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Effect of APOE genotype on amyloid plaque load and gray matter volume in Alzheimer disease

From the Departments of Nuclear Medicine (A.D., G.H., I.M., C.P., A.W., H.J.W., M.S.), Psychiatry and Psychotherapy (T.G., R.P., C.S., M.R., H.F., A.K.), Neurology (M.M.), and Neuroradiology (A.W.), Technische Universität München, Munich, Germany.

Address correspondence and reprint requests to Dr. Alexander Drzezga, Department of Nuclear Medicine, Klinikum rechts der Isar, Technischen Universität München, Ismaninger Str. 22, D-81675 München/Munich, Germany a.drzezga{at}lrz.tum.de

Objective: To examine the influence of the APOE genotype on levels of β-amyloid (Aβ) plaque load and atrophy in patients with Alzheimer disease (AD) in vivo.

Methods: Thirty-two patients with moderate AD were divided into carriers and noncarriers of the 4 allele. These groups were matched for age, disease duration, education, and cognitive impairment. In all subjects, [¹¹C]PIB-PET was performed for measurement of cerebral Aβ plaque deposition and cranial MRI for the assessment of gray matter volume by voxel-based morphometry (VBM) and for correction of partial volume effects (PVE) in the PET data. Voxel-based comparisons (SPM5) were performed between patient groups and healthy control populations and completed with multiple regression analyses between imaging data and 4 allele frequency.

Results: Compared to controls, AD-typical patterns of [¹¹C]PIB retention and atrophy were detected in both 4-positive and 4-negative patient groups. In direct comparison, significantly stronger and more extended [¹¹C]PIB uptake was found in 4-positive patients in bilateral temporoparietal and frontal cortex, surviving PVE correction. VBM analysis demonstrated comparable levels of atrophy in both patient groups. Regression analyses revealed a linear association between higher 4 allele frequency and stronger temporoparietal Aβ plaque deposition, independently of other confounds. No major correlation between 4 allele frequency and gray matter decrease was observed.

Conclusion: These results indicate that the 4-positive APOE genotype not only represents a risk factor for Alzheimer disease (AD), but also results in higher levels of Aβ plaque deposition in 4-positive patients with AD compared to age-matched 4-negative patients with similar levels of cognitive impairment and brain atrophy. The potential role of Aβ plaque imaging for patient inclusion and follow-up in anti-amyloid therapy trials is strengthened by these findings.

Abbreviations: AD = Alzheimer disease; FDR = false discovery rate; MMSE = Mini-Mental State Examination; PVE = partial volume effects; VBM = voxel-based morphometry.

Supplemental data at www.neurology.org

e-Pub ahead of print on April 1, 2009, at www.neurology.org.

Supported in part by DFG grants (Deutsche Forschungsgemeinschaft) project numbers DR 445/3-1, DR 445/4-1 (A.D.), and HE 4560/1-2 (G.H.), and by a KKF grant for clinical research of the Technische Universität München (A.D.).

Disclosure: The authors report no disclosures.

Received October 16, 2008. Accepted in final form January 20, 2009.