Apolipoprotein E Type 4 Allele and Cerebral Glucose Metabolism in Relatives at Risk for Familial Alzheimer Disease
Abstract
OBJECTIVE: Cerebral parietal hypometabolism and left-right asymmetry occur early in the course of Alzheimer disease (AD), and the apolipoprotein E type 4 allele (APOE epsilon 4) is a risk factor for familial AD. To determine if APOE epsilon 4 is associated with lowered brain function in nondemented relatives at risk for familial AD, we studied 12 relatives with APOE epsilon 4 and 19 relatives without APOE epsilon 4. We also compared them with seven patients with probable AD. DESIGN: After grouping subjects according to diagnosis and genotype, brain function measures were compared among groups. SETTING: University medical center. PATIENTS: At risk subjects had mild memory complaints, normal cognitive performance, and at least two relatives with AD. Subjects with APOE epsilon 4 did not differ from those without APOE epsilon 4 in mean age at examination (56.4 vs 55.5 years) or in neuropsychological performance (mean Mini-Mental State Examination score, 28.8 vs 29.3). MAIN OUTCOME MEASURES: Cerebral glucose metabolism was measured using positron emission tomography and fludeoxyglucose F 18. RESULTS: Parietal metabolism was significantly lower and left-right parietal asymmetry was significantly higher in at-risk subjects with APOE epsilon 4 compared with those without APOE epsilon 4. Patients with dementia had significantly lower parietal metabolism than did at-risk subjects with APOE epsilon 4. CONCLUSIONS: These results suggest that the inheritance of APOE epsilon 4 is associated with reduced cerebral parietal metabolism and increased asymmetry in non-demented relatives at risk for probable AD. Longitudinal study will determine if glucose metabolic measures provide a means to monitor experimental treatment responses during the early phases of the disorder.
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Both cross-sectional and longitudinal PET studies show that nondemented E4 carriers have more hypometabolic regions than controls.
“Moreover, both cross-sectional (21, 22) and longitudinal PET studies (23) show that nondemented E4 carriers have more hypometabolic regions than controls, but a relationship to longitudinally observed decline has not been reported.”
It has been suggested that this association may account for the earlier onset of symptoms in E4 carriers.
“It has been suggested that this association may account for the earlier onset of symptoms in E4 carriers (21–23).”
In a recent study, subjects with the apolipoprotein E e3/e4 genotype, age-associated memory impairment, and a family history of Alzheimer's disease had abnormally low and asymmetric rates of glucose metabolism in a preselected parietal region before the onset of dementia.
“In a recent study, subjects with the apolipoprotein E e 3/ e 4 genotype, age-associated memory impairment, and a family history of Alzheimer's disease had abnormally low and asymmetric rates of glucose metabolism in a preselected parietal region before the onset of dementia.15”
From Preclinical Evidence of Alzheimer's Disease in Persons Homozygous for the ε4 Allele for Apolipoprotein E (1996) · cites this paper as [15]
Case series suggest that abnormalities in glucose metabolism can be detected by PET before substantial impairment occurs in persons at risk for Alzheimer's disease.
“Case series suggest that abnormalities in glucose metabolism can be detected by PET before substantial impairment occurs in persons at risk for Alzheimer's disease [14][15][16]”
From Preclinical Evidence of Alzheimer's Disease in Persons Homozygous for the ε4 Allele for Apolipoprotein E (1996) · cites this paper as [15]
For many subjects with suspected AD or increased risk, what are currently considered downstream biomarker changes potentially precede upstream biomarker changes.
“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 [210]
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M OLECULAR I MAGING WITH P OSITRON E MISSION T OMOGRAPHY
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- Authors
- Small, G. W.
- Affiliations
- University of California, Los Angeles (US)
- Corresponding author
- Small, Gary W.
- ORCID
- Small, Gary W.
- Venue
- JAMA: The Journal of the American Medical Association
- Publisher
- American Medical Association (AMA)
- Published
- 1995-03-22
- Volume
- 273
- Issue
- 12
- Pages
- 942
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- OpenAlex
- W2159538597
- Cited by
- 604
- References
- 52
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 5 · 2023: 12 · 2022: 7 · 2021: 16 · 2020: 15 · 2019: 9 · 2018: 12 · 2017: 15 · 2016: 16 · 2015: 7 · 2014: 14 · 2013: 15 · 2012: 18
- FWCI
- 27.38
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- JAMA (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r29mh046424-05)
- National Institute on Aging (AG05 128, AG 10123, P50AG005128, P30AG010123, U24AG021886)
- National Institute of Mental Health (1R29 MH46424)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- APOE ε4, familial Alzheimer's disease, brain glucose metabolism, left-right asymmetry, at-risk relatives, early Alzheimer's disease, neuroimaging biomarkers, genetic risk
- MeSH terms
- Adult, Aged, Aged, 80 and over, Alleles, Alzheimer Disease, Analysis of Variance, Apolipoproteins E, Brain, Deoxyglucose, Family, Female, Fluorine Radioisotopes, Genotype, Glucose, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Models, Theoretical, Neuropsychological Tests, Risk Factors, Tomography, Emission-Computed, Fluorodeoxyglucose F18, Apolipoprotein E4
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