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Reduced Posterior Cingulate Mitochondrial Activity in Expired Young Adult Carriers of the APOE ε4 Allele, the Major Late-Onset Alzheimer's Susceptibility Gene
Open accessAbstract
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.
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“Our hypothesis, therefore, can accommodate a growing realization that for many subjects with suspected AD, or who have an increased risk of developing AD, what are currently considered downstream biomarker changes potentially precede upstream biomarker changes [206-213].”
From The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives (2014) · cites this paper as [208]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“APOE4 carriers show mitochondrial dysfunction in brain areas associated with AD even before the onset of amyloid or tau pathology or cognitive changes, indicating that mitochondrial dysfunction is involved in early AD pathology [31].”
From APOE4 Increases Energy Metabolism in APOE-Isogenic iPSC-Derived Neurons (2024) · cites this paper as [31]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“APOE4 carriers show mitochondrial dysfunction in brain areas associated with AD even before the onset of amyloid or tau pathology or cognitive changes, indicating that mitochondrial dysfunction is involved in early AD pathology [31].”
From APOE4 Increases Energy Metabolism in APOE-Isogenic iPSC-Derived Neurons (2024) · cites this paper as [31]
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“in nondemented apoE4 carriers, the activity of mitochondrial complex IV is decreased in cortical regions susceptible to AD [32]”
From Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function (2019) · cites this paper as [32]
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“a decrease in mitochondrial respiratory complex IV activity was observed in autopsy brains from young ApoE4 carriers [74]”
From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [74]
In the citing paper
“In most of the young adult APOE4 carriers evaluated by this study COX activity was low even in the absence of fibrillar Aβ.”
From Brain aging, Alzheimer's disease, and mitochondria (2011) · cites this paper as [133]
In the citing paper
“Young adult APOE4 carriers, who also have an increased AD risk, have lower posterior cingulate COX activities than young adult non-APOE4 carriers [133].”
From Brain aging, Alzheimer's disease, and mitochondria (2011) · cites this paper as [133]
In the citing paper
“Mitochondrial dysfunction has been suggested to occur early in the progression to AD and continues into later stages of AD31–34.”
From Large-scale proteomic analysis of human brain identifies proteins associated with cognitive trajectory in advanced age (2019) · cites this paper as [32]
In the citing paper
“In that study, young-adult participants in both groups did not have amyloid or tangle deposition in the posterior cingulate cortex (PCC); yet, APOE4 carriers, i.e., those at greater risk for developing AD, showed reduced mitochondrial activity in PCC neurons, as measured by cytochrome oxidase levels”
From Large-scale proteomic analysis of human brain identifies proteins associated with cognitive trajectory in advanced age (2019) · cites this paper as [32]
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Metadata
- Authors
- Valla, J., Yaari, R., Wolf, A. B., Kusne, Y., Beach, T. G., Roher, A. E., Corneveaux, J. J., Huentelman, M. J., Caselli, R. J., & Reiman, E. M.
- Affiliations
- Barrow Neurological Institute (US)
- University of Arizona (US)
- Banner Sun Health Research Institute (US)
- Translational Genomics Research Institute (US)
- Mayo Clinic in Arizona (US)
- Corresponding author
- Valla, Jon
- ORCID
- Venue
- Journal of Alzheimer s Disease
- Publisher
- SAGE Publications
- Published
- 2010-09-28
- Volume
- 22
- Issue
- 1
- Pages
- 307-313
- ISSN
- 1387-2877 (ISSN-L)
- 1875-8908
- PMC
- PMC3124564
- OpenAlex
- W1529577194
- Cited by
- 150
- References
- 34
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 4 · 2023: 7 · 2022: 4 · 2021: 10 · 2020: 9 · 2019: 11 · 2018: 6 · 2017: 14 · 2016: 12 · 2015: 6 · 2014: 13 · 2013: 15 · 2012: 17
- FWCI
- 9.97
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Alzheimer s Disease (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (P30-AG-19610, R01-AG 19795, R01AG019795, R01AG031581, P30AG019610)
- National Institute of Neurological Disorders and Stroke (R01NS059873)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- APOE ε4, Alzheimer's disease
- MeSH terms
- Adolescent, Adult, Alleles, Alzheimer Disease, Electron Transport Complex IV, Female, Gyrus Cinguli, Genetic Carrier Screening, Humans, Male, Mitochondria, Genetic Predisposition to Disease, Apolipoprotein E4, Young Adult
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