Apolipoprotein E, not fibrillar β-amyloid, reduces cerebral glucose metabolism in normal aging
Open accessAbstract
The ε4 allele of the polymorphic apolipoprotein E gene is associated with increased risk of Alzheimer's disease (AD), deposition of β-amyloid (Aβ), and reduction in cerebral glucose metabolism in asymptomatic people. Although ApoE4 may exert an effect on AD risk through amyloidogenic pathways, whether its effect on glucose metabolism is related to Aβ is unknown. To answer this question, we examined data from 175 cognitively normal older people (mean age, 77; 87 men, 88 women) in the Alzheimer's disease neuroimaging initiative studied concurrently with [ 18 F]flurodeoxyglucose (FDG) positron emission tomography measures of glucose metabolism and the radiotracer [ 18 F]florbetapir, an imaging agent which labels fibrillar Aβ in vivo . Based on a threshold value of florbetapir uptake determined in separate samples, subjects were categorized as florbetapir+ or florbetapir−. Glucose metabolism was measured as a continuous variable in a group of regions of interest (ROIs) selected a priori based on their involvement in AD, and also by using a whole-brain voxelwise approach. Among this sample, 29% of subjects were florbetapir+ and 23% were ApoE4 carriers. As expected, there was a significant association between ApoE4 genotype and florbetapir positivity. Florbetapir status, however, was not significantly associated with glucose metabolism, but the ApoE4 genotype was associated with lower metabolism in both voxelwise and ROI approaches. These results show that ApoE genotype, and not aggregated fibrillar forms of Aβ, contributes to reduced glucose metabolism in aging and adds to a growing list of neural consequences of ApoE that do not appear to be related to Aβ.
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APOE4 is associated with age-dependent impairments in cerebral glucose metabolism independent of Aβ accumulation and reduces ATP production in mouse prefrontal cortex.
“APOE4 is associated with age-dependent impairments in cerebral glucose metabolism independent of Aβ accumulation (Jagust et al., 2012) and reduces ATP production in mouse prefrontal cortex (Fang et al., 2021).”
From APOE4 reduces hippocampal expression of phosphoglycerate kinase 1 and sodium potassium pump to enhance seizure susceptibility in mice (2026) · cites this paper as Jagust et al., 2012
The Discussion (page unavailable) reports that APOE4 was associated with lower cerebral glucose metabolism in older adults after accounting for age, and that fibrillar Aβ did not explain the association. It does not establish an age-dependent APOE4 effect or independence from all forms of Aβ; the authors say soluble Aβ cannot be definitively excluded. The mouse ATP-production claim is attributed to Fang et al., not to this source. (LLM, conf=0.85)
Experimental — accuracy not yet measuredAPOE4 is associated with cortical ATP decline and age-dependent impairments in cerebral glucose uptake and metabolism independent of Aβ accumulation.
“APOE4 is previously shown to be associated with cortical ATP decline (Fang et al., 2021) and age-dependent impairments in cerebral glucose uptake and metabolism independent of Aβ accumulation (Jagust et al., 2012).”
From APOE4 reduces hippocampal expression of phosphoglycerate kinase 1 and sodium potassium pump to enhance seizure susceptibility in mice (2026) · cites this paper as Jagust et al., 2012
The Results report that APOE4 carriers and older participants had lower cerebral glucose metabolism, and the Discussion says the APOE4 association was not explained by fibrillar Aβ detected with florbetapir. The paper reports separate effects of age and APOE4, not an age-dependent APOE4 effect, and it does not establish independence from all Aβ accumulation: the Discussion says soluble Aβ could not be definitively excluded. Jagust et al. measured glucose metabolism with FDG-PET, not glucose uptake as a separate outcome. (LLM, conf=0.87)
Experimental — accuracy not yet measuredAPOE4 is associated with increased Aβ deposition, but its influence on metabolic pathways may contribute to AD risk independently of Aβ.
“As such, APOE4 is associated with increased Aβ deposition but accumulating evidence suggests that its influence on metabolic pathways may contribute to disease risk independently of Aβ [3][4][5][6][7] .”
From APOE4-drives brain bioenergetic shifts independent of Alzheimer’s disease pathology (2026) · cites this paper as [7]
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Zetterberg, H., & Mattsson, N. (2014) · Expert Review of Neurotherapeutics · doi:10.1586/14737175.2014.915740 · Cited by 73 · see citing works
Sex differences in the genetic architecture of Alzheimer’s disease
Dumitrescu, L., Mayeda, E. R., Sharman, K., Moore, A. M., & Hohman, T. J. (2019) · Current Genetic Medicine Reports · doi:10.1007/s40142-019-0157-1 · Cited by 48 · see citing works
Mormino, E. C. (2014) · Neuropsychology Review · doi:10.1007/s11065-014-9267-4 · Cited by 44 · see citing works
Albrecht, D. S., Sagare, A., Pachicano, M., Sweeney, M. D., Toga, A., Zlokovic, B., Chui, H., Joe, E., Schneider, L., Morris, J. C., et al. (2021) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2021.01.010 · Cited by 37 · see citing works
APOE4-drives brain bioenergetic shifts independent of Alzheimer’s disease pathology
Lysaker, C. R., Johnson, C. N., Csikos, V., Franczak, E., Benson, M., Gilmore, C. A., Birky, C. J., Davis, X., McCoin, C. S., Smith, K. P., et al. (2026) · npj Dementia · doi:10.1038/s44400-026-00105-8 · Cited by 1 · see citing works
Singh, T., Bridgeman, E., Baker, A. J., Noblet, H. A., Yang, K. Y., Kang, S., Lim, K. H., Lee, S. S., Amundsen, N. M., Lee, Y., et al. (2026) · Neurobiology of Disease · doi:10.1016/j.nbd.2025.107246 · Cited by 1 · see citing works
- Authors
- Jagust, W. J., Landau, S. M., & Initiative, F. T. A. D. N.
- Affiliations
- Lawrence Berkeley National Laboratory (US)
- ORCID
- Jagust, William J.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2012-12-12
- Volume
- 32
- Issue
- 50
- Pages
- 18227-18233
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3537830
- OpenAlex
- W1975727000
- Cited by
- 162
- References
- 19
- Citations by year
- 2026: 7 · 2025: 9 · 2024: 1 · 2023: 4 · 2022: 8 · 2021: 16 · 2020: 9 · 2019: 9 · 2018: 12 · 2017: 13 · 2016: 14 · 2015: 23 · 2014: 21 · 2013: 16
- FWCI
- 12.99
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Foundation for the National Institutes of Health (U01AG024904, Grant U01 AG024904, AG024904)
- Alzheimer's Association (U01 AG024904)
- Bristol-Myers Squibb (U01 AG024904, AG024904)
- Eli Lilly and Company (U01 AG024904, AG024904)
- Pfizer (AG024904, U01 AG024904)
- AstraZeneca
- Biogen (U01 AG024904, AG024904)
- F. Hoffmann-La Roche (AG024904, U01 AG024904)
- Medpace (U01 AG024904)
- Meso Scale Diagnostics (U01 AG024904, AG024904)
- Synarc (U01 AG024904)
- Alzheimer's Disease Neuroimaging Initiative (U01AG024904, AG024904)
- Amorfix Life Sciences
- BioClinica (U01 AG024904, AG024904)
- Novartis Pharmaceuticals Corporation (U01 AG024904, AG024904)
- Northern California Institute for Research and Education (U01 AG024904)
- Bayer HealthCare
- Eisai (U01 AG024904, AG024904)
- Servier (AG024904, U01 AG024904)
- National Institutes of Health (3u01ag024904-10s2, U01-AG024904, Grant U01 AG024904, AG024904)
- Genentech (AG024904, U01 AG024904)
- University of California, Los Angeles
- University of California, San Diego
- Canadian Institutes of Health Research (U01 AG024904)
- National Institute on Aging (U01-AG-024904, AG 024904)
- National Institute of Biomedical Imaging and Bioengineering (U01 AG024904, AG024904)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- apolipoprotein E, APOE ε4, Alzheimer's disease risk, brain glucose metabolism, normal aging, florbetapir, FDG-PET, amyloid imaging, genetic risk factors, older adults
- MeSH terms
- Aged, Aging, Alzheimer Disease, Amyloid, Aniline Compounds, Brain, Ethylene Glycols, Female, Genotype, Glucose, Humans, Male, Radiopharmaceuticals, Genetic Predisposition to Disease, Positron-Emission Tomography, Apolipoprotein E4
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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