Protein Expression of Alzheimer's disease‐ and Reduced Hippocampal Volume‐ Risk Loci in Human Hippocampus

AbstractThe aim of this study was to explore the association between genetically predicted circulating levels of immunity and inflammation, and the risk of Alzheimer’s disease (AD) and hippocampal volume, by conducting a two-sample Mendelian Randomization Study. We identified 12 markers of immune cells and derived ratios (platelet count, eosinophil count, neutrophil count, basophil count, monocyte count, lymphocyte count, platelet-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, CD4 count, CD8 count, CD4-to-CD8 ratio, and CD56) and 5 signaling molecules (IL-6, fibrinogen, CRP, and Lp-PLA2 activity and mass) as primary exposures of interest. Other genetically available immune biomarkers with a weaker a priori link to AD were considered secondary exposures. Associations with AD were evaluated in The International Genomics of Alzheimer’s Project (IGAP) GWAS dataset (21,982 cases; 41,944 controls of European ancestry). For hippocampal volume, we extracted data from a GWAS meta-analysis on 33,536 participants of European ancestry. None of the primary or secondary exposures showed statistically significant associations with AD or with hippocampal volume following P-value correction for multiple comparisons using false discovery rate < 5% (Q-value < 0.05). CD4 count showed the strongest suggestive association with AD (odds ratio 1.32, P < 0.01, Q > 0.05). There was evidence for heterogeneity in the MR inverse variance-weighted meta-analyses as measured by Cochran Q, and weighted median and weighted mode for multiple exposures. Further cluster analyses did not reveal clusters of variants that could influence the risk factor in distinct ways. This study suggests that genetically predicted circulating biomarkers of immunity and inflammation are not associated with AD risk or hippocampal volume. Future studies should assess competing risk, explore in more depth the role of adaptive immunity in AD, in particular T cells and the CD4 subtype, and confirm these findings in other ethnicities.

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Gene therapy-mediated enhancement of protective protein expression for the treatment of Alzheimer’s disease

Brain Research ◽

10.1016/j.brainres.2020.147264 ◽

2021 ◽

pp. 147264

Author(s):

Lauren V. Owens ◽

Alexandre Benedetto ◽

Neil Dawson ◽

Christopher J. Gaffney ◽

Edward T. Parkin

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Gene Therapy ◽

Protein Expression

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Elevated basal cortisol level predicts lower hippocampal volume and cognitive decline in Alzheimer’s disease

Journal of Clinical Neuroscience ◽

10.1016/j.jocn.2008.12.026 ◽

2009 ◽

Vol 16 (10) ◽

pp. 1283-1286 ◽

Cited By ~ 73

Author(s):

Chi-Wei Huang ◽

Chun-Chung Lui ◽

Weng-Neng Chang ◽

Cheng-Hsien Lu ◽

Ya-Ling Wang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Decline ◽

Cortisol Level ◽

Hippocampal Volume ◽

Basal Cortisol ◽

Basal Cortisol Level

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Network-based analysis of genetic variants associated with hippocampal volume in Alzheimer’s disease: a study of ADNI cohorts

BioData Mining ◽

10.1186/s13040-016-0082-8 ◽

2016 ◽

Vol 9 (1) ◽

Cited By ~ 17

Author(s):

Ailin Song ◽

◽

Jingwen Yan ◽

Sungeun Kim ◽

Shannon Leigh Risacher ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Genetic Variants ◽

Hippocampal Volume

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The histological validation of post mortem magnetic resonance imaging-determined hippocampal volume in Alzheimer's disease

Neuroscience ◽

10.1016/s0306-4522(99)00476-5 ◽

1999 ◽

Vol 95 (3) ◽

pp. 721-725 ◽

Cited By ~ 238

Author(s):

M. Bobinski ◽

M.J. de Leon ◽

J. Wegiel ◽

S. DeSanti ◽

A. Convit ◽

...

Keyword(s):

Magnetic Resonance Imaging ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Magnetic Resonance ◽

Hippocampal Volume ◽

Post Mortem ◽

Resonance Imaging ◽

Histological Validation

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High field magnetic resonance microscopy of the human hippocampus in Alzheimer's disease: Quantitative imaging and correlation with iron

NeuroImage ◽

10.1016/j.neuroimage.2011.08.019 ◽

2012 ◽

Vol 59 (2) ◽

pp. 1249-1260 ◽

Cited By ~ 47

Author(s):

Vijay Antharam ◽

Joanna F. Collingwood ◽

John-Paul Bullivant ◽

Mark R. Davidson ◽

Saurav Chandra ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Magnetic Resonance ◽

High Field ◽

Quantitative Imaging ◽

Magnetic Resonance Microscopy ◽

Human Hippocampus

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Herpes simplex virus, early neuroimaging markers and incidence of Alzheimer’s disease

Translational Psychiatry ◽

10.1038/s41398-021-01532-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Morgane Linard ◽

Marion Baillet ◽

Luc Letenneur ◽

Isabelle Garrigue ◽

Gwenaëlle Catheline ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Herpes Simplex Virus ◽

Herpes Simplex ◽

Diffusion Tensor ◽

Hippocampal Volume ◽

Potential Interaction ◽

Increased Risk ◽

Simplex Virus ◽

Igg Level

AbstractWhile previous studies suggest the implication of herpes simplex virus (HSV) in the onset of Alzheimer’s disease (AD), no study has investigated its association with early neuroimaging markers of AD. In the Three-City and the AMI cohorts, the associations between HSV infection and (i) hippocampal volume (n = 349), (ii) white matter alterations in the parahippocampal cingulum and fornix using diffusion tensor imaging (n = 260), and (iii) incidence of AD (n = 1599) were assessed according to APOE4 status. Regardless of APOE4 status, infected subjects presented (i) significantly more microstructural alterations of the parahippocampal cingulum and fornix, (ii) lower hippocampal volumes only when their anti-HSV IgG level was in the highest tercile—reflecting possibly more frequent reactivations of the virus (p = 0.03 for subjects with a high anti-HSV IgG level while there was no association for all infected subjects, p = 0.19), and (iii) had no increased risk of developing AD. Nevertheless, among APOE4 carriers, infected subjects presented lower hippocampal volumes, although not significant (p = 0.09), and a two or three times higher risk of developing AD (adjusted Hazard ratio (aHR) = 2.72 [1.07–6.91] p = 0.04 for infected subjects and aHR = 3.87 [1.45–10.28] p = 0.007 for infected subjects with an anti-HSV IgG level in the highest tercile) while no association was found among APOE4 noncarriers. Our findings support an association between HSV infection and AD and a potential interaction between HSV status and APOE4. This reinforces the need to further investigate the infectious hypothesis of AD, especially the associated susceptibility factors and the possibility of preventive treatments.

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Identification of a simple and novel cut-point based CSF and MRI signature for predicting Alzheimer’s disease progression that reinforces the 2018 NIA-AA research framework

10.1101/443325 ◽

2018 ◽

Cited By ~ 1

Author(s):

Priya Devanarayan ◽

Viswanath Devanarayan ◽

Daniel A. Llano ◽

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Multiple Reaction Monitoring ◽

Pharmaceutical Research ◽

Normal Subjects ◽

Hippocampal Volume ◽

National Institutes Of Health ◽

Decision Threshold ◽

Research Framework ◽

The University

AbstractThe 2018 NIA-AA research framework proposes a classification system with beta-Amyloid deposition, pathologic Tau, and neurodegeneration (ATN) for the diagnosis and staging of Alzheimer’s Disease (AD). Data from the ADNI (AD neuroimaging initiative) database can be utilized to identify diagnostic signatures for predicting AD progression, and to determine the utility of this NIA-AA research framework. Profiles of 320 peptides from baseline cerebrospinal fluid (CSF) samples of 287 normal, mild cognitive impairment (MCI) and AD subjects followed over a 3-10 year period were measured via multiple reaction monitoring (MRM) mass spectrometry. CSF Aβ42, total-Tau (tTau), phosphorylated-Tau (pTau-181) and hippocampal volume were also measured. From these candidate markers, optimal diagnostic signatures with decision thresholds to separate AD and normal subjects were first identified via unbiased regression and tree-based algorithms. The best performing signature determined via cross-validation was then tested in an independent group of MCI subjects to predict future progression. This multivariate analysis yielded a simple diagnostic signature comprising CSF pTau-181 to Aβ42 ratio, MRI hippocampal volume and a novel PTPRN peptide, with a decision threshold on each marker. When applied to a separate MCI group at baseline, subjects meeting this signature criteria experience 4.3-fold faster progression to AD compared to a 2.2-fold faster progression using only conventional markers. This novel 4-marker signature represents an advance over the current diagnostics based on widely used marker, and is much easier to use in practice than recently published complex signatures. In addition, this signature reinforces the ATN construct from the 2018 NIA-AA research framework.DisclosuresViswanath Devanarayan is an employee of Charles River Laboratories, and as such owns equity in, receives salary and other compensation from Charles River Laboratories.Data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.;Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California.

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