Volume 26, Number 4, October 2011

Pages 593-605
Review
Limbikani J Kanyenda, Giuseppe Verdile, Sherif Boulos, Sudarsan Krishnaswamy, Kevin Taddei, Bruno P Meloni, Frank L Mastaglia, Ralph N. Martins
The Dynamics of CD147 in Alzheimer’s Disease Development and Pathology
Abstract: CD147, also known as basigin, EMMPRIN, neurothelin, TCSF, M6, HT7, OX47, or gp42, is a transmembrane glycoprotein of the immunoglobulin super-family. It is expressed in many neuronal and non-neuronal tissues including the hippocampus, pre-frontal cortex thyroid, heart, early erythroid, amygdala, and placenta. This protein is involved in various cellular and biological functions, such as lymphocyte migration and maturation, tissue repair cancer progression, T and B lymphocyte activation, and induction of extracellular matrix metalloproteinase. The CD147 protein interacts with other proteins such as cyclophilin A (CyPA), Cyclophilin B (CyPB), sterol carrier protein (SCP), caveolin-1 and integrins, and can influence amyloid-β (Aβ) peptide levels, a protein that is central to Alzheimer’s disease (AD) pathogenesis. Mechanisms by which CD147 regulate Aβ levels remain unclear, thus in this review we discuss its involvement in Aβ production and clearance and potential mechanisms by which controlling CD147 levels could impact on Aβ accumulation and AD pathogenesis.

Pages 607-626
Review
Han-Chang Huang, Zhao-Feng Jiang
Amyloid-β Protein Precursor Family Members: A Review from Homology to Biological Function
Abstract: Alzheimer’s disease (AD) is one of the most common forms of neurodegenerative disease. Amyloid-β peptide (Aβ) is the most crucial molecule related to the pathological development of AD. Amyloid-β protein precursor (AβPP) is one of AβPP family members with conserved type I transmembrane. The genetic mutations of AβPP and the abnormity of its post-transcription and proteolytic processing contribute to the elevation of Aβ. The accumulation of Aβ in senile plaques is believed to be the most important event in AD pathology. Therefore, as a key upstream molecule of Aβ, AβPP is related to the AD pathology, but the biological function of AβPP is still not fully clear. AβPP-like proteins are widely expressed in multicellular eukaryotes. AβPP-like homologous genes and proteins are highly conserved in various organisms from invertebrates to mammals. AβPP-like genes undergo similarly pathways of transcription and post-transcription processing, and AβPP-like proteins is proteolyzed by the similar α-cleavage and the β-cleavage pathways. Based on the homology and the resemble domains, AβPP may play similar roles in organisms. In this article, we reviewed homology and structures of AβPP family members in organisms and further discussed potential biological function in normal and AD brains.

Pages 627-645
Lisa M. Bloudek, D. Eldon Spackman, Michael Blankenburg, Sean D. Sullivan
Review and Meta-Analysis of Biomarkers and Diagnostic Imaging in Alzheimer’s Disease
Abstract: Mild Alzheimer's disease (AD) is often difficult to differentiate from mild cognitive impairment (MCI) or non-AD dementias. A multitude of diagnostic biomarkers and advanced imaging strategies have been developed to aid in the diagnosis and management of AD. We sought to review and analyze the published evidence on key test characteristics of major diagnostic strategies to formulate best estimates of sensitivity (SN) and specificity (SP).  A systematic review was undertaken to locate and abstract all studies of biomarkers or diagnostic imaging for AD published in English from January 1990 to March 2010 that provided estimates of SN and SP.  Meta-analysis was performed using a bivariate mixed-effects binary regression model.  We calculated -SN, SP, and area under the receiver operating curves (AUROC), with confidence and prediction contours. Of 1,840 unique studies identified, 119 presented primary data sufficient for analysis. SN and SP were calculated against non-demented controls, non-AD dementias with and without MCI, if available. Compared to non-demented controls, FDG-PET demonstrated the highest AUROC (0.96), with 90% SN (95%CI 84% to 94%), and 89% SP (95% CI 81% to 94%).  FDG-PET also was most accurate in discriminating AD from demented controls (including MCI) with AUROC 0.91, and 92% SN (95%CI 84% to 96%) and 78% SP (95% CI 69% to 85%). For discrimination of AD from non-AD dementias (excluding MCI), CSF Ptau, and SPECT produced identical AUROC (0.86).  Diagnostic strategies for AD show wide variation in test characteristics and some show promise for use in clinical practice.

Supplementary Data for Bloudek et al. article (PDF)

Pages 647-655
Pauline PL So, Ci-Di Chen, Carmela R. Abraham (Handling Associate Editor: Ashley Bush)
Detection of Amyloid-β Precursor Protein Homo-Interactions Using Beta-Galactosidase Enzyme Fragment Complementation
Abstract: Amyloidogenic processing of the amyloid-β protein precursor (AβPP) produces amyloid-β peptides (Aβ), the major constituent of amyloid plaques in the brains of Alzheimer’s disease (AD) patients.  Experimental evidence suggests that increased dimerization of AβPP increases Aβ while decreased dimerization of AβPP decreases Aβ production.  If true, developing tools for detecting AβPP-AβPP interactions to understand AβPP processing leading to Aβ production would be important.  Here, we developed the method of β-galactosidase (β-gal) enzyme fragment complementation as a means to detect AβPP-AβPP interactions. Inactive β-gal fragments are independently tagged to the C-terminal ends of monomeric AβPPs, and will come together to form a functional enzyme upon AβPP-AβPP interactions. Successful detection of β-gal activity has been used to qualitatively visualize and quantify the amount of AβPP dimers or higher oligomers.  This method can be used to enhance our understanding of the biological processes dependent upon AβPP-AβPP interactions.

Pages 657-666
Peng Liu, Lisa J. Kemper, Jun Wang, Kathleen R. Zahs, Karen H. Ashe, Giulio M. Pasinetti
Grape Seed Polyphenolic Extract Specifically Decreases Aβ*56 in the Brains of Tg2576 Mice
Abstract: Amyloid-β (Aβ) oligomers, found in the brains of Alzheimer’s disease (AD) patients and transgenic mouse models of AD, cause synaptotoxicity and memory impairment.  Grape seed polyphenolic extract (GSPE) inhibits Aβ oligomerization in vitro and attenuates cognitive impairment and AD-related neuropathology in the brains of transgenic mice.  In the current study, GSPE was administered to Tg2576 mice for a period of five months.  Treatment significantly decreased brain levels of Aβ*56, a 56-kDa Aβ oligomer previously shown to induce memory dysfunction in rodents, without changing the levels of transgenic amyloid-β protein precursor, monomeric Aβ, or other Aβ oligomers.  These results thus provide the first demonstration that a safe and affordable intervention can lower the levels of a memory-impairing Aβ oligomer in vivo and strongly suggest that GSPE should be further tested as a potential prevention and/or therapy for AD.

Supplementary Data for Liu et al. article (PDF)

Pages 667-682
Laurence O’Dwyer, Franck Lamberton, Arun L.W. Bokde, Michael Ewers, Yetunde O. Faluyi, Colby Tanner, Bernard Mazoyer, Des O’Neill, Máiréad Bartley, D. Rónán Collins, Tara Coughlan, David Prvulovic, Harald Hampel (Handling Associate Editor: Massimo Filippi)
Using Diffusion Tensor Imaging and Mixed-Effects Models to Investigate Primary and Secondary White Matter Degeneration in Alzheimer’s Disease and Mild Cognitive Impairment
Abstract: White matter (WM) degeneration in Alzheimer’s disease (AD) and mild cognitive impairment (MCI) may be a key indicator of early damage in AD. Here, we analyzed WM diffusion tensor data using Tract-Based Spatial Statistics in conjunction with mixed-effects models. Four indices of diffusion were assessed in 61 healthy control, 19 non-amnestic MCIs, 14 amnestic MCIs, and 9 AD patients. The aim of the study was to use advanced mixed-effects models to investigate the retrogenesis hypothesis of AD, which suggests that tracts that are late to myelinate in ontogenetic development are the earliest to be affected in AD. Our results show that a number of late-myelinating pathways, including the parahippocampal region and the inferior longitudinal fasciculus, were predominantly affected by changes in WM volume. Conversely, early-myelinating pathways were found to be affected by a combination of both WM and gray matter (GM) atrophy. A model of the entire WM structure of the brain returned GM models for two indices of diffusion, suggesting that more complex regional landscapes of diffusion lie hidden beneath a global analysis of the entire brain. Our results warn against an explanation of white matter damage that points simply to one of two mechanisms: secondary degeneration or direct damage of myelin. We suggest that tracts may be affected by both mechanisms, with the balance depending on whether tracts are early or late-myelinating. A greater understanding of the pattern of WM changes in AD may prove useful for the early detection of AD.

Supplementary Data for O'Dwyer et al. article (PDF)

Pages 683-698
Lidia Blazquez-Llorca*, Virginia Garcia-Marin*, Paula Merino-Serrais, Jesús Ávila, Javier DeFelipe *Both authors contributed equally to this work.
Abnormal Tau Phosphorylation in the Thorny Excrescences of CA3 Hippocampal Neurons in Patients with Alzheimer’s Disease
Abstract: A key symptom in the early stages of Alzheimer’s disease (AD) is the loss of declarative memory. The anatomical substrate that supports this kind of memory involves the neural circuits of the medial temporal lobe, and in particular, of the hippocampal formation and adjacent cortex. A main feature of AD is the abnormal phosphorylation of the tau protein and the presence of tangles. The sequence of cellular changes related to tau phosphorylation and tangle formation has been studied with an antibody that binds to diffuse phosphotau (AT8). Moreover, another tau antibody (PHF-1) has been used to follow the pathway of neurofibrillary (tau aggregation) degeneration in AD. We have used a variety of quantitative immunocytochemical techniques and confocal microscopy to visualize and characterize neurons labeled with AT8 and PHF-1 antibodies. We present here the rather unexpected discovery that in AD, there is conspicuous abnormal phosphorylation of the tau protein in a selective subset of dendritic spines. We identified these spines as the typical thorny excrescences of hippocampal CA3 neurons in a pre-tangle state. Since thorny excrescences represent a major synaptic target of granule cell axons (mossy fibers), such aberrant phosphorylation may play an essential role in the memory impairment typical of AD patients.

Pages 699-708
Neil M. Davies, Patrick G Kehoe, Yoav Ben-Shlomo, Richard M. Martin (Handling Associate Editor: Francesco Panza)
Associations of Anti-Hypertensive Treatments with Alzheimer’s Disease, Vascular Dementia, and Other Dementias
Abstract: We investigated whether angiotensin II receptor blockers (ARBs) and angiotensin converting enzyme inhibitors (ACE-Is) are more strongly associated with Alzheimer’s disease (AD), vascular dementia (VaD), and other dementias, than other anti-hypertensive drugs.
We conducted a nested case-control analysis within the UK general practice research database, with prospectively recorded anti-hypertensive prescribing data. We sampled cases aged ≥60 years and diagnosed between 1997-2008 (5,797 with AD, 2,186 with VaD, 1,214 with unspecified/other dementia) which were matched to up to four controls by age, general practice and gender. We computed odds-ratios and dose response effects for AD, vascular and unspecified/other dementia, comparing those prescribed ARBs or ACE-Is for at least six months with patients prescribed other anti-hypertensives. We controlled for matching factors, co-morbidities, smoking status, an area measure of socioeconomic status, consultation rate and blood pressure and accounted for reverse causality by introducing time-lags of up to eight years prior to diagnosis/index date. Patients diagnosed with AD, vascular and unspecified/other dementia had fewer prescriptions for ARBs and ACE-Is. Inverse associations with AD were strongest for ARBs (odds-ratio; 0.47, 95%CI, 0.37-0.58) compared with ACE-Is (odds-ratio; 0.76, 95%CI, 0.69-0.84) (pdifference<0.001). Associations of ARBs with AD were stronger than for vascular dementia (pdifference=0.01) and unspecified/other dementia (pdifference=0.23). There were inverse dose-response relationships between ARBs and ACE-Is with AD (both ptrend<0.01). The inverse association of ACE-Is with AD diminished when using longer time lags but the ARB-AD association persisted. Patients with AD were around half as likely to be prescribed ARBs. Further randomized controlled trial evidence is required to rigorously test these findings.

Supplementary Data for Davies et al. article (PDF)

Pages 709-718
Christine Sattler, Kirk I. Erickson, Pablo Toro, Johannes Schröder  
Physical Fitness as a Protective Factor for Cognitive Impairment in a Prospective Population-Based Study in Germany
Abstract: To evaluate the predictive effects of subjective measures of physical activity (PA) and objective measures of physical fitness (PF) on dementia risk, Participants of the prospective population-based ILSE-study (*1930-1932;12-year follow-up) were examined at three examination waves (t1:1993/94; t2:1997/98; t3:2005/07). 381 subjects of the original cohort (n=500) were re-examined at t3. 29% of the subjects who were cognitively healthy at baseline received the diagnosis of mild cognitive impairment (MCI) and 7% of Alzheimer’s disease (AD). Subjects were screened for physical and mental health using medical interviews, physical, and neuropsychological examinations. Participants completed a questionnaire on their current and past PA at t1. Subjects were classified as physically active if they reported a regular sport activity for at least 2 h per week in the past year. Muscular strength (handgrip) and motor coordination (balance) served as objective indicators of PF.  Subjects who passed the balance-test at t1 had a reduced risk of developing MCI/AD at t3 (OR=0.38,95%CI 0.24-0.70,p<0.01) and performed significantly better on various neuropsychological measures. Muscular strength or subjective reports of PA did not predict MCI/AD development. Our results confirm the hypothesis that PF acts as a protective factor for the development of cognitive disorders. In our study, context motor coordination served as a better predictor than muscular strength or self-rated PA. Since subjects with cognitive disorders due to cerebral and/or systemic disorders were excluded from the analyses, our findings suggest that the effect of skill-related PF extends beyond the reduction of cardiovascular risk factors.

Pages 719-734
Jürgen Hänggi, Johannes Streffer, Lutz Jäncke, Christoph Hock
Volumes of Lateral Temporal and Parietal Structures Distinguish Between Healthy Aging, Mild Cognitive Impairment, and Alzheimer’s Disease
Abstract: Distinguishing amnestic mild cognitive impairment (MCI) from Alzheimer’s disease (AD) and healthy aging depends mainly on clinical evaluation, and, ultimately, on investigator’s judgment. Clinical evaluation in vivo is based primarily on cognitive assessments. The present study explores the potential of volumetric magnetic resonance imaging of parietal and lateral temporal brain structures to support the diagnosis of AD and to distinguish AD patients from patients with MCI and healthy control subjects (HCS). 52 age-matched HCS, 18 patients with MCI, and 59 patients with probable late onset AD were investigated. Using computational, neuromorphometric procedures gray matter (GM) was automatically parcellated into 28 local regions of interest, the volumes of which were computed. The left hippocampus (sensitivity/specificity: 80.8–90.4%/55.6–86.4%) and the right hippocampus (73.1–90.4%/66.7–84.7%) provided highest diagnostic accuracy in separating all three diagnostic groups. Promising diagnostic values for distinguishing MCI from HCS were found for the left superior parietal gyrus (61.5%/55.6%) and left supramarginal gyrus (65.4%/66.7%), and for distinguishing subjects with MCI from AD patients for the right middle temporal gyrus (77.8%/79.7%), left inferior temporal gyrus (83.3%/72.9%), and right superior temporal gyrus (77.8%/71.2%). The left superior temporal pole (92.3%/84.7%), left parahippocampal gyrus (86.5%/81.4%), left Heschl’s gyrus (86.5%/79.7%), and the right superior temporal pole (82.7%/78.0%) revealed most promising diagnostic values for distinguishing AD patients from HCS. Data revealed that lateral temporal and parietal GM volumes distinguish between HCS, MCI, and AD as accurate as hippocampal volumes do; hence, these volumes can be used in the diagnostic procedure. Results also suggest that cognitive functions associated with these brain regions, e.g., language and visuospatial abilities, may be tested more extensively to obtain additional information that might enhance the diagnostic accuracy further.

Pages 735-744
Yanlei Zhang, Miia Kivipelto, Alina Solomon, Anders Wimo
Cost-effectiveness of a Health Intervention Program with Risk Reductions for Getting Demented: Results of a Markov Model in a Swedish/Finnish Setting
Abstract: Risk scores based on modifiable factors have recently been developed for dementia. This study aims to estimate the cost-effectiveness of a potential preventive intervention program meant to lower the score related to increased dementia risk. Analyses were based on a Markov model adapted to Swedish circumstances. Risk score categories and risk probabilities were derived from the Cardiovascular Risk Factors, Aging and Incidence of Dementia (CAIDE) study in Finland. Figures of costs, utilities, and mortality were obtained from literature or databases. One-way sensitivity analysis and probabilistic sensitivity analysis were carried out to investigate the robustness of the model and to identify which model inputs had most impact on the results. In the base case, the usual care had a cost of 621,000 SEK and utilities of 11.8438 quality-adjusted life year (QALYs). The intervention had a cost of 599,026 SEK and utilities of 11.8950 QALYs. The cost was 21,974 SEK lower in the intervention with 0.0511 QALYs gained over a 20 years horizon, indicating absolute dominance. The support for cost-effectiveness was insensitive to changes in the value of QALY for demented, mortality, and risk of dementia. If the intervention program was assumed to run every year, the incremental cost-effectiveness ratio did not show absolute dominance but was still under the willingness-to-pay level. The probabilistic sensitivity analysis indicated cost effectiveness in 67% of the samplings given a willingness-to-pay level of 600,000 SEK/year. This is a promising outlook for future research on preventive interventions in dementia, emphasizing the need of conducting multi-domain randomized trials.

Pages 745-753
Eric Yang, Michael Farnum, Victor Lobanov, Tim Schultz, Nandini Raghavan, Mahesh N. Samtani, Gerald Novak, Vaibhav Narayan, Allitia DiBernardo, the Alzheimer’s Disease Neuroimaging Initiative
Quantifying the Pathophysiological Timeline of Alzheimer’s Disease
Abstract: Hypothetical models of AD progression typically relate clinical stages of AD to sequential changes in CSF biomarkers, imaging, and cognition. However, quantifying the continuous trajectories proposed by these models over time is difficult because of the difficulty in relating the dynamics of different biomarkers during a clinical trial that is significant shorter than the duration of the disease. We seek to show that through proper synchronization, it is possible to de-convolve the trends and quantify the periods of time associated with different pathophysiological changes associated with Alzheimer’s disease (AD). We developed a model that replicated the observed progression of ADAS-Cog 13 scores and used this as a more precise estimate of disease-duration and thus pathologic stage. We then synchronized cerebrospinal fluid (CSF) and imaging biomarkers according to our new disease timeline. By de-convolving disease progression via ADAS-Cog 13, we were able to confirm the predictions of previous hypothetical models of disease progression as well as establish concrete timelines for different pathobiological events.  Specifically, our work supports a sequential pattern of biomarker changes in AD in which reduction in CSF Aβ42 and brain atrophy precede the increases in CSF tau and phospho-tau.

Pages 755-766
Kevin H. Chen, Edmund A. Reese, Hyung-Wook Kim, Stanley I. Rapoport, Jagadeesh S. Rao
Disturbed Neurotransmitter Transporter Expression in Alzheimer’s Disease Brain
Abstract: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by memory loss and behavioral and psychological symptoms of dementia. An imbalance of different neurotransmitters—glutamate, acetylcholine, dopamine, and serotonin—has been proposed as the neurobiological basis of behavioral symptoms in AD.  The molecular changes associated with neurotransmission imbalance in AD are not clear. We hypothesized that altered reuptake of neurotransmitters by vesicular glutamate transporters (VGLUTs), excitatory amino acid transporters (EAATs), the vesicular acetylcholine transporter (VAChT), the serotonin reuptake transporter (SERT), or the dopamine reuptake transporter (DAT) are involved in the neurotransmission imbalance in AD. We tested this hypothesis by examining protein and mRNA levels of these transporters in postmortem prefrontal cortex from 10 AD patients and 10 matched non-AD controls. Compared with controls, protein and mRNA levels of VGLUTs, EAAT1-3, VAChT, and SERT were reduced significantly in AD.  Expression of DAT and catechol O-methyltransferase was unchanged. Reduced VGLUTs and EAATs may contribute to an alteration in glutamatergic recycling, and reduced SERT could exacerbate depressive symptoms in AD. The reduced VAChT expression could contribute to the recognized cholinergic deficit in AD. Altered neurotransmitter transporters could contribute to the pathophysiology of AD and are potential targets for therapy.

Pages 767-778
Hasina Akhter, Ashwini Katre, Ling Li, Xuebo Liu, Rui-Ming Liu (Handling Associate Editor: D. Allan Butterfield)
Therapeutic Potential and Anti-Amyloidosis Mechanisms of Tert-Butylhydroquinone for Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) is a major cause of dementia in the elderly with no effective treatment. Accumulation of amyloid-β peptide (Aβ) in the brain, one of the pathological features of AD, is considered to be a central disease-causing and disease-promoting event in AD.  In this study, we showed that feeding male AβPP/PS1 transgenic mice, a well established mouse model of AD, with a diet containing phenolic antioxidant tert-butylhydroquinone (TBHQ) dramatically reduced brain Aβ load with no significant effect on the amounts of alpha- and beta-C-terminal fragments or full-length AβPP.  Further studies showed that TBHQ diet inhibited the expression of plasminogen activator inhibitor-1 (PAI-1), a protease inhibitor which plays a critical role in brain Aβ accumulation in AD, accompanied by increases in the activities of tissue type and urokinase type plasminogen activators (tPA and uPA) as well as plasmin.  Moreover, we showed that TBHQ diet increased the expression of low density lipoprotein related protein-1, a multi ligand endocytotic receptor involved in transporting Aβ out of the brain, and plasma Aβ40 and Aβ42 levels.  We also showed that TBHQ diet increased the concentration of glutathione, an important antioxidant, and suppressed the expression of NADPH oxidase 2 as well as lipid peroxidation. Collectively, our data suggest that TBHQ may have therapeutic potential for AD by increasing brain antioxidant capacity/reducing oxidative stress level and by stimulating Aβ degradation/clearance pathways.

Pages 779-786
Nastasia K-H Lim, Victor L. Villemagne, Cynthia P.W. Soon, Katrina M. Laughton, Christopher C. Rowe, Catriona A. McLean, Colin L. Masters, Genevieve Evin, Qiao-Xin Li (Handling Associate Editor: Craig Atwood)
Investigation of Matrix Metalloproteinases, MMP-2 and MMP-9, in Plasma Reveals a Decrease of MMP-2 in Alzheimer’s Disease
Abstract: Pathological changes in the Alzheimer’s disease (AD) brain include amyoid-β (Aβ) plaques, and neurofibrillary tangles, as well as neuronal death and synaptic loss. Matrix metalloproteinases MMP-2 and MMP-9 are known to degrade Aβ, and their expressions are increased in the AD brain, in particular in the astrocytes surrounding amyloid plaque. To investigate a possible association between plasma metalloproteinases and AD, we quantified MMP-2 and MMP-9 activities in the plasma of healthy controls (HC, n = 56), cases with mild cognitive impairment (MCI, n = 45), and AD (n = 50). All cases had previously been imaged with Pittsburgh compound B (PiB) and had a Mini-Mental Status Examination (MMSE) assessment. MMP-2 and MMP-9 activity was determined using gelatine-zymography. There was a significant 1.5-fold decrease in MMP-2 activity in the AD group compared to HC (p < 0.001) and a 1.4-fold decrease compared to MCI (p < 0.01). There was no difference in MMP-9 levels between the three groups. A positive correlation was identified between MMP-2 plasma activity and MMSE score (r = 0.16, p < 0.05), but there was no association with PiB. This is the first report of a change in MMP-2 activity in AD plasma and these findings may provide some insight into AD pathogenesis.

Pages 787-793
Maria Serpente, Chiara Fenoglio, Chiara Villa, Francesca Cortini, Claudia Cantoni, Elisa Ridolfi, Francesca Clerici, Alessandra Marcone, Luisa Benussi, Roberta Ghidoni, Filippo Martinelli Boneschi, Salvatore Gallone,  Stefano Cappa, Giuliano Binetti, Massimo Franceschi, Innocenzo Rainero,  Maria Teresa Giordana, Claudio Mariani, Nereo Bresolin, Elio Scarpini, Daniela Galimberti (Handling Associate Editor: Andreas Reif)
Role of OLR1 and Its Regulating hsa-miR369-3p in Alzheimer’s Disease: Genetics and Expression Analysis
Abstract: The oxidized LDL receptor 1 gene (OLR1) rs1050283 single nucleotide polymorphism (SNP) has been previously shown to be associated with Alzheimer’s disease (AD).  An association analysis of OLR1 was carried out in a population of 443 patients with AD as compared with 393 age-matched controls. In addition, an expression analysis of OLR1 and its regulatory hsa-miR369-3p was performed in peripheral mononuclear blood cells (PBMC) from 20 patients and 15 controls. Logistic regression analysis, adjusted for gender and apolipoprotein E (ApoE) status, showed a statistically significant association of OLR1 rs1050283 under the assumption of a dominant model (CC and CT individuals versus TT: p=0.014, OR: 1.50, 95%CI: 1.08-2.08) and a genotypic model (TC versus TT: p=0.002, OR: 1.61, 95%CI: 1.14-2.26). No significant differences in OLR1 expression was observed between patients and controls (p>0.05). However, stratifying patients according to the rs1050283 status, significantly decreased relative PBMC expression levels of OLR1 were observed in carriers of CC+CT  genotypes  as compared with TT carriers (0.13±0.013 versus 0.46±0.028, p=0.022), whereas no differences in relative expression levels of the hsa-miR369-3p were observed (p>0.05). The effect observed was not due to the presence of the ApoE ε4 allele. The OLR1 rs1050283SNPlikely acts as a risk factor for sporadic AD. The presence of at least one C allele is associated with a decreased expression of OLR1 mRNA in the absence of hsa-miR369-3p de-regulation, suggesting that the presence of the polymorphic allele influences the binding of hsa-miR369-3p to its 3’UTR consensus sequence. Nevertheless, the limited power of the study requires further investigations with a larger sample size.

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