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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Association of Plasma Aß Peptides with Blood Pressure in the Elderly</title><author><name sortKey="Lambert, Jean Charles" sort="Lambert, Jean Charles" uniqKey="Lambert J" first="Jean-Charles" last="Lambert">Jean-Charles Lambert</name><affiliation><nlm:aff id="aff1"><addr-line>INSERM U744, Lille, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><addr-line>Institut Pasteur de Lille, Lille, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff3"><addr-line>Université Lille Nord de France, UDSL, Lille, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Dallongeville, Jean" sort="Dallongeville, Jean" uniqKey="Dallongeville J" first="Jean" last="Dallongeville">Jean Dallongeville</name><affiliation><nlm:aff id="aff1"><addr-line>INSERM U744, Lille, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><addr-line>Institut Pasteur de Lille, Lille, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff3"><addr-line>Université Lille Nord de France, UDSL, Lille, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Ellis, Kathryn A" sort="Ellis, Kathryn A" uniqKey="Ellis K" first="Kathryn A." last="Ellis">Kathryn A. Ellis</name><affiliation><nlm:aff id="aff4"><addr-line>Department of Psychiatry, University of Melbourne, St George's Hospital, Victoria, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff5"><addr-line>Mental Health Research Institute, University of Melbourne, Parkville, Victoria, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff6"><addr-line>National Ageing Research Institute, Parkville, Victoria, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Schraen Maschke, Susanna" sort="Schraen Maschke, Susanna" uniqKey="Schraen Maschke S" first="Susanna" last="Schraen-Maschke">Susanna Schraen-Maschke</name><affiliation><nlm:aff id="aff3"><addr-line>Université Lille Nord de France, UDSL, Lille, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff7"><addr-line>INSERM U837, Lille, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff10"><addr-line>Centre Hospitalier Régional Universitaire, Lille, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Lui, James" sort="Lui, James" uniqKey="Lui J" first="James" last="Lui">James Lui</name><affiliation><nlm:aff id="aff8"><addr-line>Centre of Excellence for Alzheimer's Disease Research and Care, Edith Cowan University, Joondalup, Western Australia, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff9"><addr-line>Sir James McCusker Alzheimer's Research Unit, Perth, Western Australia, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Laws, Simon" sort="Laws, Simon" uniqKey="Laws S" first="Simon" last="Laws">Simon Laws</name><affiliation><nlm:aff id="aff8"><addr-line>Centre of Excellence for Alzheimer's Disease Research and Care, Edith Cowan University, Joondalup, Western Australia, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff9"><addr-line>Sir James McCusker Alzheimer's Research Unit, Perth, Western Australia, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Dumont, Julie" sort="Dumont, Julie" uniqKey="Dumont J" first="Julie" last="Dumont">Julie Dumont</name><affiliation><nlm:aff id="aff1"><addr-line>INSERM U744, Lille, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><addr-line>Institut Pasteur de Lille, Lille, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff3"><addr-line>Université Lille Nord de France, UDSL, Lille, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Richard, Florence" sort="Richard, Florence" uniqKey="Richard F" first="Florence" last="Richard">Florence Richard</name><affiliation><nlm:aff id="aff1"><addr-line>INSERM U744, Lille, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><addr-line>Institut Pasteur de Lille, Lille, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff3"><addr-line>Université Lille Nord de France, UDSL, Lille, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff10"><addr-line>Centre Hospitalier Régional Universitaire, Lille, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Cottel, Dominique" sort="Cottel, Dominique" uniqKey="Cottel D" first="Dominique" last="Cottel">Dominique Cottel</name><affiliation><nlm:aff id="aff1"><addr-line>INSERM U744, Lille, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><addr-line>Institut Pasteur de Lille, Lille, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff3"><addr-line>Université Lille Nord de France, UDSL, Lille, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Berr, Claudine" sort="Berr, Claudine" uniqKey="Berr C" first="Claudine" last="Berr">Claudine Berr</name><affiliation><nlm:aff id="aff11"><addr-line>INSERM, U888, Université de Montpellier 1, Montpellier, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Ames, David" sort="Ames, David" uniqKey="Ames D" first="David" last="Ames">David Ames</name><affiliation><nlm:aff id="aff4"><addr-line>Department of Psychiatry, University of Melbourne, St George's Hospital, Victoria, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff6"><addr-line>National Ageing Research Institute, Parkville, Victoria, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Masters, Colin L" sort="Masters, Colin L" uniqKey="Masters C" first="Colin L." last="Masters">Colin L. Masters</name><affiliation><nlm:aff id="aff5"><addr-line>Mental Health Research Institute, University of Melbourne, Parkville, Victoria, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff12"><addr-line>Centre for Neurosciences, University of Melbourne, Parkville, Victoria, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Rowe, Christopher C" sort="Rowe, Christopher C" uniqKey="Rowe C" first="Christopher C." last="Rowe">Christopher C. Rowe</name><affiliation><nlm:aff id="aff13"><addr-line>Austin Health, Heidelberg, Victoria, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Szoeke, Cassandra" sort="Szoeke, Cassandra" uniqKey="Szoeke C" first="Cassandra" last="Szoeke">Cassandra Szoeke</name><affiliation><nlm:aff id="aff6"><addr-line>National Ageing Research Institute, Parkville, Victoria, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff14"><addr-line>Australian Commonwealth Scientific and Research Organisation (CSIRO), Parkville, Victoria, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Tzourio, Christophe" sort="Tzourio, Christophe" uniqKey="Tzourio C" first="Christophe" last="Tzourio">Christophe Tzourio</name><affiliation><nlm:aff id="aff15"><addr-line>INSERM U708, Paris, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Dartigues, Jean Francois" sort="Dartigues, Jean Francois" uniqKey="Dartigues J" first="Jean-François" last="Dartigues">Jean-François Dartigues</name><affiliation><nlm:aff id="aff16"><addr-line>INSERM U593, Victor Segalen University, Bordeaux, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Buee, Luc" sort="Buee, Luc" uniqKey="Buee L" first="Luc" last="Buée">Luc Buée</name><affiliation><nlm:aff id="aff3"><addr-line>Université Lille Nord de France, UDSL, Lille, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff7"><addr-line>INSERM U837, Lille, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff10"><addr-line>Centre Hospitalier Régional Universitaire, Lille, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Martins, Ralph" sort="Martins, Ralph" uniqKey="Martins R" first="Ralph" last="Martins">Ralph Martins</name><affiliation><nlm:aff id="aff8"><addr-line>Centre of Excellence for Alzheimer's Disease Research and Care, Edith Cowan University, Joondalup, Western Australia, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff9"><addr-line>Sir James McCusker Alzheimer's Research Unit, Perth, Western Australia, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Amouyel, Philippe" sort="Amouyel, Philippe" uniqKey="Amouyel P" first="Philippe" last="Amouyel">Philippe Amouyel</name><affiliation><nlm:aff id="aff1"><addr-line>INSERM U744, Lille, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><addr-line>Institut Pasteur de Lille, Lille, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff3"><addr-line>Université Lille Nord de France, UDSL, Lille, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff10"><addr-line>Centre Hospitalier Régional Universitaire, Lille, France</addr-line></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">21525986</idno><idno type="pmc">3078119</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3078119</idno><idno type="RBID">PMC:3078119</idno><idno type="doi">10.1371/journal.pone.0018536</idno><date when="2011">2011</date><idno type="wicri:Area/Pmc/Corpus">002C05</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">002C05</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Association of Plasma Aß Peptides with Blood Pressure in the Elderly</title><author><name sortKey="Lambert, Jean Charles" sort="Lambert, Jean Charles" uniqKey="Lambert J" first="Jean-Charles" last="Lambert">Jean-Charles Lambert</name><affiliation><nlm:aff id="aff1"><addr-line>INSERM U744, Lille, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><addr-line>Institut Pasteur de Lille, Lille, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff3"><addr-line>Université Lille Nord de France, UDSL, Lille, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Dallongeville, Jean" sort="Dallongeville, Jean" uniqKey="Dallongeville J" first="Jean" last="Dallongeville">Jean Dallongeville</name><affiliation><nlm:aff id="aff1"><addr-line>INSERM U744, Lille, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><addr-line>Institut Pasteur de Lille, Lille, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff3"><addr-line>Université Lille Nord de France, UDSL, Lille, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Ellis, Kathryn A" sort="Ellis, Kathryn A" uniqKey="Ellis K" first="Kathryn A." last="Ellis">Kathryn A. Ellis</name><affiliation><nlm:aff id="aff4"><addr-line>Department of Psychiatry, University of Melbourne, St George's Hospital, Victoria, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff5"><addr-line>Mental Health Research Institute, University of Melbourne, Parkville, Victoria, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff6"><addr-line>National Ageing Research Institute, Parkville, Victoria, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Schraen Maschke, Susanna" sort="Schraen Maschke, Susanna" uniqKey="Schraen Maschke S" first="Susanna" last="Schraen-Maschke">Susanna Schraen-Maschke</name><affiliation><nlm:aff id="aff3"><addr-line>Université Lille Nord de France, UDSL, Lille, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff7"><addr-line>INSERM U837, Lille, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff10"><addr-line>Centre Hospitalier Régional Universitaire, Lille, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Lui, James" sort="Lui, James" uniqKey="Lui J" first="James" last="Lui">James Lui</name><affiliation><nlm:aff id="aff8"><addr-line>Centre of Excellence for Alzheimer's Disease Research and Care, Edith Cowan University, Joondalup, Western Australia, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff9"><addr-line>Sir James McCusker Alzheimer's Research Unit, Perth, Western Australia, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Laws, Simon" sort="Laws, Simon" uniqKey="Laws S" first="Simon" last="Laws">Simon Laws</name><affiliation><nlm:aff id="aff8"><addr-line>Centre of Excellence for Alzheimer's Disease Research and Care, Edith Cowan University, Joondalup, Western Australia, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff9"><addr-line>Sir James McCusker Alzheimer's Research Unit, Perth, Western Australia, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Dumont, Julie" sort="Dumont, Julie" uniqKey="Dumont J" first="Julie" last="Dumont">Julie Dumont</name><affiliation><nlm:aff id="aff1"><addr-line>INSERM U744, Lille, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><addr-line>Institut Pasteur de Lille, Lille, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff3"><addr-line>Université Lille Nord de France, UDSL, Lille, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Richard, Florence" sort="Richard, Florence" uniqKey="Richard F" first="Florence" last="Richard">Florence Richard</name><affiliation><nlm:aff id="aff1"><addr-line>INSERM U744, Lille, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><addr-line>Institut Pasteur de Lille, Lille, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff3"><addr-line>Université Lille Nord de France, UDSL, Lille, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff10"><addr-line>Centre Hospitalier Régional Universitaire, Lille, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Cottel, Dominique" sort="Cottel, Dominique" uniqKey="Cottel D" first="Dominique" last="Cottel">Dominique Cottel</name><affiliation><nlm:aff id="aff1"><addr-line>INSERM U744, Lille, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><addr-line>Institut Pasteur de Lille, Lille, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff3"><addr-line>Université Lille Nord de France, UDSL, Lille, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Berr, Claudine" sort="Berr, Claudine" uniqKey="Berr C" first="Claudine" last="Berr">Claudine Berr</name><affiliation><nlm:aff id="aff11"><addr-line>INSERM, U888, Université de Montpellier 1, Montpellier, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Ames, David" sort="Ames, David" uniqKey="Ames D" first="David" last="Ames">David Ames</name><affiliation><nlm:aff id="aff4"><addr-line>Department of Psychiatry, University of Melbourne, St George's Hospital, Victoria, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff6"><addr-line>National Ageing Research Institute, Parkville, Victoria, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Masters, Colin L" sort="Masters, Colin L" uniqKey="Masters C" first="Colin L." last="Masters">Colin L. Masters</name><affiliation><nlm:aff id="aff5"><addr-line>Mental Health Research Institute, University of Melbourne, Parkville, Victoria, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff12"><addr-line>Centre for Neurosciences, University of Melbourne, Parkville, Victoria, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Rowe, Christopher C" sort="Rowe, Christopher C" uniqKey="Rowe C" first="Christopher C." last="Rowe">Christopher C. Rowe</name><affiliation><nlm:aff id="aff13"><addr-line>Austin Health, Heidelberg, Victoria, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Szoeke, Cassandra" sort="Szoeke, Cassandra" uniqKey="Szoeke C" first="Cassandra" last="Szoeke">Cassandra Szoeke</name><affiliation><nlm:aff id="aff6"><addr-line>National Ageing Research Institute, Parkville, Victoria, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff14"><addr-line>Australian Commonwealth Scientific and Research Organisation (CSIRO), Parkville, Victoria, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Tzourio, Christophe" sort="Tzourio, Christophe" uniqKey="Tzourio C" first="Christophe" last="Tzourio">Christophe Tzourio</name><affiliation><nlm:aff id="aff15"><addr-line>INSERM U708, Paris, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Dartigues, Jean Francois" sort="Dartigues, Jean Francois" uniqKey="Dartigues J" first="Jean-François" last="Dartigues">Jean-François Dartigues</name><affiliation><nlm:aff id="aff16"><addr-line>INSERM U593, Victor Segalen University, Bordeaux, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Buee, Luc" sort="Buee, Luc" uniqKey="Buee L" first="Luc" last="Buée">Luc Buée</name><affiliation><nlm:aff id="aff3"><addr-line>Université Lille Nord de France, UDSL, Lille, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff7"><addr-line>INSERM U837, Lille, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff10"><addr-line>Centre Hospitalier Régional Universitaire, Lille, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Martins, Ralph" sort="Martins, Ralph" uniqKey="Martins R" first="Ralph" last="Martins">Ralph Martins</name><affiliation><nlm:aff id="aff8"><addr-line>Centre of Excellence for Alzheimer's Disease Research and Care, Edith Cowan University, Joondalup, Western Australia, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff9"><addr-line>Sir James McCusker Alzheimer's Research Unit, Perth, Western Australia, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Amouyel, Philippe" sort="Amouyel, Philippe" uniqKey="Amouyel P" first="Philippe" last="Amouyel">Philippe Amouyel</name><affiliation><nlm:aff id="aff1"><addr-line>INSERM U744, Lille, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><addr-line>Institut Pasteur de Lille, Lille, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff3"><addr-line>Université Lille Nord de France, UDSL, Lille, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff10"><addr-line>Centre Hospitalier Régional Universitaire, Lille, France</addr-line></nlm:aff></affiliation></author></analytic><series><title level="j">PLoS ONE</title><idno type="eISSN">1932-6203</idno><imprint><date when="2011">2011</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Background</title><p>Aß peptides are often considered as catabolic by-products of the amyloid ß protein precursor (APP), with unknown physiological functions. However, several biological properties have been tentatively attributed to these peptides, including a role in vasomotion.</p><p>We assess whether plasma Aß peptide levels might be associated with systolic and diastolic blood pressure values (SBP and DBP, respectively).</p></sec><sec><title>Methodology/Principal Findings</title><p>Plasma Aß<sub>1-40</sub> and Aß<sub>1-42</sub> levels were measured using an xMAP-based assay in 1,972 individuals (none of whom were taking antihypertensive drugs) from 3 independent studies: the French population-based 3C and MONA-LISA (Lille) studies (n = 627 and n = 769, respectively) and the Australian, longitudinal AIBL study (n = 576). In the combined sample, the Aß<sub>1-42</sub>/ Aß<sub>1-40</sub> ratio was significantly and inversely associated with SBP (p = 0.03) and a similar trend was observed for DBP (p = 0.06). Using the median age (69) as a cut-off, the Aß<sub>1-42</sub>/Aß<sub>1-40</sub> ratio was strongly associated with both SBP and DBP in elderly individuals (p = 0.002 and p = 0.03, respectively). Consistently, a high Aß<sub>1-42</sub>/ Aß<sub>1-40</sub> ratio was associated with a lower risk of hypertension in both the combined whole sample (odds ratio [OR], 0.71; 95% confidence interval [CI], 0.56-0.90) and (to an even greater extent) in the elderly subjects (OR, 0.53; 95% CI, 0.37–0.75). Lastly, all these associations appeared to be primarily driven by the level of plasma Aß<sub>1-40</sub>.</p></sec><sec><title>Conclusion</title><p>The plasma Aß<sub>1-42</sub>/Aß<sub>1-40</sub> ratio is inversely associated with SBP, DBP and the risk of hypertension in elderly subjects, suggesting that Aß peptides affect blood pressure <italic>in vivo</italic>. These results may be particularly relevant in Alzheimer's disease, in which a high Aß<sub>1-42</sub>/Aß<sub>1-40</sub> plasma ratio is reportedly associated with a decreased risk of incident disease.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Le, Y" uniqKey="Le Y">Y Le</name></author><author><name sortKey="Gong, W" uniqKey="Gong W">W Gong</name></author><author><name sortKey="Tiffany, Hl" uniqKey="Tiffany H">HL Tiffany</name></author><author><name sortKey="Tumanov, A" uniqKey="Tumanov A">A Tumanov</name></author><author><name sortKey="Nedospasov, S" uniqKey="Nedospasov S">S Nedospasov</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Koldamova, Rp" uniqKey="Koldamova R">RP Koldamova</name></author><author><name sortKey="Lefterov, Im" uniqKey="Lefterov I">IM Lefterov</name></author><author><name sortKey="Lefterova, Mi" uniqKey="Lefterova M">MI Lefterova</name></author><author><name 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<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS One</journal-id><journal-id journal-id-type="publisher-id">plos</journal-id><journal-id journal-id-type="pmc">plosone</journal-id><journal-title-group><journal-title>PLoS ONE</journal-title></journal-title-group><issn pub-type="epub">1932-6203</issn><publisher><publisher-name>Public Library of Science</publisher-name><publisher-loc>San Francisco, USA</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">21525986</article-id><article-id pub-id-type="pmc">3078119</article-id><article-id pub-id-type="publisher-id">PONE-D-11-01441</article-id><article-id pub-id-type="doi">10.1371/journal.pone.0018536</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="Discipline-v2"><subject>Biology</subject><subj-group><subject>Population Biology</subject><subj-group><subject>Epidemiology</subject></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v2"><subject>Medicine</subject><subj-group><subject>Cardiovascular</subject><subj-group><subject>Hypertension</subject></subj-group></subj-group><subj-group><subject>Neurology</subject><subj-group><subject>Dementia</subject><subj-group><subject>Alzheimer Disease</subject></subj-group></subj-group></subj-group></subj-group></article-categories><title-group><article-title>Association of Plasma Aß Peptides with Blood Pressure in the Elderly</article-title><alt-title alt-title-type="running-head">Blood Pressure and Plasma Aß Peptides</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Lambert</surname><given-names>Jean-Charles</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="aff" rid="aff2"><sup>2</sup></xref><xref ref-type="aff" rid="aff3"><sup>3</sup></xref><xref ref-type="corresp" rid="cor1"><sup>*</sup></xref></contrib><contrib contrib-type="author"><name><surname>Dallongeville</surname><given-names>Jean</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="aff" rid="aff2"><sup>2</sup></xref><xref ref-type="aff" rid="aff3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Ellis</surname><given-names>Kathryn A.</given-names></name><xref ref-type="aff" rid="aff4"><sup>4</sup></xref><xref ref-type="aff" rid="aff5"><sup>5</sup></xref><xref ref-type="aff" rid="aff6"><sup>6</sup></xref></contrib><contrib contrib-type="author"><name><surname>Schraen-Maschke</surname><given-names>Susanna</given-names></name><xref ref-type="aff" rid="aff3"><sup>3</sup></xref><xref ref-type="aff" rid="aff7"><sup>7</sup></xref><xref ref-type="aff" rid="aff10"><sup>10</sup></xref></contrib><contrib contrib-type="author"><name><surname>Lui</surname><given-names>James</given-names></name><xref ref-type="aff" rid="aff8"><sup>8</sup></xref><xref ref-type="aff" rid="aff9"><sup>9</sup></xref></contrib><contrib contrib-type="author"><name><surname>Laws</surname><given-names>Simon</given-names></name><xref ref-type="aff" rid="aff8"><sup>8</sup></xref><xref ref-type="aff" rid="aff9"><sup>9</sup></xref></contrib><contrib contrib-type="author"><name><surname>Dumont</surname><given-names>Julie</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="aff" rid="aff2"><sup>2</sup></xref><xref ref-type="aff" rid="aff3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Richard</surname><given-names>Florence</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="aff" rid="aff2"><sup>2</sup></xref><xref ref-type="aff" rid="aff3"><sup>3</sup></xref><xref ref-type="aff" rid="aff10"><sup>10</sup></xref></contrib><contrib contrib-type="author"><name><surname>Cottel</surname><given-names>Dominique</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="aff" rid="aff2"><sup>2</sup></xref><xref ref-type="aff" rid="aff3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Berr</surname><given-names>Claudine</given-names></name><xref ref-type="aff" rid="aff11"><sup>11</sup></xref></contrib><contrib contrib-type="author"><name><surname>Ames</surname><given-names>David</given-names></name><xref ref-type="aff" rid="aff4"><sup>4</sup></xref><xref ref-type="aff" rid="aff6"><sup>6</sup></xref></contrib><contrib contrib-type="author"><name><surname>Masters</surname><given-names>Colin L.</given-names></name><xref ref-type="aff" rid="aff5"><sup>5</sup></xref><xref ref-type="aff" rid="aff12"><sup>12</sup></xref></contrib><contrib contrib-type="author"><name><surname>Rowe</surname><given-names>Christopher C.</given-names></name><xref ref-type="aff" rid="aff13"><sup>13</sup></xref></contrib><contrib contrib-type="author"><name><surname>Szoeke</surname><given-names>Cassandra</given-names></name><xref ref-type="aff" rid="aff6"><sup>6</sup></xref><xref ref-type="aff" rid="aff14"><sup>14</sup></xref></contrib><contrib contrib-type="author"><name><surname>Tzourio</surname><given-names>Christophe</given-names></name><xref ref-type="aff" rid="aff15"><sup>15</sup></xref></contrib><contrib contrib-type="author"><name><surname>Dartigues</surname><given-names>Jean-François</given-names></name><xref ref-type="aff" rid="aff16"><sup>16</sup></xref></contrib><contrib contrib-type="author"><name><surname>Buée</surname><given-names>Luc</given-names></name><xref ref-type="aff" rid="aff3"><sup>3</sup></xref><xref ref-type="aff" rid="aff7"><sup>7</sup></xref><xref ref-type="aff" rid="aff10"><sup>10</sup></xref></contrib><contrib contrib-type="author"><name><surname>Martins</surname><given-names>Ralph</given-names></name><xref ref-type="aff" rid="aff8"><sup>8</sup></xref><xref ref-type="aff" rid="aff9"><sup>9</sup></xref></contrib><contrib contrib-type="author"><name><surname>Amouyel</surname><given-names>Philippe</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="aff" rid="aff2"><sup>2</sup></xref><xref ref-type="aff" rid="aff3"><sup>3</sup></xref><xref ref-type="aff" rid="aff10"><sup>10</sup></xref></contrib></contrib-group><aff id="aff1"><label>1</label><addr-line>INSERM U744, Lille, France</addr-line></aff><aff id="aff2"><label>2</label><addr-line>Institut Pasteur de Lille, Lille, France</addr-line></aff><aff id="aff3"><label>3</label><addr-line>Université Lille Nord de France, UDSL, Lille, France</addr-line></aff><aff id="aff4"><label>4</label><addr-line>Department of Psychiatry, University of Melbourne, St George's Hospital, Victoria, Australia</addr-line></aff><aff id="aff5"><label>5</label><addr-line>Mental Health Research Institute, University of Melbourne, Parkville, Victoria, Australia</addr-line></aff><aff id="aff6"><label>6</label><addr-line>National Ageing Research Institute, Parkville, Victoria, Australia</addr-line></aff><aff id="aff7"><label>7</label><addr-line>INSERM U837, Lille, France</addr-line></aff><aff id="aff8"><label>8</label><addr-line>Centre of Excellence for Alzheimer's Disease Research and Care, Edith Cowan University, Joondalup, Western Australia, Australia</addr-line></aff><aff id="aff9"><label>9</label><addr-line>Sir James McCusker Alzheimer's Research Unit, Perth, Western Australia, Australia</addr-line></aff><aff id="aff10"><label>10</label><addr-line>Centre Hospitalier Régional Universitaire, Lille, France</addr-line></aff><aff id="aff11"><label>11</label><addr-line>INSERM, U888, Université de Montpellier 1, Montpellier, France</addr-line></aff><aff id="aff12"><label>12</label><addr-line>Centre for Neurosciences, University of Melbourne, Parkville, Victoria, Australia</addr-line></aff><aff id="aff13"><label>13</label><addr-line>Austin Health, Heidelberg, Victoria, Australia</addr-line></aff><aff id="aff14"><label>14</label><addr-line>Australian Commonwealth Scientific and Research Organisation (CSIRO), Parkville, Victoria, Australia</addr-line></aff><aff id="aff15"><label>15</label><addr-line>INSERM U708, Paris, France</addr-line></aff><aff id="aff16"><label>16</label><addr-line>INSERM U593, Victor Segalen University, Bordeaux, France</addr-line></aff><contrib-group><contrib contrib-type="editor"><name><surname>Gravenor</surname><given-names>Mike B.</given-names></name><role>Editor</role><xref ref-type="aff" rid="edit1"></xref></contrib></contrib-group><aff id="edit1">University of Swansea, United Kingdom</aff><author-notes><corresp id="cor1">* E-mail: <email>jean-charles.lambert@pasteur-lille.fr</email></corresp><fn fn-type="con"><p>Analyzed the data: J-CL FR. Wrote the paper: J-CL J. Dallongeville J. Dumont. Project management and design: J-CL. Phenotype collection, data management, 3C study: CB CT J-FD PA. MONA-LISA (Lille): J. Dallongeville DC PA. AIBL study: KAE DA CLM CCR CS RM. Performed the experiments, Ab ELISA: SS-M JL SL LB RM.</p></fn></author-notes><pub-date pub-type="collection"><year>2011</year></pub-date><pub-date pub-type="epub"><day>15</day><month>4</month><year>2011</year></pub-date><volume>6</volume><issue>4</issue><elocation-id>e18536</elocation-id><history><date date-type="received"><day>5</day><month>1</month><year>2011</year></date><date date-type="accepted"><day>3</day><month>3</month><year>2011</year></date></history><permissions><copyright-statement>Lambert et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</copyright-statement></permissions><abstract><sec><title>Background</title><p>Aß peptides are often considered as catabolic by-products of the amyloid ß protein precursor (APP), with unknown physiological functions. However, several biological properties have been tentatively attributed to these peptides, including a role in vasomotion.</p><p>We assess whether plasma Aß peptide levels might be associated with systolic and diastolic blood pressure values (SBP and DBP, respectively).</p></sec><sec><title>Methodology/Principal Findings</title><p>Plasma Aß<sub>1-40</sub> and Aß<sub>1-42</sub> levels were measured using an xMAP-based assay in 1,972 individuals (none of whom were taking antihypertensive drugs) from 3 independent studies: the French population-based 3C and MONA-LISA (Lille) studies (n = 627 and n = 769, respectively) and the Australian, longitudinal AIBL study (n = 576). In the combined sample, the Aß<sub>1-42</sub>/ Aß<sub>1-40</sub> ratio was significantly and inversely associated with SBP (p = 0.03) and a similar trend was observed for DBP (p = 0.06). Using the median age (69) as a cut-off, the Aß<sub>1-42</sub>/Aß<sub>1-40</sub> ratio was strongly associated with both SBP and DBP in elderly individuals (p = 0.002 and p = 0.03, respectively). Consistently, a high Aß<sub>1-42</sub>/ Aß<sub>1-40</sub> ratio was associated with a lower risk of hypertension in both the combined whole sample (odds ratio [OR], 0.71; 95% confidence interval [CI], 0.56-0.90) and (to an even greater extent) in the elderly subjects (OR, 0.53; 95% CI, 0.37–0.75). Lastly, all these associations appeared to be primarily driven by the level of plasma Aß<sub>1-40</sub>.</p></sec><sec><title>Conclusion</title><p>The plasma Aß<sub>1-42</sub>/Aß<sub>1-40</sub> ratio is inversely associated with SBP, DBP and the risk of hypertension in elderly subjects, suggesting that Aß peptides affect blood pressure <italic>in vivo</italic>. These results may be particularly relevant in Alzheimer's disease, in which a high Aß<sub>1-42</sub>/Aß<sub>1-40</sub> plasma ratio is reportedly associated with a decreased risk of incident disease.</p></sec></abstract><counts><page-count count="6"></page-count></counts></article-meta></front><body><sec id="s1"><title>Introduction</title><p>Aß peptides are the main component of ß-amyloid deposits in the brains of Alzheimer's disease (AD) patients. Many different cell types from the brain and the peripheral tissues produce these peptides. They are catabolic by-products of the amyloid ß protein precursor (APP) and do not have a known physiological function. However, several lines of evidence suggest that Aß peptides may have biological functions by acting as ligands for various receptors and other molecules <xref ref-type="bibr" rid="pone.0018536-Le1">[1]</xref>–<xref ref-type="bibr" rid="pone.0018536-Maezawa1">[3]</xref>. The peptides are transported between tissues and across the blood brain barrier via complex trafficking pathways <xref ref-type="bibr" rid="pone.0018536-Zlokovic1">[4]</xref>. Lastly, at physiological concentrations, the peptides may possess neurotrophic <xref ref-type="bibr" rid="pone.0018536-Yankner1">[5]</xref>, antioxidant <xref ref-type="bibr" rid="pone.0018536-Kontush1">[6]</xref>, platelet aggregation modulation <xref ref-type="bibr" rid="pone.0018536-Li1">[7]</xref>, antimicrobial <xref ref-type="bibr" rid="pone.0018536-Soscia1">[8]</xref> and/or vasoconstriction properties <xref ref-type="bibr" rid="pone.0018536-Thomas1">[9]</xref>.</p><p>With respect to vascular tone, Aß peptides are produced by the vascular smooth muscular cells (SMCs) <xref ref-type="bibr" rid="pone.0018536-Frackowiak1">[10]</xref> involved in blood pressure (BP) control and are known to have vasoactive properties <xref ref-type="bibr" rid="pone.0018536-Wynne1">[11]</xref>. Indeed, in <italic>in vitro</italic> studies, Aß peptides enhance constriction of isolated vessels via the release of endothelin 1 <xref ref-type="bibr" rid="pone.0018536-Crawford1">[12]</xref>, a vasoactive peptide which produces smooth muscle contraction <italic>in vivo</italic> <xref ref-type="bibr" rid="pone.0018536-Wynne1">[11]</xref>. Taken as a whole, these observations suggest that the Aß peptides may affect BP control. Interestingly, the Aß peptides decrease cerebral blood flow and volume in rodents <xref ref-type="bibr" rid="pone.0018536-Deane1">[13]</xref>–<xref ref-type="bibr" rid="pone.0018536-Iadecola1">[15]</xref>.</p><p>In the present study, we hypothesized that plasma Aß peptide concentrations may be associated with variations in systolic and/or diastolic blood pressure values (SBP and DBP, respectively). To this end, we analysed a pooled analysis of 1972 individuals from three independent cohorts in which plasma Aß<sub>1-40</sub> and Aß<sub>1-42</sub> concentrations were available.</p></sec><sec sec-type="methods" id="s2"><title>Methods</title><p>The three samples were selected according to the availability of (i) plasma Aß concentration assays using the same method (the INNO-BIA plasma Aß forms assay; this point is of particular importance, since the assay methodology can significantly influence interpretation of the data <xref ref-type="bibr" rid="pone.0018536-Lui1">[16]</xref>), (ii) SBP and DBP measurements; (iii) information on demographic variables, smoking and medication use.</p><sec id="s2a"><title>Populations</title><p>Written, informed consent was obtained from study participants. The study protocols for all populations were reviewed and approved by the appropriate independent ethics committees in each country. The institutional ethics committees of Austin Health, St Vincent's Health, Hollywood Private Hospital and Edith Cowan University granted ethics approval for the AIBL study. The institutional ethics committees of the Kremlin-Bicetre Hospital granted ethics approval for the 3C study. The institutional ethics committees of the Lille Hospital granted ethics approval for the MONA-LISA study.</p><p>The 3C Study is a population-based, prospective study of the relationship between vascular factors and dementia <xref ref-type="bibr" rid="pone.0018536-C1">[17]</xref>. It has been carried out in three French cities: Bordeaux (southwest France), Montpellier (southern France) and Dijon (central eastern France). A sample of non-institutionalised, over-65 subjects was randomly selected from the electoral rolls of each city between January 1999 and March 2001. In the present work, the study population was based on a sub-cohort of 1254 subjects randomly selected from the source sample totalling 8,414 individuals (i.e. a sampling ratio of 15%) stratified by centre, 5-year age class and gender. Aß plasma concentrations were measured in the whole sample <xref ref-type="bibr" rid="pone.0018536-Lambert1">[18]</xref>. Individuals taking antihypertensive drugs were excluded from our analysis (n = 615). Individuals for whom at least one Aß plasma concentration or co-variable measurement was missing were also excluded (n = 4), together with individuals exhibiting at least one aberrant Aß plasma concentration measurement (n = 8). These selection steps allowed us to define a sample of 627 individuals.</p><p>The MONA-LISA (LILLE) study is an epidemiological, cross-sectional, population-based study performed in the Lille urban area in northern France. Inhabitants aged 35-74 years were randomly sampled from electoral rolls after stratification by town size, gender and 10-year age groups (n = 1,602) <xref ref-type="bibr" rid="pone.0018536-Ferrires1">[19]</xref>. Only individuals older than 45 years old were selected (n = 1217) and blood samples were obtained from 1201 individuals. Our analysis excluded individuals taking antihypertensive drugs (n = 422), those for whom at least one Aß plasma concentration, SBP, DBP or co-variable measurement was also missing (n = 7) and those exhibiting at least one aberrant Aß plasma concentration measurement (n = 3). These selection steps allowed us to define a sample of 769 individuals.</p><p>The Australian Imaging Biomarkers and Lifestyle (AIBL) study of ageing has been described elsewhere <xref ref-type="bibr" rid="pone.0018536-Ellis1">[20]</xref>. It is a longitudinal study performed in Perth and Melbourne (Australia). A total of 1,112 volunteers constituted the AIBL inception cohort. Our analysis excluded individuals taking antihypertensive drugs (n = 375), those for whom at least one Aß plasma concentration, SBP, DBP or co-variable measurement was also missing (n = 147) and those exhibiting at least one aberrant Aß plasma concentration measurement (n = 14). Again, these selection steps enabled us to define a sample of 576 individuals from the AIBL cohort.</p></sec><sec id="s2b"><title>Amyloid beta peptide assay</title><p>Fasting plasma samples were collected in tubes containing sodium EDTA as an anticoagulant. Following centrifugation, plasma samples were aliquoted into polypropylene tubes, stored at –80°C and only thawed immediately prior to Aß quantification. The plasma Aß peptide assay was performed using the INNO-BIA plasma Aß forms assay (Innogenetics, Ghent, Belgium) based on the multiplex xMAP technique with a LABScan-100 system (Luminex BV, The Netherlands). The 3C and MONA-LISA (LILLE) studies were analyzed in the same centre (INSERM U837, Alzheimer & Tauopathies, Lille, France).</p></sec><sec id="s2c"><title>Blood pressure measurements and co-variables</title><p>During inclusion in the 3C study, BP was measured twice after 5 minutes in the seated position by using a standard cuff placed around the right arm and an electronic monitor (OMRON M4). In the MONA-LISA (LILLE) population, SBP and DBP were measured after the subject had been seated for at least 10 min with an automatic sphygmomanometer (OMRON 705IT) and an appropriately sized cuff, with the arm at heart level. In the AIBL study, BP for each participant was measured between 8.15 am and 9.30 am and after 10 minutes in the seated position by using the Welch Allyn “DuraShock” handheld unit (DS65). If a measurement was high (>140/90) or low, the procedure was repeated after 10 minutes.</p><p>The average of two measurements (available for 84% of the study sample) was used for analysis, whenever possible. Hypertension was defined as a SBP ≥140 mm Hg or DBP ≥90 mmHg (n = 337 in the 3C sample, n = 307 in the MONA-LISA (LILLE) sample and n = 270 in the AIBL sample).</p><p>Age, centre and gender were always used as adjusting factors. Several other co-variables were also considered as potential confounders: smoking status (current or not), plasma cholesterol (total, high-density lipoprotein), creatinine levels and body mass index (BMI, as defined by the Quetelet equation).</p></sec><sec id="s2d"><title>Statistics</title><p>The data were analysed using SAS statistical software (release 9.1, SAS Institute Inc., Cary NC, USA). In each centre, each quantitative variable was transformed into a z-score (equal to (observed value minus the sample mean), divided by the sample standard deviation). The relationships between the Aß<sub>1-40</sub>, Aß<sub>1-42</sub> and Aß<sub>1-42</sub>/Aß<sub>1-40</sub> z-scores on one hand and the SBP or DBP z-scores on the other were assessed using a general linear model (GLM) adjusted for age, centre and gender (model 1). Analyses were subsequently adjusted for other confounders, as defined below: smoking status, total cholesterol z-score, HDL z-score, creatinine z-score and BMI z-score (model 2). Interactions between Aß<sub>1-42</sub>/Aß<sub>1-40</sub> z-scores, SBP or DBP z-scores and age or gender were tested in a GLM adjusted as for model 2.</p><p>We analysed the association of Aß<sub>1-40</sub>, Aß<sub>1-42</sub> and Aß<sub>1-42</sub>/Aß<sub>1-40</sub> z-scores with the risk of hypertension. Aß<sub>1-40</sub>, Aß<sub>1-42</sub> and Aß<sub>1-42</sub>/Aß<sub>1-40</sub> z-scores tertiles were defined and the lowest was used as a reference in a logistic regression model. Odds ratios were systematically adjusted for centre, age, gender, smoking status, cholesterol (total, high-density lipoprotein), creatinine levels and BMI z-scores (model 2).</p></sec></sec><sec id="s3"><title>Results</title><p>The characteristics of the three independent, constituent samples are presented in <xref ref-type="table" rid="pone-0018536-t001">Table 1</xref>. There was a statistically significant, inverse association between plasma Aß<sub>1-42</sub>/Aß<sub>1-40</sub> and SBP (p = 0.03; <xref ref-type="table" rid="pone-0018536-t002">Table 2</xref>). A similar trend was observed for DBP (p = 0.06; <xref ref-type="table" rid="pone-0018536-t002">Table 2</xref>). We also looked at whether or not Aß<sub>1-42</sub>/Aß<sub>1-40</sub> was associated with the risk of hypertension. In fact, individuals in the upper Aß<sub>1-42</sub>/Aß<sub>1-40</sub> tertile had a 1.4-fold lower risk of hypertension than subjects in the lower tertile (<xref ref-type="table" rid="pone-0018536-t003">Table 3</xref>).</p><table-wrap id="pone-0018536-t001" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0018536.t001</object-id><label>Table 1</label><caption><title>Baseline sociodemographic variables and potential confounding factors in the 3C, ABLI and MONA-LISA (LILLE) populations (individuals not taking antihypertensive drugs; for details, see the Materials and <xref ref-type="sec" rid="s2">Methods</xref> section).</title></caption><alternatives><graphic id="pone-0018536-t001-1" xlink:href="pone.0018536.t001"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col></colgroup><thead><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">3C study (n = 627)</td><td align="left" rowspan="1" colspan="1">AIBL study (n = 576)</td><td align="left" rowspan="1" colspan="1">MONA-LISA study (n = 769)</td></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1">Age (years)</td><td align="left" rowspan="1" colspan="1">73.1±5.3</td><td align="left" rowspan="1" colspan="1">71.6±7.8</td><td align="left" rowspan="1" colspan="1">58.1±8.2</td></tr><tr><td align="left" rowspan="1" colspan="1">% women</td><td align="left" rowspan="1" colspan="1">59.7%</td><td align="left" rowspan="1" colspan="1">57.8%</td><td align="left" rowspan="1" colspan="1">49.4%</td></tr><tr><td align="left" rowspan="1" colspan="1">Smoking (% current)</td><td align="left" rowspan="1" colspan="1">6.7%</td><td align="left" rowspan="1" colspan="1">3.0%</td><td align="left" rowspan="1" colspan="1">18.6%</td></tr><tr><td align="left" rowspan="1" colspan="1">Body mass index (kg/m<sup>2</sup>)</td><td align="left" rowspan="1" colspan="1">24.9±3.5</td><td align="left" rowspan="1" colspan="1">25.5±4.1</td><td align="left" rowspan="1" colspan="1">26.5±4.5</td></tr><tr><td align="left" rowspan="1" colspan="1">Plasma HDL cholesterol (mmol/L)</td><td align="left" rowspan="1" colspan="1">1.67±0.41</td><td align="left" rowspan="1" colspan="1">1.70±0.44</td><td align="left" rowspan="1" colspan="1">1.50±0.39</td></tr><tr><td align="left" rowspan="1" colspan="1">Plasma cholesterol (mmol/L)</td><td align="left" rowspan="1" colspan="1">6.0±1.0</td><td align="left" rowspan="1" colspan="1">5.7±1.1</td><td align="left" rowspan="1" colspan="1">5.87±1.1</td></tr><tr><td align="left" rowspan="1" colspan="1">Plasma creatinine</td><td align="left" rowspan="1" colspan="1">80.5±15.6</td><td align="left" rowspan="1" colspan="1">81.1±17.3</td><td align="left" rowspan="1" colspan="1">85.0±15.8</td></tr><tr><td align="left" rowspan="1" colspan="1">SBP (mmHg)</td><td align="left" rowspan="1" colspan="1">141.9±20.4</td><td align="left" rowspan="1" colspan="1">136.5±14.7</td><td align="left" rowspan="1" colspan="1">136.5±18.6</td></tr><tr><td align="left" rowspan="1" colspan="1">DBP (mmHg)</td><td align="left" rowspan="1" colspan="1">81.3±11.0</td><td align="left" rowspan="1" colspan="1">78.0±9.3</td><td align="left" rowspan="1" colspan="1">82.2±10.6</td></tr><tr><td align="left" rowspan="1" colspan="1">Plasma Aß<sub>1-40</sub> (pg/ml)</td><td align="left" rowspan="1" colspan="1">227.8±48.0</td><td align="left" rowspan="1" colspan="1">153.6±40.4</td><td align="left" rowspan="1" colspan="1">205.4±42.8</td></tr><tr><td align="left" rowspan="1" colspan="1">Plasma Aß<sub>1-42</sub> (pg/ml)</td><td align="left" rowspan="1" colspan="1">37.5±10.3</td><td align="left" rowspan="1" colspan="1">31.3±10.0</td><td align="left" rowspan="1" colspan="1">36.7±11.45</td></tr><tr><td align="left" rowspan="1" colspan="1">Plasma Aß<sub>1-42</sub>/ Aß<sub>1-40</sub></td><td align="left" rowspan="1" colspan="1">0.169±0.049</td><td align="left" rowspan="1" colspan="1">0.209±0.059</td><td align="left" rowspan="1" colspan="1">0.184±0.069</td></tr></tbody></table></alternatives></table-wrap><table-wrap id="pone-0018536-t002" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0018536.t002</object-id><label>Table 2</label><caption><title>Associations between plasma Aß peptides and SBP & DBP values.</title></caption><alternatives><graphic id="pone-0018536-t002-2" xlink:href="pone.0018536.t002"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col></colgroup><thead><tr><td align="left" rowspan="1" colspan="1">Combined sample</td><td colspan="2" align="left" rowspan="1">Model 1</td><td colspan="2" align="left" rowspan="1">Model 2</td></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1"><bold>Aß<sub>1-40</sub></bold></td><td align="left" rowspan="1" colspan="1">ß</td><td align="left" rowspan="1" colspan="1">p</td><td align="left" rowspan="1" colspan="1">ß</td><td align="left" rowspan="1" colspan="1">p</td></tr><tr><td align="left" rowspan="1" colspan="1">SBP z-score</td><td align="left" rowspan="1" colspan="1">+0.006±0.023</td><td align="left" rowspan="1" colspan="1">0.80</td><td align="left" rowspan="1" colspan="1">+0.006±0.023</td><td align="left" rowspan="1" colspan="1">0.80</td></tr><tr><td align="left" rowspan="1" colspan="1">DBP z-score</td><td align="left" rowspan="1" colspan="1">+0.011±0.026</td><td align="left" rowspan="1" colspan="1">0.65</td><td align="left" rowspan="1" colspan="1">+0.005±0.023</td><td align="left" rowspan="1" colspan="1">0.83</td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>Aß<sub>1-42</sub></bold></td><td align="left" rowspan="1" colspan="1">ß</td><td align="left" rowspan="1" colspan="1">p</td><td align="left" rowspan="1" colspan="1">ß</td><td align="left" rowspan="1" colspan="1">p</td></tr><tr><td align="left" rowspan="1" colspan="1">SBP z-score</td><td align="left" rowspan="1" colspan="1">−0.036±0.021</td><td align="left" rowspan="1" colspan="1">0.09</td><td align="left" rowspan="1" colspan="1">−0.039±0.021</td><td align="left" rowspan="1" colspan="1">0.10</td></tr><tr><td align="left" rowspan="1" colspan="1">DBP z-score</td><td align="left" rowspan="1" colspan="1">−0.023±0.022</td><td align="left" rowspan="1" colspan="1">0.31</td><td align="left" rowspan="1" colspan="1">−0.031±0.022</td><td align="left" rowspan="1" colspan="1">0.16</td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>Aß<sub>1-42</sub>/Aß<sub>1-40</sub></bold></td><td align="left" rowspan="1" colspan="1">ß</td><td align="left" rowspan="1" colspan="1">p</td><td align="left" rowspan="1" colspan="1">ß</td><td align="left" rowspan="1" colspan="1">p</td></tr><tr><td align="left" rowspan="1" colspan="1">SBP z-score</td><td align="left" rowspan="1" colspan="1">−0.044±0.022</td><td align="left" rowspan="1" colspan="1">0.04</td><td align="left" rowspan="1" colspan="1">−0.045±0.021</td><td align="left" rowspan="1" colspan="1">0.03</td></tr><tr><td align="left" rowspan="1" colspan="1">DBP z-score</td><td align="left" rowspan="1" colspan="1">−0.037±0.022</td><td align="left" rowspan="1" colspan="1">0.10</td><td align="left" rowspan="1" colspan="1">−0.040±0.022</td><td align="left" rowspan="1" colspan="1">0.06</td></tr></tbody></table></alternatives><table-wrap-foot><fn id="nt101"><label></label><p>Data are ß coefficients ± 95% CI.</p></fn><fn id="nt102"><label></label><p>Model 1: Adjusted for age, gender, centre.</p></fn><fn id="nt103"><label></label><p>Model 2: Adjusted for age, gender, centre, smoking status, total cholesterol z-score, HDL z-score, creatinine z-score and BMI z-score.</p></fn></table-wrap-foot></table-wrap><table-wrap id="pone-0018536-t003" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0018536.t003</object-id><label>Table 3</label><caption><title>Associations between the plasma Aß<sub> 1-42</sub>/A ß<sub>1-40</sub> ratio and hypertension.</title></caption><alternatives><graphic id="pone-0018536-t003-3" xlink:href="pone.0018536.t003"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col></colgroup><thead><tr><td align="left" rowspan="1" colspan="1"></td><td colspan="3" align="left" rowspan="1">A ß<sub> 1-42</sub>/A ß<sub> 1-40</sub> z-score</td><td align="left" rowspan="1" colspan="1"></td></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1">Risk of hypertension</td><td align="left" rowspan="1" colspan="1">1<sup>st</sup> tertile</td><td align="left" rowspan="1" colspan="1">2<sup>nd</sup> tertile</td><td align="left" rowspan="1" colspan="1">3<sup>rd</sup> tertile</td><td align="left" rowspan="1" colspan="1">p</td></tr><tr><td align="left" rowspan="1" colspan="1">Whole sample</td><td align="left" rowspan="1" colspan="1">1.00 (ref)</td><td align="left" rowspan="1" colspan="1">0.81 (0.65–1.03)</td><td align="left" rowspan="1" colspan="1">0.71 (0.56–0.90)</td><td align="left" rowspan="1" colspan="1">0.004</td></tr><tr><td align="left" rowspan="1" colspan="1">>69 years of age</td><td align="left" rowspan="1" colspan="1">1.00 (ref)</td><td align="left" rowspan="1" colspan="1">0.69 (0.49–0.98)</td><td align="left" rowspan="1" colspan="1">0.53 (0.37–0.75)</td><td align="left" rowspan="1" colspan="1">0.0003</td></tr></tbody></table></alternatives><table-wrap-foot><fn id="nt104"><label></label><p>The odds ratio (95% CI) for hypertension (n = 914) was adjusted for age, gender, centre, smoking status, total cholesterol z-score, HDL z-score, creatinine z-score and BMI z-score.</p></fn></table-wrap-foot></table-wrap><p>We next searched for potential interactions between age, gender and the associations described above. We observed significant interactions with age when analysing the association between SBP or the risk of hypertension and plasma Aß<sub>1-42</sub>/Aß<sub>1-40</sub> (p = 0.02 and p = 0.04, respectively). These observations are particular relevant, since BP and plasma Aß concentrations are already known to be strongly age-dependent <xref ref-type="bibr" rid="pone.0018536-Lambert1">[18]</xref>, <xref ref-type="bibr" rid="pone.0018536-Casiglia1">[21]</xref>.</p><p>We thus stratified the combined sample using the median age (>69) as a cut-off and observed more pronounced inverse associations between BP levels and Aß<sub>1-42</sub>/Aß<sub>1-40</sub> in the elderly individuals (<xref ref-type="table" rid="pone-0018536-t004">Table 4</xref>). Importantly, the association of Aß<sub>1-42</sub>/Aß<sub>1-40</sub> with BP levels appeared to be primarily linked to plasma Aß<sub>1-40</sub> levels (<xref ref-type="table" rid="pone-0018536-t004">Table 4</xref>). Similarly, this association was even more pronounced in the elderly, where individuals in the upper Aß<sub>1-42</sub>/Aß<sub>1-40</sub> tertile had a 2-fold lower risk of hypertension (<xref ref-type="table" rid="pone-0018536-t003">Table 3</xref>). The plasma Aß<sub>1-42</sub>/Aß<sub>1-40</sub> ratio's associations with hypertension again appeared to be mainly driven by plasma Aß<sub>1-40</sub> in the oldest subjects. Individuals in the upper Aß<sub>1-40</sub> z-score tertile had a greater risk of suffering from hypertension (OR = 1.61, 95% CI [1.09–2.39], p = 0.01), whereas no association with the Aß<sub>1-42</sub> z-score was found (OR = 1.03, 95% CI [0.74–1.45], p = 0.85).</p><table-wrap id="pone-0018536-t004" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0018536.t004</object-id><label>Table 4</label><caption><title>Associations between plasma Aß peptides and SBP & DBP values.</title></caption><alternatives><graphic id="pone-0018536-t004-4" xlink:href="pone.0018536.t004"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col></colgroup><thead><tr><td align="left" rowspan="1" colspan="1">≤69 years of age</td><td colspan="2" align="left" rowspan="1">Model 1</td><td colspan="2" align="left" rowspan="1">Model 2</td></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1"><bold>Aß<sub>1-40</sub></bold></td><td align="left" rowspan="1" colspan="1">ß</td><td align="left" rowspan="1" colspan="1">p</td><td align="left" rowspan="1" colspan="1">ß</td><td align="left" rowspan="1" colspan="1">p</td></tr><tr><td align="left" rowspan="1" colspan="1">SBP z-score</td><td align="left" rowspan="1" colspan="1">−0.046±0.030</td><td align="left" rowspan="1" colspan="1">0.12</td><td align="left" rowspan="1" colspan="1">−0.049±0.029</td><td align="left" rowspan="1" colspan="1">0.10</td></tr><tr><td align="left" rowspan="1" colspan="1">DBP z-score</td><td align="left" rowspan="1" colspan="1">−0.025±0.031</td><td align="left" rowspan="1" colspan="1">0.41</td><td align="left" rowspan="1" colspan="1">−0.035±0.030</td><td align="left" rowspan="1" colspan="1">0.24</td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>Aß<sub>1-42</sub></bold></td><td align="left" rowspan="1" colspan="1">ß</td><td align="left" rowspan="1" colspan="1">p</td><td align="left" rowspan="1" colspan="1">ß</td><td align="left" rowspan="1" colspan="1">p</td></tr><tr><td align="left" rowspan="1" colspan="1">SBP z-score</td><td align="left" rowspan="1" colspan="1">−0.028±0.030</td><td align="left" rowspan="1" colspan="1">0.34</td><td align="left" rowspan="1" colspan="1">−0.036±0.030</td><td align="left" rowspan="1" colspan="1">0.23</td></tr><tr><td align="left" rowspan="1" colspan="1">DBP z-score</td><td align="left" rowspan="1" colspan="1">−0.008±0.031</td><td align="left" rowspan="1" colspan="1">0.80</td><td align="left" rowspan="1" colspan="1">−0.032±0.031</td><td align="left" rowspan="1" colspan="1">0.54</td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>Aß<sub>1-42</sub>/Aß<sub>1-40</sub></bold></td><td align="left" rowspan="1" colspan="1">ß</td><td align="left" rowspan="1" colspan="1">p</td><td align="left" rowspan="1" colspan="1">ß</td><td align="left" rowspan="1" colspan="1">p</td></tr><tr><td align="left" rowspan="1" colspan="1">SBP z-score</td><td align="left" rowspan="1" colspan="1">+0.013±0.022</td><td align="left" rowspan="1" colspan="1">0.56</td><td align="left" rowspan="1" colspan="1">+0.006±0.022</td><td align="left" rowspan="1" colspan="1">0.78</td></tr><tr><td align="left" rowspan="1" colspan="1">DBP z-score</td><td align="left" rowspan="1" colspan="1">−0.010±0.024</td><td align="left" rowspan="1" colspan="1">0.67</td><td align="left" rowspan="1" colspan="1">−0.013±0.022</td><td align="left" rowspan="1" colspan="1">0.57</td></tr></tbody></table><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col></colgroup><thead><tr><td align="left" rowspan="1" colspan="1">>69 years of age</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1"><bold>Aß<sub>1-40</sub></bold></td><td align="left" rowspan="1" colspan="1">ß</td><td align="left" rowspan="1" colspan="1">p</td><td align="left" rowspan="1" colspan="1">ß</td><td align="left" rowspan="1" colspan="1">p</td></tr><tr><td align="left" rowspan="1" colspan="1">SBP z-score</td><td align="left" rowspan="1" colspan="1">+0.099±0.034</td><td align="left" rowspan="1" colspan="1">0.004</td><td align="left" rowspan="1" colspan="1">+0.098±0.035</td><td align="left" rowspan="1" colspan="1">0.005</td></tr><tr><td align="left" rowspan="1" colspan="1">DBP z-score</td><td align="left" rowspan="1" colspan="1">+0.066±0.035</td><td align="left" rowspan="1" colspan="1">0.06</td><td align="left" rowspan="1" colspan="1">+0.066±0.035</td><td align="left" rowspan="1" colspan="1">0.07</td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>Aß<sub>1-42</sub></bold></td><td align="left" rowspan="1" colspan="1">ß</td><td align="left" rowspan="1" colspan="1">p</td><td align="left" rowspan="1" colspan="1">ß</td><td align="left" rowspan="1" colspan="1">p</td></tr><tr><td align="left" rowspan="1" colspan="1">SBP z-score</td><td align="left" rowspan="1" colspan="1">−0.032±0.031</td><td align="left" rowspan="1" colspan="1">0.30</td><td align="left" rowspan="1" colspan="1">−0.039±0.031</td><td align="left" rowspan="1" colspan="1">0.21</td></tr><tr><td align="left" rowspan="1" colspan="1">DBP z-score</td><td align="left" rowspan="1" colspan="1">−0.028±0.031</td><td align="left" rowspan="1" colspan="1">0.38</td><td align="left" rowspan="1" colspan="1">−0.032±0.031</td><td align="left" rowspan="1" colspan="1">0.30</td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>Aß<sub>1-42</sub>/Aß<sub>1-40</sub></bold></td><td align="left" rowspan="1" colspan="1">ß</td><td align="left" rowspan="1" colspan="1">p</td><td align="left" rowspan="1" colspan="1">ß</td><td align="left" rowspan="1" colspan="1">p</td></tr><tr><td align="left" rowspan="1" colspan="1">SBP z-score</td><td align="left" rowspan="1" colspan="1">−0.090±0.030</td><td align="left" rowspan="1" colspan="1">0.003</td><td align="left" rowspan="1" colspan="1">−0.092±0.030</td><td align="left" rowspan="1" colspan="1">0.002</td></tr><tr><td align="left" rowspan="1" colspan="1">DBP z-score</td><td align="left" rowspan="1" colspan="1">−0.064±0.031</td><td align="left" rowspan="1" colspan="1">0.04</td><td align="left" rowspan="1" colspan="1">−0.067±0.031</td><td align="left" rowspan="1" colspan="1">0.03</td></tr></tbody></table></alternatives><table-wrap-foot><fn id="nt105"><label></label><p>Data are ß coefficients ± 95% CI.</p></fn><fn id="nt106"><label></label><p>Model 1: Adjusted for age, gender, centre.</p></fn><fn id="nt107"><label></label><p>Model 2: Adjusted for age, gender, centre, smoking status, total cholesterol z-score, HDL z-score, creatinine z-score and BMI z-score.</p></fn></table-wrap-foot></table-wrap><p>Importantly, all the reported associations appeared homogenous and in the same direction in the three samples when analysed separately (<xref ref-type="supplementary-material" rid="pone.0018536.s001">Table S1</xref> and <xref ref-type="supplementary-material" rid="pone.0018536.s002">S2</xref>) and remained significant when pairs of populations were compared in a sensitivity analysis (data not shown).</p></sec><sec id="s4"><title>Discussion</title><p>Here, we have shown that an elevated plasma Aß<sub>1-42</sub>/Aß<sub>1-40</sub> ratio is significantly associated with low SBP and DBP values. In the elderly, we estimate that a 0.01 unit increment in Aß<sub>1-42</sub>/Aß<sub>1-40</sub> was associated with a 0.29±0.09 mmHg decline in SBP and a 0.10±0.05 mmHg decline in DBP. Consistently, an elevated Aß<sub>1-42</sub>/Aß<sub>1-40</sub> plasma ratio was also associated with a lower risk of hypertension in the elderly.</p><p>Importantly, the plasma Aß<sub>1-42</sub>/Aß<sub>1-40</sub> ratio's associations with SBP, DBP and hypertension appeared to be mainly driven by plasma Aß<sub>1-40</sub> in the oldest subjects. Our observation of an association between plasma Aß<sub>1-40</sub> and SBP agrees with the report of a similar trend (in a small sample) by Abdullah et al <xref ref-type="bibr" rid="pone.0018536-Abdullah1">[22]</xref>. The mechanisms underlying this preferential association may be related to the Aß<sub>1-40</sub> peptide's properties on vascular vessels. Earlier studies have shown that Aß<sub>1-40</sub> peptides can constrict cerebral blood vessels <italic>in vitro</italic><sup>9</sup> and decrease cerebral flow and cerebral blood volume <italic>in vivo</italic> <xref ref-type="bibr" rid="pone.0018536-Frackowiak1">[10]</xref>–<xref ref-type="bibr" rid="pone.0018536-Crawford1">[12]</xref>. and that Aß<sub>1-40</sub> has greater vasoconstriction effects on the cerebral vasculature than Aß<sub>1-42</sub> does <xref ref-type="bibr" rid="pone.0018536-Crawford1">[12]</xref>. Furthermore, in rodents, injection of Aß<sub>1-40</sub> into the tail modulates cerebral blood flow and volume, suggesting that Aß peptides have a direct impact on blood pressure. Finally, Aß peptides have been described to potentially modulate the vasoactivity of the rat aorta <xref ref-type="bibr" rid="pone.0018536-Paris1">[23]</xref>. Thus, by extension our observation of an association between an elevated Aß<sub>1-42</sub>/Aß<sub>1-40</sub> ratio and low SBP may be related to the properties of Aß<sub>1-40</sub> on vascular wall in the elderly. <italic>In vitro</italic> and <italic>in vivo</italic> experiments will be needed to underpin this epidemiological observation and to extend knowledge of the Aß peptides' vasoactivity from the cerebral vasculature to the vascular system as a whole. Alternatively, we cannot rule out the possibility that the plasma Aß<sub>1-42</sub>/Aß<sub>1-40</sub> ratio is merely a marker of other parameters involved in BP variations or that the plasma Aß<sub>1-42</sub>/Aß<sub>1-40</sub> association with BP is a consequence of BP variations by themselves. These possibilities may help explain the stronger association of the plasma Aß<sub>1-42</sub>/Aß<sub>1-40</sub> ratio with SBP and DBP in the elderly individuals. Age-related arterial wall stiffening may lead indirectly to subtle changes in APP metabolism in the SMCs (one of the main non-brain cell types able to produce Aß peptides). Again, only <italic>in vitro</italic> and <italic>in vivo</italic> experiments will be able to clarify this question.</p><p>Nonetheless, and notwithstanding the consistent effects that we have observed, our study suffered from a number of limitations. Firstly, quantification of Aß peptides in plasma is not fully standardized and it varied from one centre to another (<xref ref-type="table" rid="pone-0018536-t001">Table 1</xref>). Even though centre-to-centre variations are well known for quantitative variables, we cannot rule out the possible presence of assay-related of bias. Therefore, in order to minimize between-centre variability, we transformed the data in to z-scores prior to our statistical analyses. Secondly, it is still unclear whether the assay used here does indeed quantify all the various free, bound, monomeric and oligomeric forms of plasma Aß<sub>1-40</sub> and Aß<sub>1-42</sub> peptides. Accordingly, we may only have a partial picture of the Aß<sub>1-40</sub> and Aß<sub>1-42</sub> concentrations in plasma - a picture which is also likely to be influenced by sample conditioning, storage and analyses. In order to minimize this problem, we analysed three independent cohorts in which the same plasma Aß peptide assay method had been used. Interestingly, the assay performed in the present study uses xMAP technology to quantify several epitopes and thus several different Aß species. Furthermore, we observed a strong correlation between plasma Aß<sub>1-40</sub> and Aß<sub>1-42</sub> in all the populations analysed (data not shown) - indicating that the plasma Aß peptide concentrations are representative of the physiological processes leading to Aß peptide production (i.e. APP metabolism). Furthermore, sensitivity analyses indicated that the observed results are homogeneous for the elderly individuals in the different studies and support the existence of a real impact of Aß peptides on BP values and hypertension (<xref ref-type="supplementary-material" rid="pone.0018536.s001">Tables S1</xref> and <xref ref-type="supplementary-material" rid="pone.0018536.s002">S2</xref>).</p><p>Our data may be of particular interest in the field of dementia. On the epidemiological level, an increased risk of dementia in individuals with high BP (and especially very high SBP) has been reported <xref ref-type="bibr" rid="pone.0018536-Yoshitake1">[24]</xref>, although there is no clear consensus to indicate that raised BP in later life is a risk factor in dementia <xref ref-type="bibr" rid="pone.0018536-Qiu1">[25]</xref>–<xref ref-type="bibr" rid="pone.0018536-Feldstein1">[27]</xref>. Furthermore, use of antihypertensive agents was suggested to reduce the risk of dementia and cognitive decline observed in clinical trials <xref ref-type="bibr" rid="pone.0018536-Nagai1">[28]</xref>. Interestingly, we and others have observed that an elevated Aß<sub>1-42</sub>/Aß<sub>1-40</sub> ratio is strongly associated with a decreased risk of incident Alzheimer's disease and mixed/vascular dementia <xref ref-type="bibr" rid="pone.0018536-Lambert1">[18]</xref>, <xref ref-type="bibr" rid="pone.0018536-VanOijen1">[29]</xref>. Consequently, we can justifiably postulate that high plasma Aß<sub>1-42</sub>/Aß<sub>1-40</sub> may reduce and/or delay the risk of developing dementia in the elderly by decreasing SBP and lowering the risk of hypertension. Our data might be also consistent with the finding that plasma Aß<sub>1-40</sub> is associated with microvascular brain injury in subjects with AD, mild cognitive impairment or cerebral amyloid angiopathy <xref ref-type="bibr" rid="pone.0018536-Gurol1">[30]</xref>.</p><p>In conclusion, our data support the potential vasoactive properties of the Aß peptides and suggest that the latter are able to subtly modulate BP in the elderly. Furthermore, these observations may offer new opportunities for better understanding the vascular component of dementia in general and Alzheimer's disease in particular.</p></sec><sec sec-type="supplementary-material" id="s5"><title>Supporting Information</title><supplementary-material content-type="local-data" id="pone.0018536.s001"><label>Table S1</label><caption><p>Associations between plasma Aß peptides and SBP & DBP values in the elderly participants in the 3C (n = 445), MONA-LISA (LILLE) (n = 102) and AIBL (n = 323) studies. Adjusted for age, gender, centre, smoking status, total cholesterol z-score, HDL z-score, creatinine z-score and BMI z-score.</p><p>(DOC)</p></caption><media xlink:href="pone.0018536.s001.doc" mimetype="application" mime-subtype="msword"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pone.0018536.s002"><label>Table S2</label><caption><p>Associations between plasma Aß<sub>1-42</sub>/Aß<sub>1-40</sub> ratio and hypertension in the elderly. Odds ratio (95% CI) for hypertension in the 3C study (n = 265), in the MONA-LISA (LILLE) study (n = 58) and the AIBL study (n = 180). Adjusted for age, gender, centre (when necessary), smoking status, total cholesterol z-score, HDL z-score, creatinine z-score and BMI z-score.</p><p>(DOC)</p></caption><media xlink:href="pone.0018536.s002.doc" mimetype="application" mime-subtype="msword"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material></sec></body><back><ack><p>We thank Amélie Labudeck for her excellent technical assistance.</p></ack><fn-group><fn fn-type="conflict"><p><bold>Competing Interests: </bold>There are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials, as detailed online in the guide for authors. CSIRO involvement does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.</p></fn><fn fn-type="financial-disclosure"><p><bold>Funding: </bold>The 3C Study was performed as part of a collaboration between the Institut National de la Santé et de la Recherche Médicale (INSERM), the Victor Segalen-Bordeaux II University and Sanofi-Synthélabo. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The 3C Study was also funded by the Caisse Nationale Maladie des Travailleurs Salariés, Direction Générale de la Santé, MGEN, Institut de la Longévité, Agence Française de Sécurité Sanitaire des Produits de Santé, the Aquitaine and Bourgogne Regional Councils, Fondation de France and the joint French Ministry of Research/INSERM “Cohortes et collections de données biologiques” programme. Sanofi-Synthélabo provided funding for this study. Lille Génopôle received an unconditional grant from Eisai. This work was additionally funded by the CNRS, the Nord Pas-de-Calais Regional Council, the European Regional Development Fund and grants from INSERM-DHOS-INCA (Project A08037ECS) and the European Community's cNEUPRO programme (contract LSHM-CT-2007-037950). 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