Levine
DNA Damage Increases Secreted Aβ40 and Aβ42 in Neuronal Progenitor Cells: Relevance to Alzheimer’s Disease
Abstract: Background: Recent studies suggest a strong association between neuronal DNA damage, elevated levels of amyloid-β (Aβ), and regions of the brain that degenerate in Alzheimer’s disease (AD). Objective: To investigate the nature of this association, we tested the hypothesis that extensive DNA damage leads to an increase in Aβ40 and Aβ42 generation. Methods: We utilized an immortalized human neuronal progenitor cell line (NPCs), ReN VM GA2. NPCs or 20 day differentiated neurons were treated with hydrogen peroxide or etoposide and allowed to recover for designated times. Sandwich ELISA was used to assess secreted Aβ40 and Aβ42. Western blotting, immunostaining, and neutral comet assay were used to evaluate the DNA damage response and processes indicative of AD pathology. Results: We determined that global hydrogen peroxide damage results in increased cellular Aβ40 and Aβ42 secretion 24 h after treatment in ReN GA2 NPCs. Similarly, DNA double strand break (DSB)-specific etoposide damage leads to increased Aβ40 and Aβ42 secretion 2 h and 4 h after treatment in ReN GA2 NPCs. In contrast, etoposide damage does not increase Aβ40 and Aβ42 secretion in post-mitotic ReN GA2 neurons. Conclusion: These findings provide evidence that in our model, DNA damage is associated with an increase in Aβ secretion in neuronal progenitors, which may contribute to the early stages of neuronal pathology in AD.

Tushar K. Das*, Maria P. Blasco-Conesa*, Janelle Korf, Pedram Honarpisheh, Matthew R. Chapman, Bhanu P. Ganesh *These authors contributed equally to this work.
Bacterial Amyloid Curli Associated Gut Epithelial Neuroendocrine Activation Predominantly Observed in Alzheimer’s Disease Mice with Central Amyloid-β Pathology
Abstract: Background: Substantial evidence from recent research suggests an influential and underappreciated force in Alzheimer’s disease (AD) pathogenesis: the pathological signals originate from outside the brain. Pathogenic bacteria produce amyloid-like proteins “curli” that form biofilms and show functional similarities to human amyloid-β (Aβ). These proteins may contribute to neurological disease progression via signaling cascade from the gut to the brain. Objective: We propose that curli causes neuroendocrine activation from the gut to brain that promotes central Aβ pathology. Methods: PGP9.5 and TLR2 levels in response to curli in the lumen of Tg2576 AD mice were analyzed by immunohistochemical and qRT-PCR analysis. Western blot and human 3D in vitro enteroids culture systems were also used. 16S rRNA gene sequencing was used to investigate bacterial dysbiosis. Results: We found significant increase in bacterial-amyloid curli with elevated TLR2 at the mRNA level in the pre- and symptomatic Tg-AD gut compared to littermate WT controls. This data associates with increased gram-positive bacterial colonization in the ileum of the symptomatic AD mice. We found fundamental evidence for vagus nerve activation in response to bacterial curli. Neuroendocrine marker PGP9.5 was significantly elevated in the gut epithelium of symptomatic AD mice, and this was colocalized with increased TLR2 expression. Enteroids, 3D-human ileal mini-gut monolayer in vitro model system also revealed increase levels of TLR2 upon stimulation with purified bacterial curli fibrils. Conclusion: These findings reveal the importance of pathological changes within the gut-vagus-brain signaling in response to luminal bacterial amyloid that might play a vital role in central Aβ pathogenesis seen in the AD brain.

Lone Helboe, Nina Rosenqvist, Christiane Volbracht, Lars Ø. Pedersen, Jan T. Pedersen, Søren Christensen, Jan Egebjerg, Claus T. Christoffersen, Benny Bang-Andersen, Thomas G. Beach, Geidy E. Serrano, Jeppe Falsig (Handling Associate Editor: Colin Masters)
Highly Specific and Sensitive Target Binding by the Humanized pS396-Tau Antibody hC10.2 Across a Wide Spectrum of Alzheimer’s Disease and Primary Tauopathy Postmortem Brains
Abstract: Background: Deposits of hyperphosphorylated tau fibrils are hallmarks of a broad spectrum of tauopathies, including Alzheimer’s disease (AD). Objective: To investigate heterogeneity of tau pathology across brain extracts from a broad selection of different tauopathies and examine the binding properties of the humanized pS396-tau antibody hC10.2 and six other anti-tau antibodies. Methods: 76 individual tauopathy tissue samples were analyzed in a battery of assays: immunohistochemistry, ELISA, tau aggregation assay, western blot, [3H]PI-2620 and [3H]MK-6240 tau tracer binding, and aggregated seeding activity in RD_P301S HEK293T Biosensor cells. The efficiency of seven anti-tau antibodies to engage with pathological tau species was directly compared. Results: Our data indicate that a strong correlation existed between the tau tracer binding, amount of tau aggregates, pS396-tau phosphorylation, and seeding activity. The hC10.2 antibody, which has entered clinical development, effectively engaged with its epitope across all individual cases of mid-stage and late AD, and primary tauopathies. hC10.2 was superior compared to other phospho- and total tau antibodies to prevent seeded tau aggregation in the biosensor cells. hC10.2 effectively depleted hyperphosphorylated and aggregated tau species across all tauopathy samples proportionally to the amount of tau aggregates. In AD samples, hC10.2 bound to ghost tangles which represent extracellular pathological tau species. Conclusion: S396 hyperphosphorylation is a feature of the formation of seeding-competent tau across different tauopathies and it is present both in intra- and extracellular pathological tau. hC10.2 represents an excellent candidate for a hyperphosphorylation-selective therapeutic tau antibody for the treatment of AD and primary tauopathies.

Stevie Hendriks, Kirsten Peetoom, Huibert Tange, Marloes A. van Bokhoven, Wiesje M. van der Flier, Christian Bakker, Janne M. Papma, Raymond Koopmans, Frans Verhey, Sebastian Köhler, Marjolein de Vugt
Pre-Diagnostic Symptoms of Young-Onset Dementia in the General Practice up to Five Years Before Diagnosis
Abstract: Background: Young-onset dementia (YOD) has many underlying etiologies, leading to a large heterogeneity in first symptoms. This makes it difficult for general practitioners (GPs) to recognize YOD. Objective: Identify early symptoms that are more common in the pre-diagnostic phase of YOD. Methods: We performed a case-control study nested in a primary-care registry on 89 cases and 162 matched controls, where we compared symptoms of people with YOD up to 5 years before diagnosis to their matched control group without YOD. The variables included in this study were International Classification of Primary Care codes and symptoms extracted from written GP notes and categorized in groups. We used Generalized Equation Estimation to analyze symptom's time-trajectories and logistic regression and ROC-curves to analyze differences in number of symptom categories reported. Results: Cognitive symptoms were more common in people with YOD 5 years before diagnosis, affective symptoms 4 years before diagnosis, social symptoms 3 years, behavioral symptoms 2 years, and daily functioning disturbances 1 year before diagnosis. The ROC-curve suggested that reporting two or more symptom categories at the GP gave the best trade-off between sensitivity (85%) and specificity (77%), for the highest percentage of correctly diagnosed persons. Conclusion: This study showed people with YOD present differently than people without YOD. However, it may still be difficult for GPs to use these symptom categories to distinguish people with YOD, since the symptoms also occur in people with other diseases. A combination of reported symptom categories increases the probability of an underlying cause of YOD.

Su Fen Ang, Serena Low, Tze Pin Ng, Clara S.H. Tan, Keven Ang, Ziliang Lim, Wern Ee Tang, Tavintharan Subramaniam, Chee Fang Sum, Su Chi Lim (Handling Associate Editor: Nagaendran Kandiah)
Ethnic-Specific Type 2 Diabetes Risk Factor PAX4 R192H Is Associated with Attention-Specific Cognitive Impairment in Chinese with Type 2 Diabetes
Abstract: Background: Type 2 diabetes mellitus (T2DM) has been shown to increase the risks of cognitive decline and dementia. Paired box gene 4 (PAX4), a transcription factor for beta cell development and function, has recently been implicated in pathways intersecting Alzheimer’s disease and T2DM. Objective: In this report, we evaluated the association of the ethnic-specific PAX4 R192H variant, a T2DM risk factor for East Asians which contributes to earlier diabetes onset, and cognitive function of Chinese T2DM patients. Methods: 590 Chinese patients aged 45-86 from the SMART2D study were genotyped for PAX4 R192H variation using Illumina OmniExpress-24 Array. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) which had been validated in the Singapore population was administered to assess five cognitive domains: immediate memory, visuospatial/constructional, language, attention, and delayed memory. Multiple linear regression was used to assess the association of the R192H risk allele and cognitive domains. Results: Patients with two PAX4 R192H risk alleles showed significantly lower attention index score (β=-8.46, 95% CI [-13.71, -3.21], p=0.002) than patients with wild-type alleles after adjusting for age, gender, diabetes onset age, HbA1c, body-mass index, renal function, lipid profiles, systolic blood pressure, metformin usage, smoking history, education level, Geriatric Depression Scale score, and presence of APOE ε4 allele. Conclusion: Ethnic-specific R192H variation in PAX4 is associated with attention-specific cognitive impairment in Chinese with T2DM. Pending further validation studies, determining PAX4 R192H genotype may be helpful for early risk assessment of early-onset T2DM and cognitive impairment to improve diabetes care.

Fen Wu*, Samuel Davey*, Tess V. Clendenen, Karen L. Koenig, Yelena Afanasyeva, Boyan Zhou, Sukhleen Bedi, Huilin Li, Anne Zeleniuch-Jacquotte, Yu Chen *These authors contributed equally to this work.
Gut Microbiota and Subjective Memory Complaints in Older Women
Abstract: Background: Epidemiological studies that investigate alterations in gut microbial composition associated with cognitive dysfunction are limited. Objective: To examine the association between the gut microbiota and subjective memory complaints (SMCs), a self-reported, validated indicator of cognitive dysfunction. Methods: In this cross-sectional study of 95 older women selected from the New York University Women’s Health Study (NYUWHS), we characterized the gut microbial composition using 16S rRNA gene sequencing. We estimated odds ratio (OR) from beta regression which approximates the ratio of mean relative abundances of individual bacterial taxon from phylum to genus levels by binary (2+ versus < 2) and continuous SMCs. Results: Women reporting 2 or more SMCs had higher relative abundances of genus Holdemania and family Desulfovibrionaceae compared with those reporting one or no complaint. Compared with women with < 2 SMCs, the relative abundances of Holdemania and family Desulfovibrionaceae were 2.09 times (OR: 2.09, 95% confidence interval [CI]: 1.38-3.17) and 2.10 times (OR: 2.10, 95% CI: 1.43-3.09) higher in women with 2+ SMCs, respectively (false discovery rate (FDR)-adjusted p = 0.038 and 0.010, respectively). A dose-response association was observed for genus Sutterella and family Desulfovibrionaceae. Every one-unit increase in SMCs was associated with 25% and 27% higher relative abundances of Sutterella (OR: 1.25; 95% CI: 1.11-1.40) and Desulfovibrionaceae (OR: 1.27; 95% CI: 1.13-1.42), respectively (FDR-adjusted p = 0.018 and 0.006, respectively). Conclusion: Our findings support an association between alterations in the gut bacterial composition and cognitive dysfunction.

Yajun Liang*, Ya Gao*, Rui Wang, Giulia Grande, Roberto Monastero, Yanhong Dong, Xin Jiang, Peiyuan Lv, Chengxuan Qiu *These authors contributed equally to this work.
Migraine, Cognitive Decline, and Dementia in Older Adults: A Population-Based Study
Abstract: Background: The potential impact of migraine on cognitive aging among older adults remains controversial. Objective: To examine the relationship of migraine and subtypes with cognitive decline and dementia in an older Swedish population. Methods: This population-based study included 3,069 participants (age≥60 years) from the Swedish National study on Aging and Care in Kungsholmen, Stockholm. Baseline examination was conducted in 2001-2004, and participants were followed every 3 or 6 years until 2013-2016. Data were collected through face-to-face interviews, clinical examinations, laboratory tests, and linkage with registers. Global cognitive function was measured with the Mini-Mental State Examination (MMSE). Dementia was diagnosed according to the DSM-IV criteria. Migraine and subtypes were defined following the international classification system. Data were analyzed using logistic regression, Cox regression, and linear mixed-effects models. Results: At baseline, 305 participants were defined with non-migraine headache and 352 with migraine. The cross-sectional analysis showed that the multivariable-adjusted odds ratio (95% confidence interval) of prevalent dementia was 0.49 (0.20–1.21) for migraine and 0.66 (0.26–1.66) for migraine without aura. The longitudinal analysis showed that the multivariable-adjusted hazard ratios of incident dementia associated with migraine and subtypes ranged 0.68-0.89 (p>0.05). Furthermore, migraine and subtypes were not significantly associated with either baseline MMSE score or MMSE changes during follow-ups (p>0.05). The nonsignificant associations did not vary substantially by age, APOE ε4 allele, cerebrovascular disease, and antimigraine treatment (p for interactions>0.05). Conclusion: This study shows no evidence supporting the associations of migraine and its subtypes with cognitive decline and dementia among older adults.

Xingxing Zhang, Qing Guan, Yingjia Li, Jianfeng Zhang, Wanlin Zhu, Yuejia Luo, Haobo Zhang, Alzheimer’s Disease Neuroimaging Initiative
Aberrant Cross-Tissue Functional Connectivity in Alzheimer’s Disease: Static, Dynamic, and Directional Properties
Abstract: Background: BOLD signals in the gray matter (GM) and white matter (WM) are tightly coupled. However, our understanding of the cross-tissue functional network in Alzheimer's disease (AD) is limited. Objective: We investigated the changes of cross-tissue functional connectivity (FC) metrics for the GM regions susceptible to AD damage. Methods: For each GM region in the default mode (DMN) and limbic networks, we obtained its low-order static FC with any WM region, and the high-order static FC between any two WM regions based on their FC pattern similarity with multiple GM regions. The dynamic and directional properties of cross-tissue FC were then acquired, specifically for the regional pairs whose low- or high-order static FCs showed significant differences between AD and normal control (NC). Moreover, these cross-tissue FC metrics were correlated with voxel-based GM volumes and MMSE in all participants. Results: Compared to NC, AD patients showed decreased low-order static FCs between the intra-hemispheric GM-WM pairs (right ITG-right fornix; left MoFG-left posterior corona radiata), and increased low-order static, dynamic, and directional FCs between the inter-hemispheric GM-WM pairs (right MTG-left superior/posterior corona radiata). The high-order static and directional FCs between the left cingulate bundle-left tapetum were increased in AD, based on their FCs with the GMs of DMN. Those decreased and increased cross-tissue FC metrics in AD had opposite correlations with memory-related GM volumes and MMSE (positive for the decreased and negative for the increased). Conclusion: Cross-tissue FC metrics showed opposite changes in AD, possibly as useful neuroimaging biomarkers to reflect neurodegenerative and compensatory mechanisms.

Israel Contador, Patricia Alzola, Félix Bermejo-Pareja, Teodoro del Ser, Sara Llamas-Velasco, Bernardino Fernández-Calvo, Julián Benito-León
Education and Literacy as Risk Factors of Dementia after Stroke and Transient Ischemic Attack: NEDICES Study
Abstract: Background: A protective effect of education on cognitive decline after stroke has been claimed, but evidence from prospective population-based cohorts is very limited. The differential role of literacy and education on dementia after stroke remains unexplored. Objective: This research addresses the role of education and literacy in dementia incidence after stroke and transient ischemic attack (TIA). Methods: 131 participants with stroke or TIA were identified within the population-based NEDICES study (N = 5,278 persons). Participants were fully assessed at baseline (1994–1995) and incident dementia diagnosis was made by expert neurologists (DSM-IV criteria) after a mean follow-up of 3.4 years. Adjusted Cox regression analyses were applied to test the association between education, literacy, and dementia risk. Results: Within the 131 subjects with stroke or TIA, 19 (14%) developed dementia at follow-up. The Cox’s regression model (age and sex adjusted) showed that low education (HR = 3.48, 95% CI = 1.28, 9.42, p = 0.014) and literacy (HR = 3.16, 95% CI = 1.08, 9.22, p = 0.035) were significantly associated with a higher dementia risk. Low education was also associated with dementia when main confounders (i.e., cognitive/functional performance) were considered in the Cox’s model. However, after including stroke recurrence, only low/null literacy (versus education) remained as significant predictor of dementia. Finally, low/null literacy showed an effect over-and-above education on dementia risk when both factors were introduced in the adjusted Cox’s regression. Conclusion: These findings underline the importance of literacy to estimate cognitive decline after stroke in low-educated populations.

Michael K. Yeung, Tsz-lok Lee, Agnes S. Chan
Prefrontal Activation During Effortful Processing Differentiates Memory Abilities in Adults with Memory Complaints
Abstract: Background: Identifying individuals at increased risks for developing Alzheimer’s disease (AD) is crucial for early intervention. Memory complaints are associated with brain abnormalities characteristic of AD in cognitively normal older people. However, the utility of memory complaints for predicting mild cognitive impairment (MCI) or AD onset remains controversial, likely due to the heterogeneous nature of this construct. Objective: We investigated whether prefrontal oxygenation changes measured by functional near-infrared spectroscopy (fNIRS) during an arduous cognitive task, previously shown to be associated with the AD syndrome, could differentiate memory abilities among individuals with memory complaints. Episodic memory performance was adopted as a proxy for MCI/AD risks since it has been shown to predict AD progression across stages. Methods: Thirty-six adults self-reporting memory complaints in the absence of memory impairment completed a verbal list learning test and underwent a digit n-back paradigm with an easy (0-back) and a difficult (2-back) condition. K-means clustering was applied to empirically derive memory complaint subgroups based on fNIRS-based prefrontal oxygenation changes during the effortful 2-back task. Results: Cluster analysis revealed two subgroups characterized by high (n = 12) and low (n = 24) bilateral prefrontal activation during the 2-back but not a 0-back task. The low activation group was significantly less accurate across the n-back task and recalled significantly fewer words on the verbal memory test compared to the high activation group. Conclusion: fNIRS may have the potential to differentiate verbal memory abilities in individuals with self-reported memory complaints.

Katharina Wittfeld*, Mekala R. Raman*, Sarah C. Conner, Asra Aslam, Alexander Teumer, Matthias Nauck, Norbert Hosten, Mohamad Habes, Charles DeCarli, Ramachandran S. Vasan, Alexa S. Beiser, Jayandra J. Himali, Sudha Seshadri, Hans J. Grabe, Claudia L. Satizabal *These authors contributed equally to the manuscript.
Insulin-Like Growth Factor, Inflammation, and MRI Markers of Alzheimer’s Disease in Predominantly Middle-Aged Adults
Abstract: Background: Insulin-like growth factor 1 (IGF-1) signaling has been implicated in Alzheimer’s disease pathogenesis, and further evidence suggests inflammation can be a moderator of this association. However, most research to date has been conducted on older adults. Objective: To investigate the association of serum IGF-1 and IGF binding protein 3 (IGFBP-3) concentrations with MRI markers of Alzheimer’s disease in predominantly middle-aged adults, and further assess moderation by chronic inflammation. Methods: We included participants from the Framingham Heart Study (n=1,852, mean age 46±8, 46% men) and the Study of Health in Pomerania (n=674, mean age 50±13, 42% men) with available serum IGF-1, IFGBP-3, as well as brain MRI. IGF-1 and IFGBP-3 were related to MRI outcomes (i.e., total brain, cortical gray matter, white matter, white matter hyperintensities (WMH), and hippocampal volumes) using multivariable regression models adjusting for potential confounders. Subgroup analyses by C-reactive protein (CRP) concentrations were also performed. Cohort-specific summary statistics were meta-analyzed using random-effects models and corrected for multiple comparisons. Results: Meta-analysis results revealed that higher IGF-1 concentrations were associated with lower WMH (estimate [β] [95% CI], -0.05 [-0.09, -0.02], p=0.006) and larger hippocampal volumes (0.07 [0.02, 0.12], p=0.01), independent of vascular risk factors. These associations occurred predominantly in individuals with CRP concentrations < 75th percentile. We did not observe associations between IGFBP-3 and MRI outcomes. Conclusion: Our findings suggest that IGF-1-related signaling may be implicated in brain health as early as midlife.

Jenna Katherine Blujus, Laura Elizabeth Korthauer, Elizabeth Awe, Marijam Frahmand, Ira Driscoll
BDNF and KIBRA Polymorphisms Are Related to Altered Resting State Network Connectivity in Middle Age
Abstract: Background: Disease-modifying treatments for Alzheimer’s disease (AD) may be more successful if interventions occur early, prior to significant neurodegeneration and subsequent to the onset of clinical symptoms, potentially during middle age. Polymorphisms within BDNF, COMT, and KIBRA have been implicated in AD and relate to episodic memory and executive functioning, two domains that decline early in AD. Objective: The purpose of the current study was to use an endophenotype approach to examine in healthy, non-demented middle-aged adults the association between polymorphisms in BDNF, COMT, and KIBRA and functional connectivity within networks related to episodic memory and executive function (i.e., default mode network (DMN), executive control network (ECN), and frontoparietal network (FPN)). Methods: Resting state networks were identified using independent component analysis and spatial maps with associated time courses were extracted using a dual regression approach. Results: Functional connectivity within the DMN was associated with polymorphisms in BDNF (rs11030096, rs1491850) and KIBRA (rs1030182, rs6555791, rs6555802) (ps < 0.05), ECN connectivity was associated with polymorphisms in KIBRA (rs10475878, rs6555791) (ps < 0.05), and FPN connectivity was associated with KIBRA rs6555791 (p < 0.05). There were no COMT-related differences in functional connectivity of any of the three networks investigated (ps > 0.05). Conclusion: Our study demonstrates that in middle age, polymorphisms in BDNF and KIBRA are associated with altered functional connectivity in networks that are affected early in AD. Future preclinical work should consider these polymorphisms to further elucidate their role in pathological aging and to aid in the identification of biomarkers.

Mikkel Pejstrup Agger*, Marcus Schultz Carstensen*, Mark Alexander Henney, Luna Skytte Hansen, Anders Ohlhues Baandrup, Mai Nguyen, Paul Michael Petersen, Kristoffer Hougaard Madsen, Troels Wesenberg Kjær *These authors contributed equally to this work.
Novel Invisible Spectral Flicker Induces 40 Hz Neural Entrainment with Similar Spatial Distribution as 40 Hz Stroboscopic Light
Abstract: Background: Exposure to 40 Hz stroboscopic light, for one hour a day, has previously been published as a potential treatment option for Alzheimer’s disease in animal models. However, exposure for an hour a day to 40 Hz stroboscopic light can be strenuous and examining other types of 40 Hz inducing stimuli is paramount if chronic treatment is wanted. Objective: A core assumption behind ensuring a therapeutic outcome is that the visual stimuli can induce 40 Hz gamma entrainment. Here, we examine whether a specific visual stimulus, 40 Hz invisible spectral flicker (ISF), can induce gamma entrainment and how it differs from both continuous light (CON) and 40 Hz stroboscopic light (STROBE). Methods: The study included non-simultaneous EEG-fMRI neuroimaging of 13 young healthy volunteers during light exposure. Each light condition (i.e., CON, ISF, or STROBE) was active for 30 seconds followed immediately by the next. Results: Entrainment of 40 Hz neural activity were significantly higher signal-to-noise ratio during exposure to ISF (mean: 3.03, 95% CI 2.07 to 3.99) and STROBE (mean: 12.04, 95% CI 10.18 to 13.87) compared to CON. Additionally STROBE had a higher entrainment than ISF (mean: 9.01, 95 % CI 7.16 to 12.14). Conclusion: This study presents a novel method of 40 Hz entrainment using ISF. This enables the possibility of future randomized placebo-controlled clinical trials with acceptable double blinding due to the essentially imperceivable flicker, which is expected to substantially reduce discomfort compared to interventions with stroboscopic flicker.

Katrin Wolfova, Byron Creese, Dag Aarsland, Zahinoor Ismail, Anne Corbett, Clive Ballard, Adam Hampshire, Pavla Cermakova (Handling Associate Editor: Michelle Mielke)
Gender/Sex Differences in the Association of Mild Behavioral Impairment with Cognitive Aging
Abstract: Background: While the gender/sex differences in neuropsychiatric symptoms in dementia population are well described, gender/sex differences in mild behavioral impairment (MBI) in dementia-free populations and the relationship to cognitive performance and to subsequent cognitive decline have not been studied. Objective: We aimed to explore gender/sex differences in the association of MBI with the level of cognitive performance and its rate of decline in a dementia-free cohort. Methods: We studied 8,181 older adults enrolled in the online PROTECT UK Study. MBI was assessed using the MBI Checklist and cognition was measured by digit span, paired associate learning, spatial working memory, and verbal reasoning. Statistical analysis was conducted using linear regression models and linear mixed-effects models. Results: Out of 8,181 individuals (median age 63 years, 73% females), 11% of females and 14% of males had MBI syndrome. Females exhibited less often symptoms of decreased motivation (45% versus 36% in males), impulse dyscontrol (40% versus 44% in males; p=0.001) and social inappropriateness (12% versus 15%; p<0.001), while they showed more often symptoms of emotional dysregulation (45% versus 36%; p<0.001). The associations of MBI domains with some measures of cognitive performance and decline were stronger in males than females, with the exception of the association of emotional dysregulation with the rate of cognitive decline in verbal reasoning, which was present exclusively in females. Conclusion: MBI may influence cognition to a greater extent in males than in females. We propose that predictors and biomarkers of dementia should consider gender/sex as an effect modifier.

Kaixia Zhang*, Xiaoying Ma*, Rui Zhang, Zanchao Liu, Lei Jiang, Yushi Qin, Di Zhang, Pei Tian, ZhaoYu Gao, Nan Zhang, Zhongli Shi, Shunjiang Xu *These authors contributed equally to this work.
Crosstalk Between Gut Microflora and Vitamin D Receptor SNPs Are Associated with the Risk of Amnestic Mild Cognitive Impairment in a Chinese Elderly Population
Abstract: Background: The interactions between environmental factors and genetic variants have been implicated in the pathogenesis of Alzheimer’s disease (AD). The altered gut microbiota (GM) and vitamin D deficiency are closely associated with the higher risk of AD. Objective: This study was performed to evaluate whether the crosstalk between GM and single nucleotide polymorphisms (SNPs) of vitamin D receptor (VDR) or vitamin D binding protein (VDBP) have a link with the risk of amnestic mild cognitive impairment (aMCI) in the Chinese elderly population. Methods: A total of 171 aMCI patients and 261 cognitive normal controls (NC) were enrolled in this study. Six tag SNPs of VDR and VDBP were genotyped by PCR-RFLP. The serum levels of vitamin D, Aβ1-42, and p-tau (181P) were determined by using of ELISA kits. The alterations in the GM were analyzed by full-length 16S ribosomal RNA (rRNA) gene sequencing. Results: The frequencies of AG genotype and A allele of VDR rs1544410 in aMCI group were significantly higher than that in NC group (genotype: p = 0.002, allele: p = 0.003). Patients with aMCI showed an abnormal GM composition compared with NC group. Interestingly, significant differences in GM composition were found between aMCI and NC group among individuals with AG genotype, as well as between individuals with AG and GG genotype of VDR rs1544410 among patients with aMCI. Conclusion: These results implicated that the crosstalk between gut microflora and vitamin D receptor variants are associated with the risk of aMCI in Chinese elderly population.

Yuan Cheng*, Jie-Ming Jian*, Chen-Yang He, Jun-Rong Ren, Man-Yu Xu, Wang-Sheng Jin, Cheng-Rong Tan, Gui-Hua Zeng, Ying-Ying Shen, Dong-Wan Chen, Hui-Yun Li, Xu Yi, Yuan Zhang, Fan Zeng, Yan-Jiang Wang (Handling Associate Editor: Jin-Tai Yu) *These authors contributed equally to this work.
The Correlations of Plasma Liver-Type Fatty Acid-Binding Protein with Amyloid-β and Tau Levels in Patients with Alzheimer’s Disease
Abstract: Background: The dysregulation of lipid metabolism plays an important role in the pathogenesis of Alzheimer’s disease (AD). Liver-type fatty acid-binding protein (L-FABP, also known as FABP1) is critical for fatty acid transport and may be involved in AD. Objective: To investigate whether the FABP1 level is altered in patients with AD, and its associations with levels of amyloid-β (Aβ) and tau in the plasma and cerebrospinal fluid (CSF). Methods: A cross-sectional study was conducted in a Chinese cohort consisting of 39 cognitively normal controls and 47 patients with AD. The levels of FABP1 in plasma, and Aβ and tau in CSF, were measured by enzyme-linked immunosorbent assay (ELISA). A single-molecule array (SIMOA) was used to detect plasma Aβ levels. Results: The level of plasma FABP1 was significantly elevated in the AD group (p = 0.0109). Further analysis showed a positive correlation of FABP1 with CSF total tau (t-tau) and phosphorylated tau (p-tau) levels. Besides, plasma FABP1/Aβ42 (AUC = 0.6794, p = 0.0071) and FABP1/t-tau (AUC = 0.7168, p = 0.0011) showed fair diagnostic efficacy for AD. When combined with other common AD biomarkers including plasma Aβ42, Aβ40, and t-tau, both FABP1/Aβ42 and FABP1/t-tau showed better diagnostic efficacy than using these biomarkers alone. Among all AUC analyses, the combination of plasma FABP1/t-tau and Aβ42 had the highest diagnostic value (AUC = 0.8075, p < 0.0001). Conclusion: These findings indicate that FABP1 may play a role in AD pathogenesis and be worthy of further investigation in the future.