MITOCHONDRIAL DNA VARIANT C2639T IS AN APOE4 RESILIENCE FACTOR

Miller B, Kim S, Wan J, Mehta H, Yen K, Cohen P

Innovation in aging1 Nov 2019

PMCIDPMC6845116PepBankPUB-92865932

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Summary

Abstract The APOE4 allele is the greatest genetic risk factor for sporadic Alzheimer’s disease, yet select APOE4 carriers remain cognitively intact and become centenarians due to unclear reasons. In order to identify resilience genes for APOE4 carriers, we (1) sequenced whole mitochondrial DNA in a centenarian cohort, (2) searched for differentially expressed genes in the temporal cortex of APOE4 carriers, and (3) experimentally simulated the effects of a novel mitochondrial DNA variant that confers APOE4 resilience. The mitochondrial DNA variant, C2639T, is highly enriched in centenarians and APOE4 carriers, which changes the third amino acid of the mitochondrial-derived peptide humanin from proline to serine (humanin P3S). In addition, APOE4 carriers differentially expressed 127 genes in the humanin genetic network that map back to mitochondrial function. Therefore, we experimentally characterized the relationship between humanin, centenarian-enriched humanin P3S, and APOE. We found that humanin is a novel APOE binding partner, humanin P3S binds APOE nearly 15 times greater than wild type humanin, and humanin P3S modifies the APOE4 metabolic profile.

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study5

1 result from studies that gave the peptide. No result from this study comes from people.

01LabOther designMechanism
Experiments showed that humanin is a novel APOE binding partner.
In plain wordsIn lab tests, humanin was found to bind the APOE protein.
Peptide
Humanin
Outcome
Not applicableHumanin binding to APOE
Study
n: not reported in source
Outcome group
Receptor activity and mechanism · Nervous system and cognition
Studied dose
Dose not stated
Source sentences
Summary
We found that humanin is a novel APOE binding partner
1 context sentence(design, population, supporting numbers)
Summary · context
In order to identify resilience genes for APOE4 carriers, we (1) sequenced whole mitochondrial DNA in a centenarian cohort, (2) searched for differentially expressed genes in the temporal cortex of APOE4 carriers, and (3) experimentally simulated the effects of a novel mitochondrial DNA variant that confers APOE4 resilience.
Show in the study text Report a problemFND-9286593201

Studies that did not test the peptide alone4

In this study, Humanin was a lab tool or a carrier, part of a mix, or the subject of a lab method. These results are not evidence about taking Humanin.

02HumanNot a test of Humanin aloneObservational studyOther
The mitochondrial DNA variant C2639T, which changes humanin proline 3 to serine, was highly enriched in centenarians and APOE4 carriers.
In plain wordsA mitochondrial DNA variant that alters humanin was much more common in centenarians and APOE4 carriers.
Peptide
Humanin
Outcome
IncreaseEnrichment of mitochondrial DNA variant C2639T in centenarians and APOE4 carriers
Study
n: not reported in source
Outcome group
Aging markers · Aging and longevity
Source sentences
Summary
The mitochondrial DNA variant, C2639T, is highly enriched in centenarians and APOE4 carriers, which changes the third amino acid of the mitochondrial-derived peptide humanin from proline to serine (humanin P3S).
1 context sentence(design, population, supporting numbers)
Summary · context
In order to identify resilience genes for APOE4 carriers, we (1) sequenced whole mitochondrial DNA in a centenarian cohort, (2) searched for differentially expressed genes in the temporal cortex of APOE4 carriers, and (3) experimentally simulated the effects of a novel mitochondrial DNA variant that confers APOE4 resilience.
In this study, Humanin was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Humanin.
Show in the study text Report a problemFND-9286593204
03HumanNot a test of Humanin aloneObservational studyOther
APOE4 carriers differentially expressed 127 genes in the humanin genetic network that map back to mitochondrial function.
In plain wordsIn APOE4 carriers, 127 genes in the humanin gene network, linked to mitochondrial function, were expressed differently.
Peptide
Humanin
Outcome
MixedDifferentially expressed genes in the humanin genetic network in APOE4 carriers
Study
n: not reported in source
Outcome group
Mitochondrial function · Nervous system and cognition
Measurements
differentially expressed genes
127 genes
APOE4 carriers
Source sentences
Summary
In addition, APOE4 carriers differentially expressed 127 genes in the humanin genetic network that map back to mitochondrial function.
1 context sentence(design, population, supporting numbers)
Summary · context
In order to identify resilience genes for APOE4 carriers, we (1) sequenced whole mitochondrial DNA in a centenarian cohort, (2) searched for differentially expressed genes in the temporal cortex of APOE4 carriers, and (3) experimentally simulated the effects of a novel mitochondrial DNA variant that confers APOE4 resilience.
In this study, Humanin was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Humanin.
Show in the study text Report a problemFND-9286593205
04LabNot a test of Humanin aloneOther designMechanism
Humanin P3S, the variant encoded by C2639T, bound APOE nearly 15 times more than wild-type humanin.
In plain wordsIn lab tests, the humanin P3S variant bound APOE nearly 15 times more than normal humanin.
Peptide
Humanin
Outcome
IncreaseBinding of humanin P3S to APOE versus wild-type humanin
Study
n: not reported in source
Comparator
Wild-type humanin
Outcome group
Receptor activity and mechanism · Nervous system and cognition
Measurements
relative APOE binding
≈ 15 fold
humanin P3S vs wild-type humanin
Source sentences
Summary
humanin P3S binds APOE nearly 15 times greater than wild type humanin
1 context sentence(design, population, supporting numbers)
Summary · context
In order to identify resilience genes for APOE4 carriers, we (1) sequenced whole mitochondrial DNA in a centenarian cohort, (2) searched for differentially expressed genes in the temporal cortex of APOE4 carriers, and (3) experimentally simulated the effects of a novel mitochondrial DNA variant that confers APOE4 resilience.
In this study, Humanin was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Humanin.
Show in the study text Report a problemFND-9286593202
05LabNot a test of Humanin aloneOther designMechanism
Humanin P3S modified the APOE4 metabolic profile.
In plain wordsIn lab tests, the humanin P3S variant changed the metabolic profile linked to APOE4.
Peptide
Humanin
Outcome
MixedAPOE4 metabolic profile with humanin P3S
Study
n: not reported in source
Outcome group
Mitochondrial function · Nervous system and cognition
Source sentences
Summary
humanin P3S modifies the APOE4 metabolic profile.
1 context sentence(design, population, supporting numbers)
Summary · context
In order to identify resilience genes for APOE4 carriers, we (1) sequenced whole mitochondrial DNA in a centenarian cohort, (2) searched for differentially expressed genes in the temporal cortex of APOE4 carriers, and (3) experimentally simulated the effects of a novel mitochondrial DNA variant that confers APOE4 resilience.
In this study, Humanin was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Humanin.
Show in the study text Report a problemFND-9286593203

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

Version 2Current
13 Oct 2026, 21:44 UTC
Study results updated
Version 1
13 Oct 2026, 16:31 UTC
First added · source update from Europe PMC

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Abstract

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