Reduced posterior cingulate mitochondrial activity in expired young adult carriers of the APOE ε4 allele, the major late-onset Alzheimer's susceptibility gene.
In vivo PET imaging studies of young-adult carriers of the apolipoprotein E ε4 allele (APOEε4), the major Alzheimer's disease (AD) susceptibility gene, have demonstrated declines in glucose metabolism in brain areas later vulnerable to AD, such as posterior cingulate cortex, decades before the possible onset of symptoms. We have previously shown in postmortem studies that such metabolic declines in AD are associated with brain regional mitochondrial dysfunction. To determine whether young adult at-risk individuals demonstrate similar mitochondrial functional decline, we histochemically assessed postmortem tissues from the posterior cingulate cortex of young-adult carriers and noncarriers of APOEε4. At-risk ε4 carriers had lower mitochondrial cytochrome oxidase activity than noncarriers in posterior cingulate cortex, particularly within the superficial cortical lamina, a pattern similar to that seen in AD patients. Except for one 34 year-old ε4 homozygote, the ε4 carriers did not have increased soluble amyloid-β, histologic amyloid-β, or tau pathology in this same region. This functional biomarker may prove useful in early detection and tracking of AD and indicates that mitochondrial mechanisms may contribute to the predisposition to AD before any evidence of amyloid or tau pathology.
Valla
Jon
J
Barrow Neurological Institute, St. Joseph's Hospital & Medical Center, Phoenix, AZ, USA. jvalla@midwestern.edu
Yaari
Roy
R
Wolf
Andrew B
AB
Kusne
Yael
Y
Beach
Thomas G
TG
Roher
Alex E
AE
Corneveaux
Jason J
JJ
Huentelman
Matthew J
MJ
Caselli
Richard J
RJ
Reiman
Eric M
EM
D000293:Adolescent; D000328:Adult; D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D053327:Apolipoprotein E4 / Q000235:genetics*; D003576:Electron Transport Complex IV / Q000235:genetics; D005260:Female; D006580:Genetic Carrier Screening; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006179:Gyrus Cinguli / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D055815:Young Adult
D053327:Apolipoprotein E4; D003576:Electron Transport Complex IV