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<meta name="DC.Title" content="Apolipoprotein E ε4 Does Not Modulate Amyloid-β–Associated Neurodegeneration in Preclinical Alzheimer Disease" />
<meta name="DC.Identifier" content="10.3174/ajnr.A3267" />
<meta name="DC.Date" content="2013-03-01" />
<meta name="DC.Publisher" content="American Journal of Neuroradiology" />
<meta name="DC.Rights" content="© 2013 by American Journal of Neuroradiology. Indicates open access to non-subscribers at www.ajnr.org" />
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<meta name="DC.Description" content="BACKGROUND AND PURPOSE: Among cognitively healthy older individuals, the relationship among the 2 hallmark proteins of AD (Aβ and τ APOE ε4) and neurodegeneration is not well-understood. Here, we investigated the relationship between Aβ, p-τ, and APOE ε4 on longitudinal brain atrophy in preclinical AD.

MATERIALS AND METHODS: We examined 107 cognitively healthy older adults who underwent longitudinal MR imaging and baseline lumbar puncture. Within the same linear mixed-effects model, we concurrently investigated main and interactive effects between the APOE ε4 genotype and CSF Aβ1–42, CSF p-τ and CSF Aβ1–42, and the APOE ε4 genotype and CSF p-τ on entorhinal cortex atrophy rate. We also examined the relationship of APOE ε4, CSF p-τ, and CSF Aβ1–42 on the atrophy rate of other AD-vulnerable neuroanatomic regions.

RESULTS: The full model with main and interactive effects demonstrated a significant interaction only between CSF p-τ and CSF Aβ1–42 on entorhinal cortex atrophy rate, indicating elevated atrophy with time in individuals with increased CSF p-τ and decreased CSF Aβ1–42. The APOE ε4 genotype was significantly and specifically associated with CSF Aβ1–42. However, the interaction between the APOE ε4 genotype and either CSF Aβ1–42 or CSF p-τ on entorhinal cortex atrophy rate was not significant. We found similar results in other AD-vulnerable regions.

CONCLUSIONS: On the basis of our findings and building on prior experimental evidence, we propose a model of the pathogenic cascade underlying preclinical AD in which APOE ε4 primarily influences the pathology of Alzheimer disease via Aβ-related mechanisms, and in turn, Aβ-associated neurodegeneration occurs only in the presence of p-τ.

Aβ
:   amyloid-β
AD
:   Alzheimer disease
APOE ε4
:   ε4 allele of apolipoprotein E 
HC
:   healthy controls
p-τ
:   phospho-τ181p
SE
:   standard error of the mean" />
<meta name="DC.Contributor" content="R.S. Desikan" />
<meta name="DC.Contributor" content="L.K. McEvoy" />
<meta name="DC.Contributor" content="D. Holland" />
<meta name="DC.Contributor" content="W.K. Thompson" />
<meta name="DC.Contributor" content="J.B. Brewer" />
<meta name="DC.Contributor" content="P.S. Aisen" />
<meta name="DC.Contributor" content="O.A. Andreassen" />
<meta name="DC.Contributor" content="B.T. Hyman" />
<meta name="DC.Contributor" content="R.A. Sperling" />
<meta name="DC.Contributor" content="A.M. Dale" />
<meta name="DC.Contributor" content="for the Alzheimer's Disease Neuroimaging Initiative" />
<meta name="article:published_time" content="2013-03-01" />
<meta name="article:section" content="Brain" />
<meta name="citation_title" content="Apolipoprotein E ε4 Does Not Modulate Amyloid-β–Associated Neurodegeneration in Preclinical Alzheimer Disease" />
<meta name="citation_abstract" lang="en" content="&lt;h3&gt;BACKGROUND AND PURPOSE:&lt;/h3&gt;
&lt;p&gt;Among cognitively healthy older individuals, the relationship among the 2 hallmark proteins of AD (Aβ and τ &lt;i&gt;APOE&lt;/i&gt; ε4) and neurodegeneration is not well-understood. Here, we investigated the relationship between Aβ, p-τ, and &lt;i&gt;APOE&lt;/i&gt; ε4 on longitudinal brain atrophy in preclinical AD.&lt;/p&gt;&lt;h3&gt;MATERIALS AND METHODS:&lt;/h3&gt;
&lt;p&gt;We examined 107 cognitively healthy older adults who underwent longitudinal MR imaging and baseline lumbar puncture. Within the same linear mixed-effects model, we concurrently investigated main and interactive effects between the &lt;i&gt;APOE&lt;/i&gt; ε4 genotype and CSF Aβ&lt;sub&gt;1–42&lt;/sub&gt;, CSF p-τ and CSF Aβ&lt;sub&gt;1–42&lt;/sub&gt;, and the &lt;i&gt;APOE&lt;/i&gt; ε4 genotype and CSF p-τ on entorhinal cortex atrophy rate. We also examined the relationship of &lt;i&gt;APOE&lt;/i&gt; ε4, CSF p-τ, and CSF Aβ&lt;sub&gt;1–42&lt;/sub&gt; on the atrophy rate of other AD-vulnerable neuroanatomic regions.&lt;/p&gt;&lt;h3&gt;RESULTS:&lt;/h3&gt;
&lt;p&gt;The full model with main and interactive effects demonstrated a significant interaction only between CSF p-τ and CSF Aβ&lt;sub&gt;1–42&lt;/sub&gt; on entorhinal cortex atrophy rate, indicating elevated atrophy with time in individuals with increased CSF p-τ and decreased CSF Aβ&lt;sub&gt;1–42&lt;/sub&gt;. The &lt;i&gt;APOE&lt;/i&gt; ε4 genotype was significantly and specifically associated with CSF Aβ&lt;sub&gt;1–42&lt;/sub&gt;. However, the interaction between the &lt;i&gt;APOE&lt;/i&gt; ε4 genotype and either CSF Aβ&lt;sub&gt;1–42&lt;/sub&gt; or CSF p-τ on entorhinal cortex atrophy rate was not significant. We found similar results in other AD-vulnerable regions.&lt;/p&gt;&lt;h3&gt;CONCLUSIONS:&lt;/h3&gt;
&lt;p&gt;On the basis of our findings and building on prior experimental evidence, we propose a model of the pathogenic cascade underlying preclinical AD in which &lt;i&gt;APOE&lt;/i&gt; ε4 primarily influences the pathology of Alzheimer disease via Aβ-related mechanisms, and in turn, Aβ-associated neurodegeneration occurs only in the presence of p-τ.&lt;/p&gt;" />
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<meta name="twitter:title" content="Apolipoprotein E ε4 Does Not Modulate Amyloid-β–Associated Neurodegeneration in Preclinical Alzheimer Disease" />
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<meta name="twitter:description" content="BACKGROUND AND PURPOSE: Among cognitively healthy older individuals, the relationship among the 2 hallmark proteins of AD (Aβ and τ APOE ε4) and neurodegeneration is not well-understood. Here, we investigated the relationship between Aβ, p-τ, and APOE ε4 on longitudinal brain atrophy in preclinical AD.

MATERIALS AND METHODS: We examined 107 cognitively healthy older adults who underwent longitudinal MR imaging and baseline lumbar puncture. Within the same linear mixed-effects model, we concurrently investigated main and interactive effects between the APOE ε4 genotype and CSF Aβ1–42, CSF p-τ and CSF Aβ1–42, and the APOE ε4 genotype and CSF p-τ on entorhinal cortex atrophy rate. We also examined the relationship of APOE ε4, CSF p-τ, and CSF Aβ1–42 on the atrophy rate of other AD-vulnerable neuroanatomic regions.

RESULTS: The full model with main and interactive effects demonstrated a significant interaction only between CSF p-τ and CSF Aβ1–42 on entorhinal cortex atrophy rate, indicating elevated atrophy with time in individuals with increased CSF p-τ and decreased CSF Aβ1–42. The APOE ε4 genotype was significantly and specifically associated with CSF Aβ1–42. However, the interaction between the APOE ε4 genotype and either CSF Aβ1–42 or CSF p-τ on entorhinal cortex atrophy rate was not significant. We found similar results in other AD-vulnerable regions.

CONCLUSIONS: On the basis of our findings and building on prior experimental evidence, we propose a model of the pathogenic cascade underlying preclinical AD in which APOE ε4 primarily influences the pathology of Alzheimer disease via Aβ-related mechanisms, and in turn, Aβ-associated neurodegeneration occurs only in the presence of p-τ.

Aβ
:   amyloid-β
AD
:   Alzheimer disease
APOE ε4
:   ε4 allele of apolipoprotein E 
HC
:   healthy controls
p-τ
:   phospho-τ181p
SE
:   standard error of the mean" />
<meta name="og-title" property="og:title" content="Apolipoprotein E ε4 Does Not Modulate Amyloid-β–Associated Neurodegeneration in Preclinical Alzheimer Disease" />
<meta name="og-url" property="og:url" content="http://ajnr-stage2.stage.highwire.org/content/34/3/505" />
<meta name="og-site-name" property="og:site_name" content="American Journal of Neuroradiology" />
<meta name="og-description" property="og:description" content="BACKGROUND AND PURPOSE: Among cognitively healthy older individuals, the relationship among the 2 hallmark proteins of AD (Aβ and τ APOE ε4) and neurodegeneration is not well-understood. Here, we investigated the relationship between Aβ, p-τ, and APOE ε4 on longitudinal brain atrophy in preclinical AD.

MATERIALS AND METHODS: We examined 107 cognitively healthy older adults who underwent longitudinal MR imaging and baseline lumbar puncture. Within the same linear mixed-effects model, we concurrently investigated main and interactive effects between the APOE ε4 genotype and CSF Aβ1–42, CSF p-τ and CSF Aβ1–42, and the APOE ε4 genotype and CSF p-τ on entorhinal cortex atrophy rate. We also examined the relationship of APOE ε4, CSF p-τ, and CSF Aβ1–42 on the atrophy rate of other AD-vulnerable neuroanatomic regions.

RESULTS: The full model with main and interactive effects demonstrated a significant interaction only between CSF p-τ and CSF Aβ1–42 on entorhinal cortex atrophy rate, indicating elevated atrophy with time in individuals with increased CSF p-τ and decreased CSF Aβ1–42. The APOE ε4 genotype was significantly and specifically associated with CSF Aβ1–42. However, the interaction between the APOE ε4 genotype and either CSF Aβ1–42 or CSF p-τ on entorhinal cortex atrophy rate was not significant. We found similar results in other AD-vulnerable regions.

CONCLUSIONS: On the basis of our findings and building on prior experimental evidence, we propose a model of the pathogenic cascade underlying preclinical AD in which APOE ε4 primarily influences the pathology of Alzheimer disease via Aβ-related mechanisms, and in turn, Aβ-associated neurodegeneration occurs only in the presence of p-τ.

Aβ
:   amyloid-β
AD
:   Alzheimer disease
APOE ε4
:   ε4 allele of apolipoprotein E 
HC
:   healthy controls
p-τ
:   phospho-τ181p
SE
:   standard error of the mean" />
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    	<div class="highwire-cite-authors"><span  class="highwire-citation-authors"><span class="highwire-citation-author first" data-delta="0">R.S. Desikan</span>, <span class="highwire-citation-author" data-delta="1">L.K. McEvoy</span>, <span class="highwire-citation-author" data-delta="2">D. Holland</span>, <span class="highwire-citation-author" data-delta="3">W.K. Thompson</span>, <span class="highwire-citation-author" data-delta="4">J.B. Brewer</span>, <span class="highwire-citation-author" data-delta="5">P.S. Aisen</span>, <span class="highwire-citation-author" data-delta="6">O.A. Andreassen</span>, <span class="highwire-citation-author" data-delta="7">B.T. Hyman</span>, <span class="highwire-citation-author" data-delta="8">R.A. Sperling</span>, <span class="highwire-citation-author" data-delta="9">A.M. Dale</span> and <span class="highwire-citation-author" data-delta="10"><span class="nlm-collab" data-xlink-type="simple" data-hwp-id="collab-1">for the Alzheimer's Disease Neuroimaging Initiative</span></span></span></div>
  
    	<div class="highwire-cite-metadata"><span  class="highwire-cite-metadata-journal highwire-cite-metadata">American Journal of Neuroradiology </span><span  class="highwire-cite-metadata-date highwire-cite-metadata">March 2013,  </span><span  class="highwire-cite-metadata-volume highwire-cite-metadata">34 </span><span  class="highwire-cite-metadata-issue highwire-cite-metadata">(3) </span><span  class="highwire-cite-metadata-pages highwire-cite-metadata">505-510; </span><span  class="highwire-cite-metadata-doi highwire-cite-metadata">DOI: https://doi.org/10.3174/ajnr.A3267 </span></div>
  
  
  
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<div id="hw-article-author-popups-top-node-12294--62097885490" style="display: none;"><div class="author-tooltip-0"><div class="author-tooltip-name">R.S. Desikan </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>a</span>From the Departments of Radiology (R.S.D., L.K.E., J.B.B., A.M.D.)</div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&amp;gs_type=author&amp;author%5B0%5D=R.S.%2BDesikan%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=Desikan%20R&amp;link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link last"><a href="/search/author1%3AR.S.%2BDesikan%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li></ul></div><div class="author-tooltip-1"><div class="author-tooltip-name">L.K. McEvoy </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>a</span>From the Departments of Radiology (R.S.D., L.K.E., J.B.B., A.M.D.)</div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&amp;gs_type=author&amp;author%5B0%5D=L.K.%2BMcEvoy%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=McEvoy%20L&amp;link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link last"><a href="/search/author1%3AL.K.%2BMcEvoy%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li></ul></div><div class="author-tooltip-2"><div class="author-tooltip-name">D. Holland </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>b</span>Neuroscience (D.H., J.B.B., P.S.A., A.M.D.)</div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&amp;gs_type=author&amp;author%5B0%5D=D.%2BHolland%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=Holland%20D&amp;link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link last"><a href="/search/author1%3AD.%2BHolland%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li></ul></div><div class="author-tooltip-3"><div class="author-tooltip-name">W.K. Thompson </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>c</span>Psychiatry (W.K.T., O.A.A.), University of California, San Diego, La Jolla, California</div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&amp;gs_type=author&amp;author%5B0%5D=W.K.%2BThompson%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=Thompson%20W&amp;link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link last"><a href="/search/author1%3AW.K.%2BThompson%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li></ul></div><div class="author-tooltip-4"><div class="author-tooltip-name">J.B. Brewer </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>a</span>From the Departments of Radiology (R.S.D., L.K.E., J.B.B., A.M.D.)</div><div class='author-affiliation'><span class='nlm-sup'>b</span>Neuroscience (D.H., J.B.B., P.S.A., A.M.D.)</div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&amp;gs_type=author&amp;author%5B0%5D=J.B.%2BBrewer%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=Brewer%20J&amp;link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link last"><a href="/search/author1%3AJ.B.%2BBrewer%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li></ul></div><div class="author-tooltip-5"><div class="author-tooltip-name">P.S. Aisen </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>b</span>Neuroscience (D.H., J.B.B., P.S.A., A.M.D.)</div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&amp;gs_type=author&amp;author%5B0%5D=P.S.%2BAisen%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=Aisen%20P&amp;link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link last"><a href="/search/author1%3AP.S.%2BAisen%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li></ul></div><div class="author-tooltip-6"><div class="author-tooltip-name">O.A. Andreassen </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>c</span>Psychiatry (W.K.T., O.A.A.), University of California, San Diego, La Jolla, California</div><div class='author-affiliation'><span class='nlm-sup'>d</span>Institute of Clinical Medicine (O.A.A.), University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway</div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&amp;gs_type=author&amp;author%5B0%5D=O.A.%2BAndreassen%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=Andreassen%20O&amp;link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link last"><a href="/search/author1%3AO.A.%2BAndreassen%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li></ul></div><div class="author-tooltip-7"><div class="author-tooltip-name">B.T. Hyman </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>e</span>Department of Neurology (B.T.H., R.A.S.), Massachusetts General Hospital, Boston, Massachusetts</div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&amp;gs_type=author&amp;author%5B0%5D=B.T.%2BHyman%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=Hyman%20B&amp;link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link last"><a href="/search/author1%3AB.T.%2BHyman%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li></ul></div><div class="author-tooltip-8"><div class="author-tooltip-name">R.A. Sperling </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>e</span>Department of Neurology (B.T.H., R.A.S.), Massachusetts General Hospital, Boston, Massachusetts</div><div class='author-affiliation'><span class='nlm-sup'>f</span>Department of Neurology (R.A.S.), Brigham and Women's Hospital, Boston, Massachusetts.</div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&amp;gs_type=author&amp;author%5B0%5D=R.A.%2BSperling%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=Sperling%20R&amp;link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link last"><a href="/search/author1%3AR.A.%2BSperling%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li></ul></div><div class="author-tooltip-9"><div class="author-tooltip-name">A.M. Dale </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>a</span>From the Departments of Radiology (R.S.D., L.K.E., J.B.B., A.M.D.)</div><div class='author-affiliation'><span class='nlm-sup'>b</span>Neuroscience (D.H., J.B.B., P.S.A., A.M.D.)</div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&amp;gs_type=author&amp;author%5B0%5D=A.M.%2BDale%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=Dale%20A&amp;link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link last"><a href="/search/author1%3AA.M.%2BDale%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li></ul></div></div></div>  </div>

  
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    <div class="highwire-markup"><div xmlns="http://www.w3.org/1999/xhtml" xmlns:xhtml="http://www.w3.org/1999/xhtml" class="section ref-list" id="ref-list-1"><h2>References</h2><ol class="cit-list ref-use-labels"><li><span class="ref-label">1.</span><a class="rev-xref-ref" href="#xref-ref-1-1" title="View reference 1. in text" id="ref-1">↵</a>

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<div class="cit ref-cit ref-journal" id="cit-34.3.505.3" data-doi="10.1016/j.neuron.2008.06.008"><div class="cit-metadata"><ol class="cit-auth-list"><li><span class="cit-auth"><span class="cit-name-surname">Kuchibhotla</span>  <span class="cit-name-given-names">KV</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Goldman</span>  <span class="cit-name-given-names">ST</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Lattarulo</span>  <span class="cit-name-given-names">CR</span></span>, </li><li><span class="cit-etal">et al</span></li></ol><cite>. <span class="cit-article-title">Abeta plaques lead to aberrant regulation of calcium homeostasis in vivo resulting in structural and functional disruption of neuronal networks</span>. <abbr class="cit-jnl-abbrev">Neuron</abbr> <span class="cit-pub-date">2008</span>;<span class="cit-vol">59</span>:<span class="cit-fpage">214</span>–<span class="cit-lpage">25</span></cite></div><div class="cit-extra"><a href="/lookup/external-ref?access_num=10.1016/j.neuron.2008.06.008&amp;link_type=DOI" class="cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref"><span>CrossRef</span></a><a href="/lookup/external-ref?access_num=18667150&amp;link_type=MED&amp;atom=%2Fajnr%2F34%2F3%2F505.atom" class="cit-ref-sprinkles cit-ref-sprinkles-medline"><span>PubMed</span></a><a href="/lookup/external-ref?access_num=000258252700007&amp;link_type=ISI" class="cit-ref-sprinkles cit-ref-sprinkles-newisilink cit-ref-sprinkles-webofscience"><span>Web of Science</span></a></div></div></li><li><span class="ref-label">4.</span><a class="rev-xref-ref" href="#xref-ref-4-1" title="View reference 4. in text" id="ref-4">↵</a>

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<div class="cit ref-cit ref-journal" id="cit-34.3.505.30" data-doi="10.1126/scitranslmed.3002369"><div class="cit-metadata"><ol class="cit-auth-list"><li><span class="cit-auth"><span class="cit-name-surname">Holtzman</span>  <span class="cit-name-given-names">DM</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Morris</span>  <span class="cit-name-given-names">JC</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Goate</span>  <span class="cit-name-given-names">AM</span></span></li></ol><cite>. <span class="cit-article-title">Alzheimer's disease: the challenge of the second century</span>. <abbr class="cit-jnl-abbrev">Sci Transl Med</abbr> <span class="cit-pub-date">2011</span>;<span class="cit-vol">3</span>:<span class="cit-fpage">77sr1</span></cite></div><div class="cit-extra"><a href="/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiRlVMTCI7czoxMToiam91cm5hbENvZGUiO3M6MTE6InNjaXRyYW5zbWVkIjtzOjU6InJlc2lkIjtzOjEwOiIzLzc3Lzc3c3IxIjtzOjQ6ImF0b20iO3M6MTk6Ii9ham5yLzM0LzMvNTA1LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==" class="cit-ref-sprinkles cit-ref-sprinkles-ijlink"><span><span class="cit-reflinks-full-text"><span class="free-full-text">FREE </span>Full Text</span></span></a></div></div></li><li><span class="ref-label">31.</span><a class="rev-xref-ref" href="#xref-ref-31-1" title="View reference 31. in text" id="ref-31">↵</a>

<div class="cit ref-cit ref-journal" id="cit-34.3.505.31" data-doi="10.1001/archneurol.2011.70"><div class="cit-metadata"><ol class="cit-auth-list"><li><span class="cit-auth"><span class="cit-name-surname">Hyman</span>  <span class="cit-name-given-names">BT</span></span></li></ol><cite>. <span class="cit-article-title">Amyloid-dependent and amyloid-independent stages of Alzheimer disease</span>. <abbr class="cit-jnl-abbrev">Arch Neurol</abbr> <span class="cit-pub-date">2011</span>;<span class="cit-vol">68</span>:<span class="cit-fpage">1062</span>–<span class="cit-lpage">64</span></cite></div><div class="cit-extra"><a href="/lookup/external-ref?access_num=10.1001/archneurol.2011.70&amp;link_type=DOI" class="cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref"><span>CrossRef</span></a><a href="/lookup/external-ref?access_num=21482918&amp;link_type=MED&amp;atom=%2Fajnr%2F34%2F3%2F505.atom" class="cit-ref-sprinkles cit-ref-sprinkles-medline"><span>PubMed</span></a><a href="/lookup/external-ref?access_num=000293647500015&amp;link_type=ISI" class="cit-ref-sprinkles cit-ref-sprinkles-newisilink cit-ref-sprinkles-webofscience"><span>Web of Science</span></a></div></div></li></ol></div></div>  </div>

  
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        	<div class="highwire-cite-metadata"><span  class="highwire-cite-metadata-volume highwire-cite-metadata">Vol. 34</span>, <span  class="highwire-cite-metadata-issue highwire-cite-metadata">Issue 3 </span><div  class="highwire-cite-metadata-pubdate highwire-cite-metadata">1 Mar 2013 </div></div>
      
      
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      <div class="highwire-cite-title"><em>Apolipoprotein E</em> ε4 Does Not Modulate Amyloid-β–Associated Neurodegeneration in Preclinical Alzheimer Disease</div>  
    	<div class="highwire-cite-authors"><span  class="highwire-citation-authors"><span class="highwire-citation-author first" data-delta="0"><span class="nlm-given-names">R.S.</span> <span class="nlm-surname">Desikan</span></span>, <span class="highwire-citation-author" data-delta="1"><span class="nlm-given-names">L.K.</span> <span class="nlm-surname">McEvoy</span></span>, <span class="highwire-citation-author" data-delta="2"><span class="nlm-given-names">D.</span> <span class="nlm-surname">Holland</span></span>, <span class="highwire-citation-author" data-delta="3"><span class="nlm-given-names">W.K.</span> <span class="nlm-surname">Thompson</span></span>, <span class="highwire-citation-author" data-delta="4"><span class="nlm-given-names">J.B.</span> <span class="nlm-surname">Brewer</span></span>, <span class="highwire-citation-author" data-delta="5"><span class="nlm-given-names">P.S.</span> <span class="nlm-surname">Aisen</span></span>, <span class="highwire-citation-author" data-delta="6"><span class="nlm-given-names">O.A.</span> <span class="nlm-surname">Andreassen</span></span>, <span class="highwire-citation-author" data-delta="7"><span class="nlm-given-names">B.T.</span> <span class="nlm-surname">Hyman</span></span>, <span class="highwire-citation-author" data-delta="8"><span class="nlm-given-names">R.A.</span> <span class="nlm-surname">Sperling</span></span>, <span class="highwire-citation-author" data-delta="9"><span class="nlm-given-names">A.M.</span> <span class="nlm-surname">Dale</span></span>, <span class="highwire-citation-author" data-delta="10"><span class="nlm-collab" data-xlink-type="simple" data-hwp-id="collab-1">for the Alzheimer's Disease Neuroimaging Initiative</span></span></span></div>
  
    	<div class="highwire-cite-metadata"><span  class="highwire-cite-metadata-oa-ind highwire-cite-metadata"><i class="highwire-oa-indicator"></i> </span><span  class="highwire-cite-metadata-journal highwire-cite-metadata">American Journal of Neuroradiology </span><span  class="highwire-cite-metadata-date highwire-cite-metadata">Mar 2013, </span><span  class="highwire-cite-metadata-volume highwire-cite-metadata">34 </span><span  class="highwire-cite-metadata-issue highwire-cite-metadata">(3) </span><span  class="highwire-cite-metadata-pages highwire-cite-metadata">505-510; </span><span  class="highwire-cite-metadata-doi highwire-cite-metadata"><span class="label">DOI:</span> 10.3174/ajnr.A3267 </span></div>
  
  
  
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      <div class="highwire-cite-title"><em>Apolipoprotein E</em> ε4 Does Not Modulate Amyloid-β–Associated Neurodegeneration in Preclinical Alzheimer Disease</div>  
    	<div class="highwire-cite-authors"><span  class="highwire-citation-authors"><span class="highwire-citation-author first" data-delta="0"><span class="nlm-given-names">R.S.</span> <span class="nlm-surname">Desikan</span></span>, <span class="highwire-citation-author" data-delta="1"><span class="nlm-given-names">L.K.</span> <span class="nlm-surname">McEvoy</span></span>, <span class="highwire-citation-author" data-delta="2"><span class="nlm-given-names">D.</span> <span class="nlm-surname">Holland</span></span>, <span class="highwire-citation-author" data-delta="3"><span class="nlm-given-names">W.K.</span> <span class="nlm-surname">Thompson</span></span>, <span class="highwire-citation-author" data-delta="4"><span class="nlm-given-names">J.B.</span> <span class="nlm-surname">Brewer</span></span>, <span class="highwire-citation-author" data-delta="5"><span class="nlm-given-names">P.S.</span> <span class="nlm-surname">Aisen</span></span>, <span class="highwire-citation-author" data-delta="6"><span class="nlm-given-names">O.A.</span> <span class="nlm-surname">Andreassen</span></span>, <span class="highwire-citation-author" data-delta="7"><span class="nlm-given-names">B.T.</span> <span class="nlm-surname">Hyman</span></span>, <span class="highwire-citation-author" data-delta="8"><span class="nlm-given-names">R.A.</span> <span class="nlm-surname">Sperling</span></span>, <span class="highwire-citation-author" data-delta="9"><span class="nlm-given-names">A.M.</span> <span class="nlm-surname">Dale</span></span>, <span class="highwire-citation-author" data-delta="10"><span class="nlm-collab" data-xlink-type="simple" data-hwp-id="collab-1">for the Alzheimer's Disease Neuroimaging Initiative</span></span></span></div>
  
    	<div class="highwire-cite-metadata"><span  class="highwire-cite-metadata-oa-ind highwire-cite-metadata"><i class="highwire-oa-indicator"></i> </span><span  class="highwire-cite-metadata-journal highwire-cite-metadata">American Journal of Neuroradiology </span><span  class="highwire-cite-metadata-date highwire-cite-metadata">Mar 2013, </span><span  class="highwire-cite-metadata-volume highwire-cite-metadata">34 </span><span  class="highwire-cite-metadata-issue highwire-cite-metadata">(3) </span><span  class="highwire-cite-metadata-pages highwire-cite-metadata">505-510; </span><span  class="highwire-cite-metadata-doi highwire-cite-metadata"><span class="label">DOI:</span> 10.3174/ajnr.A3267 </span></div>
  
  
  
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