Metabolic interaction between ApoE genotype and onset age in Alzheimer’s disease: implications for brain reserve

• Published in: Journal of neurology, neurosurgery and psychiatry Vol. 76; no. 1; pp. 15 - 23
• Main Authors: Mosconi, L, Herholz, K, Prohovnik, I, Nacmias, B, De Cristofaro, M T R, Fayyaz, M, Bracco, L, Sorbi, S, Pupi, A
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd 01.01.2005; BMJ; BMJ Publishing Group LTD; BMJ Group
• Subjects: Activities of daily living; Age; Age of Onset; Aged; Aged, 80 and over; Alzheimer Disease - diagnostic imaging; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer's disease; ApoE; apolipoprotein E; Apolipoproteins E - genetics; basal frontal cortex; BFC; Biological and medical sciences; Brain - diagnostic imaging; Brain - metabolism; brain reserve; brain reserve capacity; BRC; Case-Control Studies; CDR; Clinical Dementia Rating; Cognitive ability; computed tomography; controls; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Dementia; early onset; early onset AD; EOAD; FDG-PET; Female; field of view; Fluorodeoxyglucose F18 - pharmacokinetics; fluorodeoxyglucose positron emission tomography; FOV; General Linear Model; Genotype; Genotype & phenotype; GLM; Glucose; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; Humans; IADL; Inventory of Activities of Daily Living; late onset AD; LOAD; magnetic resonance imaging; Male; medial temporal lobe; Medical sciences; Metabolism; Middle Aged; Mini-Mental State Examination; MMSE; MRI; MTL; Nervous system (semeiology, syndromes); NEST-DD; Network for Efficiency and Standardization of Dementia Diagnosis; neuritic plaques; neurofibrillary tangles; Neurology; Neuropsychology; NFT; Positron-Emission Tomography; Radiopharmaceuticals - pharmacokinetics; SPM; statistical parametric map; Tomography; Nervous system diseases; Alzheimer disease; Interaction; Central nervous system disease; Genotype; Degenerative disease; Cerebral disorder
• ISSN: 0022-3050; 1468-330X
• DOI: 10.1136/jnnp.2003.030882

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.