Metabolic interaction between ApoE genotype and onset age in Alzheimer’s disease: implications for brain reserve
- L Mosconi1,
- K Herholz2,
- I Prohovnik3,
- B Nacmias4,
- M T R De Cristofaro1,
- M Fayyaz1,
- L Bracco4,
- S Sorbi4,
- A Pupi1
- 1Department of Clinical Pathophysiology, Nuclear Medicine Unit, University of Florence, Florence, Italy
- 2Neurological Clinic and Max-Planck-Institute for Neurological Research, University of Cologne, Cologne, Germany
- 3Department of Psychiatry and Radiology, Mount Sinai School of Medicine, New York, NY 10468, USA
- 4Department of Neurological and Psychiatric Sciences, University of Florence, Florence, Italy
- Correspondence to: Dr Alberto Pupi Department of Clinical Pathophysiology, Nuclear Medicine Unit, University of Florence, viale Morgagni 85, 50134 Florence, Italy; a.pupidfc.unifi.it
- Received 21 October 2003
- Accepted 14 April 2004
- Revised 17 March 2004
Abstract
Background: Clinically apparent Alzheimer’s disease (AD) is thought to result when brain tissue damage exceeds a critical threshold of “brain reserve”, a process possibly accelerated by the apolipoprotein E (ApoE) E4 allele. The interaction between onset age and ApoE genotype was investigated to assess whether early disease onset (<65 years) in patients carrying the E4 allele is associated with greater cerebral metabolic (regional cerebral metabolic rate of glucose utilisation, rCMRgl) reduction.
Methods: AD patients, divided into early (EOAD; 27 patients) and late onset (LOAD; 65 patients) groups, both groups balanced as to the number of E4 carriers (E4+) and non-carriers (E4−), and matched controls (NC; 35 cases) underwent 18F-FDG PET ([18F]fluorodeoxyglucose positron emission tomography) scanning. SPM’99 software was used to compare AD patients to NC and to perform a two way ANOVA with onset age and ApoE genotype as grouping factors. Results were considered significant at p<0.001, uncorrected.
Results: AD patients demonstrated rCMRgl reductions compared to NC, with rCMRgl lower in association cortex and relatively higher in limbic areas in EOAD compared to LOAD subjects. rCMRgl was lower in the anterior cingulate and frontal cortex for E4+ compared to E4− subjects. A significant onset age by ApoE interaction was detected in the hippocampi and basal frontal cortex, with EOAD E4+ subjects having the greatest rCMRgl reduction.
Conclusions: The interactive effects of early onset age, possibly reflecting lower brain reserve, and ApoE E4 allele, possibly leading to greater tissue damage, lead to reduced tolerance to the pathophysiological effects of AD in key brain regions.
- AD, Alzheimer’s disease
- ApoE, apolipoprotein E
- BFC, basal frontal cortex
- BRC, brain reserve capacity
- CDR, Clinical Dementia Rating
- CT, computed tomography
- EOAD, early onset AD
- FDG-PET, fluorodeoxyglucose positron emission tomography
- FOV, field of view
- GLM, General Linear Model
- IADL, Inventory of Activities of Daily Living
- LOAD, late onset AD
- MMSE, Mini-Mental State Examination
- MRI, magnetic resonance imaging
- MTL, medial temporal lobe
- NC, controls
- NEST-DD, Network for Efficiency and Standardization of Dementia Diagnosis
- NFT, neurofibrillary tangles
- NP, neuritic plaques
- SPM, statistical parametric map
Footnotes
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This study was conducted to comply with the Network for Efficiency and Standardization of Dementia Diagnosis (NEST-DD) with support from the European Commission (Framework V; European Union grants QLK-6-CT-1999-02178 and QLK-6-CT-1999-02112). Work at Florence was also supported by the Ministero dell’Università e della Ricerca Scientifica e Tecnologica (MURST), and by Regione Toscana, Progetto MINISTERO della SANITA, “Diagnosi Tempestiva e Differenziale della Malattia di Alzheimer. Uso delle Tecnologie avanzate”.
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Competing interests: none declared
