<pre><FONT COLOR = BLACK>
<B>Effect of APOE genotype on longevity
 </B>
   Lead Investigator:    Mitsuru Shinohara
   Institution      :    Mayo
   E-Mail           :    shinohara@ncgg.go.jp
   Proposal ID      :    758
</FONT>
<BR>
   Proposal Description:
   <textarea name="description" rows="12" cols="85" wrap="virtual" readonly>Although the e4 allele of the apolipoprotein E (APOE4) and #3042 allele (APOE2) are risk and protective factors, respectively, for Alzheimer?s disease, APOE is also associated with longevity several cross-sectional studies comparing centenarians and younger adults showed that higher frequency of APOE2 in centenarians abd lower frequency of APOE4. Despite such interesting observations, fewer longitudinal studies exist demonstrating its effects on longevity. Moreover, it remains unclear whether APOE effects on longevity are mediated by affecting cognitive decline or AD neuropathology, and whether there are sex-dependent effects. Mechanistically, studies on APOE-associated cholesterol during aging in human are scarce. Through accessing comprehensive longitudinal NACC clinical records and a large collection of plasma/CSF samples from Mayo Clinic Study of Aging, we will address how APOE contributes to longevity. Specific Aim 1.Determine the effects of APOE on longevity, depending on cardiovascular health, cognitive decline, and Alzheimer?s neuropathology in NACC cohorts: By reviewing prospective clinical records of NACC cohorts, we will assess whether APOE affect longevity in these cohorts, and how gender, cognitive decline, and cardiovascular disease influence this effect. Moreover, by retrospectively analyzing the relationship between APOE-mediated longevity and AD neuropathology, we well determine whether the effects of APOE on longevity are mediated through reducing AD neuropathology. Specific Aim 2. Address the mechanism underlying APOE-regulated longevity by examining the association among aging-related biomarkers and apoE-associated cholesterol: By using human plasma and CSF, we will assess changes of levels of biomarkers associated with apoE-cholesterol metabolism during aging. By analyzing levels of apoE, cholesterols, apoE-associated cholesterols, and other APOE or aging-related molecules in human plasma and CSF, we will determine the relationship between apoE- </textarea>