Apolipoprotein E type 4 allele and cerebral glucose metabolism in relatives at risk for familial Alzheimer disease

G. W. Small, J. C. Mazziotta, M. T. Collins, L. R. Baxter, M. E. Phelps, M. A. Mandelkern, A. Kaplan, A. La Rue, C. F. Adamson, L. Chang and al. et
Department of Psychiatry, University of California, Los Angeles School of Medicine.

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.

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES

Correlating Cerebral Hypometabolism With Future Memory Decline in Subsequent Converters to Amnestic Pre-Mild Cognitive Impairment
Caselli et al.
Arch Neurol 2008;65:1231-1236.
ABSTRACT | FULL TEXT  

Cognitive Discrepancies Versus APOE Genotype as Predictors of Cognitive Decline in Normal-Functioning Elderly Individuals: A Longitudinal Study
Fine et al.
AJGP 2008;16:366-374.
ABSTRACT | FULL TEXT  

Alzheimer's disease is associated with reduced expression of energy metabolism genes in posterior cingulate neurons
Liang et al.
Proc. Natl. Acad. Sci. USA 2008;105:4441-4446.
ABSTRACT | FULL TEXT  

Positron emission tomography imaging in dementia
HERHOLZ et al.
Br. J. Radiol. 2007;80:S160-S167.
ABSTRACT | FULL TEXT  

PET sheds light on Alzheimer's disease genetic risk
Swerdlow
Proc. Natl. Acad. Sci. USA 2007;104:18881-18882.
FULL TEXT  

Hypometabolism Exceeds Atrophy in Presymptomatic Early-Onset Familial Alzheimer's Disease
Mosconi et al.
JNM 2006;47:1778-1786.
ABSTRACT | FULL TEXT  

Hypoperfusion in frontotemporal dementia and Alzheimer disease by arterial spin labeling MRI.
Du et al.
Neurology 2006;67:1215-1220.
ABSTRACT | FULL TEXT  

Diagnostic Issues in Dementia: Neuroimaging as a Surrogate Marker of Disease
Small
J Geriatr Psychiatry Neurol 2006;19:180-185.
ABSTRACT  

Reduced functional brain activity response in cognitively intact apolipoprotein E {varepsilon}4 carriers
Lind et al.
Brain 2006;129:1240-1248.
ABSTRACT | FULL TEXT  

Inaugural Article: Apolipoprotein E4: A causative factor and therapeutic target in neuropathology, including Alzheimer's disease
Mahley et al.
Proc. Natl. Acad. Sci. USA 2006;103:5644-5651.
ABSTRACT | FULL TEXT  

Recognition and treatment of Alzheimer's disease: A case-based review
Marseille and Silverman
AM J ALZHEIMERS DIS OTHER DEMEN 2006;21:119-125.
ABSTRACT  

Pre-symptomatic diagnosis in fatal familial insomnia: serial neurophysiological and 18FDG-PET studies
Cortelli et al.
Brain 2006;129:668-675.
ABSTRACT | FULL TEXT  

Apolipoprotein E Genotype and Age-Related Myelin Breakdown in Healthy Individuals: Implications for Cognitive Decline and Dementia
Bartzokis et al.
Arch Gen Psychiatry 2006;63:63-72.
ABSTRACT | FULL TEXT  

Lipid- and receptor-binding regions of apolipoprotein E4 fragments act in concert to cause mitochondrial dysfunction and neurotoxicity
Chang et al.
Proc. Natl. Acad. Sci. USA 2005;102:18694-18699.
ABSTRACT | FULL TEXT  

Similar Neurocognitive Performance of Adults With and Without a History of Parental Alzheimer's Disease: A Pilot Study
Ercoli et al.
J Geriatr Psychiatry Neurol 2005;18:208-212.
ABSTRACT  

APOE related alterations in cerebral activation even at college age
Scarmeas et al.
J. Neurol. Neurosurg. Psychiatry 2005;76:1440-1444.
ABSTRACT | FULL TEXT  

From The Cover: Correlations between apolipoprotein E {epsilon}4 gene dose and brain-imaging measurements of regional hypometabolism
Reiman et al.
Proc. Natl. Acad. Sci. USA 2005;102:8299-8302.
ABSTRACT | FULL TEXT  

Sex, Apolipoprotein E {varepsilon}4 Status, and Hippocampal Volume in Mild Cognitive Impairment
Fleisher et al.
Arch Neurol 2005;62:953-957.
ABSTRACT | FULL TEXT  

Pattern of Cerebral Hypoperfusion in Alzheimer Disease and Mild Cognitive Impairment Measured with Arterial Spin-labeling MR Imaging: Initial Experience
Johnson et al.
Radiology 2005;234:851-859.
ABSTRACT | FULL TEXT  

Altered PET Functional Brain Responses in Cognitively Intact Elderly Persons at Risk for Alzheimer Disease (Carriers of the {epsilon}4 Allele)
Scarmeas et al.
AJGP 2004;12:596-605.
ABSTRACT | FULL TEXT  

Longitudinal changes in cognition and behavior in asymptomatic carriers of the APOE e4 allele
Caselli et al.
Neurology 2004;62:1990-1995.
ABSTRACT | FULL TEXT  

Applications of positron emission tomography (PET) in neurology
Tai and Piccini
J. Neurol. Neurosurg. Psychiatry 2004;75:669-676.
ABSTRACT | FULL TEXT  

Brain metabolic decreases related to the dose of the ApoE e4 allele in Alzheimer's disease
Mosconi et al.
J. Neurol. Neurosurg. Psychiatry 2004;75:370-376.
ABSTRACT | FULL TEXT  

Insulin Resistance, Affective Disorders, and Alzheimer's Disease: Review and Hypothesis
Rasgon and Jarvik
J. Gerontol. A Biol. Sci. Med. Sci. 2004;59:M178-183.
ABSTRACT | FULL TEXT  

Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's dementia
Reiman et al.
Proc. Natl. Acad. Sci. USA 2004;101:284-289.
ABSTRACT | FULL TEXT  

Apolipoprotein {epsilon}4 Allele Status, Depressive Symptoms, and Cognitive Decline in Middle-Aged and Elderly Persons Without Dementia
Lavretsky et al.
AJGP 2003;11:667-673.
ABSTRACT | FULL TEXT  

Looking Backward to Move Forward: Early Detection of Neurodegenerative Disorders
DeKosky and Marek
Science 2003;302:830-834.
ABSTRACT | FULL TEXT  

APOE Genotype and Cerebral Blood Flow in Healthy Young Individuals
Scarmeas et al.
JAMA 2003;290:1581-1582.
FULL TEXT  

MMSE Items Predict Cognitive Decline in Persons with Genetic Risk for Alzheimer's Disease
Ercoli et al.
J Geriatr Psychiatry Neurol 2003;16:67-73.
ABSTRACT  

Drug Development and Alzheimer Disease
Roses and Pangalos
AJGP 2003;11:123-130.
FULL TEXT  

Imaging genomics
Hariri and Weinberger
Br Med Bull 2003;65:259-270.
ABSTRACT | FULL TEXT  

Influence of the Apolipoprotein E Type 4 Allele on Cerebral Glucose Metabolism in Alzheimer's Disease Patients
Lee et al.
J. Neuropsychiatry Clin. Neurosi. 2003;15:78-83.
ABSTRACT | FULL TEXT  

Neuroimaging and Early Diagnosis of Alzheimer Disease: A Look to the Future
Petrella et al.
Radiology 2003;226:315-336.
ABSTRACT | FULL TEXT  

Endocytic Pathway Alterations in Human Hippocampus after Global Ischemia and the Influence of APOE Genotype
McColl et al.
Am. J. Pathol. 2003;162:273-281.
ABSTRACT | FULL TEXT  

Biological Markers in Alzheimer Disease
Neugroschl and Davis
AJGP 2002;10:660-677.
ABSTRACT | FULL TEXT  

Joint Effect of Genes and Environment Distorted by Selection Biases: Implications for Hospital-based Case-Control Studies
Wacholder et al.
Cancer Epidemiol. Biomarkers Prev. 2002;11:885-889.
ABSTRACT | FULL TEXT  

Brain function and cognition in a community sample of elderly Latinos
Jagust et al.
Neurology 2002;59:378-383.
ABSTRACT | FULL TEXT  

Women at risk for AD show increased parietal activation during a fluency task
Smith et al.
Neurology 2002;58:1197-1202.
ABSTRACT | FULL TEXT  

The effect of APOE {epsilon}4 allele on cerebral glucose metabolism in AD is a function of age at onset
Hirono et al.
Neurology 2002;58:743-750.
ABSTRACT | FULL TEXT  

Specificity of Brain Activation Patterns in People at Genetic Risk for Alzheimer Disease
Burggren et al.
AJGP 2002;10:44-51.
ABSTRACT | FULL TEXT  

Evaluating Early Dementia With and Without Assessment of Regional Cerebral Metabolism by PET: A Comparison of Predicted Costs and Benefits
Silverman et al.
JNM 2002;43:253-266.
ABSTRACT | FULL TEXT  

Past Glory and Future Promise: Maximizing and Improving Understanding of Atrophy Patterns in the Diagnosis of Degenerative Dementias
Miller
Am. J. Neuroradiol. 2002;23:33-34.
FULL TEXT  

Effect of Apolipoprotein E Genotype on Cerebral Autoregulation During Cardiopulmonary Bypass
Ti et al.
Stroke 2001;32:1514-1519.
ABSTRACT | FULL TEXT  

Presenilin-1-associated abnormalities in regional cerebral perfusion
Johnson et al.
Neurology 2001;56:1545-1551.
ABSTRACT | FULL TEXT  

Declining brain activity in cognitively normal apolipoprotein E varepsilon 4 heterozygotes: A foundation for using positron emission tomography to efficiently test treatments to prevent Alzheimer's disease
Reiman et al.
Proc. Natl. Acad. Sci. USA 2001;98:3334-3339.
ABSTRACT | FULL TEXT  

Single Photon Emission Computed Tomography and Apolipoprotein E in Alzheimer's Disease: Impact of the {varepsilon}4 Allele on Regional Cerebral Blood Flow
Hogh et al.
J Geriatr Psychiatry Neurol 2001;14:42-51.
ABSTRACT  

Frontal Lobe Hypometabolism Predicts Cognitive Decline in Patients With Lacunar Infarcts
Reed et al.
Arch Neurol 2001;58:493-497.
ABSTRACT | FULL TEXT  

Investigations Into Geriatric Psychiatry Challenges: AAGP Senior Investigator Award 2000
Small
AJGP 2000;8:276-283.
ABSTRACT | FULL TEXT  

Dementia, Quantitative Neuroimaging, and Apolipoprotein E Genotype
Bigler et al.
Am. J. Neuroradiol. 2000;21:1857-1868.
ABSTRACT | FULL TEXT  

Correlates of Disability Among Elderly Retirees With "Subclinical" Cognitive Impairment
Royall et al.
J. Gerontol. A Biol. Sci. Med. Sci. 2000;55:541M-546.
ABSTRACT | FULL TEXT  

Patterns of Brain Activation in People at Risk for Alzheimer's Disease
Bookheimer et al.
NEJM 2000;343:450-456.
ABSTRACT | FULL TEXT  

Inaugural Article: Positron emission tomography provides molecular imaging of biological processes
Phelps
Proc. Natl. Acad. Sci. USA 2000;97:9226-9233.
ABSTRACT | FULL TEXT  

The Preclinical Phase of Alzheimer Disease: A 22-Year Prospective Study of the Framingham Cohort
Elias et al.
Arch Neurol 2000;57:808-813.
ABSTRACT | FULL TEXT  

APOE-{epsilon}4 is associated with memory decline in cognitively impaired elderly
Dik et al.
Neurology 2000;54:1492-1497.
ABSTRACT | FULL TEXT  

APOE and AD concordance in twin pairs as predictors of AD in first-degree relatives
Steffens et al.
Neurology 2000;54:593-593.
ABSTRACT | FULL TEXT  

Event-Related Potential Changes in Groups at Increased Risk for Alzheimer Disease
Green and Levey
Arch Neurol 1999;56:1398-1403.
ABSTRACT | FULL TEXT  

Altered brain activation in cognitively intact individuals at high risk for Alzheimer's disease
Smith et al.
Neurology 1999;53:1391-1391.
ABSTRACT | FULL TEXT  

Long term effects of refractory temporal lobe epilepsy on cognitive abilities: a cross sectional study
Jokeit and Ebner
J. Neurol. Neurosurg. Psychiatry 1999;67:44-50.
ABSTRACT | FULL TEXT  

Clinical Epidemiological Quality in Molecular Genetic Research: The Need for Methodological Standards
Bogardus et al.
JAMA 1999;281:1919-1926.
ABSTRACT | FULL TEXT  

Prediction of AD with MRI-based hippocampal volume in mild cognitive impairment
Jack et al.
Neurology 1999;52:1397-1397.
ABSTRACT | FULL TEXT  

Opening a window on cerebral cholinergic function
Reed and Jagust
Neurology 1999;52:680-680.
FULL TEXT  

Specific Regional Transcription of Apolipoprotein E in Human Brain Neurons
Xu et al.
Am. J. Pathol. 1999;154:601-611.
ABSTRACT | FULL TEXT  

Absence of an Apolipoprotein E {epsilon}4 Allele Is Associated With Increased Parietal Regional Cerebral Blood Flow Asymmetry in Alzheimer Disease
van Dyck et al.
Arch Neurol 1998;55:1460-1466.
ABSTRACT | FULL TEXT  

Enhanced Upregulation of the Fc{gamma} Receptor IIIa (CD16a) During In Vitro Differentiation of ApoE4/4 Monocytes
Stohr et al.
Arterioscler. Thromb. Vasc. Bio. 1998;18:1424-1432.
ABSTRACT | FULL TEXT  

Apolipoprotein E {epsilon}4 Allele and Whole Brain Atrophy in Late-Onset Alzheimer's Disease
Yasuda et al.
Am. J. Psychiatry 1998;155:779-784.
ABSTRACT | FULL TEXT  

Longitudinal SPECT study in Alzheimer's disease: relation to apolipoprotein E polymorphism
Lehtovirta et al.
J. Neurol. Neurosurg. Psychiatry 1998;64:742-746.
ABSTRACT | FULL TEXT  

Differential Diagnosis and Early Detection of Dementia
Small
AJGP 1998;6:26S-33.
ABSTRACT | FULL TEXT  

Alzheimer's Disease: Cholinergic Therapy and Beyond
Sunderland
AJGP 1998;6:56S-63.
ABSTRACT | FULL TEXT  

Preclinical Evidence of Alzheimer's Disease in Persons Homozygous for the {epsilon}4 Allele for Apolipoprotein E
Reiman et al.
NEJM 1996;334:752-758.
ABSTRACT | FULL TEXT  

When a Mind Dies
Campion
NEJM 1996;334:791-792.
FULL TEXT  

Researching the Aging Well Process
PERRY
American Behavioral Scientist 1995;39:152-171.
 

Patients with Alzheimer's disease have reduced activities in midlife compared with healthy control-group members
Friedland et al.
Proc. Natl. Acad. Sci. USA 2001;98:3440-3445.
ABSTRACT | FULL TEXT  

From the Cover: Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer's disease
Small et al.
Proc. Natl. Acad. Sci. USA 2000;97:6037-6042.
ABSTRACT | FULL TEXT  

Functional brain imaging to identify affected subjects genetically at risk for Alzheimer's disease
Rapoport
Proc. Natl. Acad. Sci. USA 2000;97:5696-5698.
FULL TEXT  

Prediction of cognitive decline in normal elderly subjects with 2-[18F]fluoro-2-deoxy-D-glucose/positron-emission tomography (FDG/PET)
de Leon et al.
Proc. Natl. Acad. Sci. USA 2001;98:10966-10971.
ABSTRACT | FULL TEXT