Neurology -- Correspondence for van der Flier et al., 67 (3) 526-527

Correspondence published:

The effect of APOE genotype on clinical phenotype in Alzheimer disease: Barbara Borroni, Monica Di Luca, and Alessandro Padovani (19 September 2006)

Reply from the Authors: Wiesje M van der Flier, Niki SM Schoonenboom, Yolande AL Pijnenburg, Nick C Fox, and Philip Scheltens. (19 September 2006)

The effect of APOE genotype on clinical phenotype in Alzheimer disease 19 September 2006

Barbara Borroni,
Department of Neurology
University of Brescia, Italy,
Monica Di Luca, and Alessandro Padovani
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Re: The effect of APOE genotype on clinical phenotype in Alzheimer disease

borroni{at}med.unibs.it Barbara Borroni, et al.

We read with interest the article by van der Flier et al in which the authors conclude that two subtypes of Alzheimer Disease (AD) can be identified based on initial clinical presentation. Among 100 AD patients the “typical amnestic” and “nonmemory” phenotypes were characterized. The former seems to be promoted by Apolipoprotein E (APOE) epsilon4 allele, suggesting a different underscored genetic predisposition. [1]
These findings concur with our ongoing study carried out on a consecutive series of more than 500 AD patients fulfilling current criteria for probable AD. [2] Among them, 319 were genotyped for ApoE, [2] and were classified into two subgroups as presenting with complaints of forgetfulness (memory phenotype, MP) or complaints clearly different in character (nonmemory phenotype, NMP). As reported by van der Flier et al, in our work, MP was present in 70.2% of patients (n=224), while NMP in 29.8% (n=95). There were no differences between groups in gender, age, age at onset or education.
The prevalence of APOE epsilon4 was 43.3% (n=138/319), with 5% (n=16) of homozygous in the overall sample. APOE epsilon4-carriers (mean±Standard Deviation, age=75.4±4.0 years, female=69.3%, education=5.7±2.8 years) and APOE non-epsilon4 carriers (age=76.8±6.8 years, female=68.5%, education=5.4±2.8 years) did not differ for demographic characteristics. APOE genotype was associated with clinical phenotype. In APOE epsilon4 carriers the MP at presentation was more prevalent (77.6%) compared to APOE non-epsilon4 carriers (64.6%, P<0.02). The results did not change when age at onset, gender and education were entered as covariates (P<0.03).
van der Flier et al's and our results both show that APOE genotype might be considered a disease-modifying factor in AD contributing to define a specific clinical presentation. Further, this association was not only true in early-onset AD, as suggested by the authors, but further extended in late-onset AD, as in the present sample. The role of APOE genotype is well established in AD and it has been demonstrated that APOE genotype may affect cognitive performance in normal aging, epsilon4 allele-carriers showing altered memory-related cognitive processing. [4]
Considering the role of APOE genotype not only as a risk factor, but also as a disease modulator opens a novel approach in the field for a better understanding of disease variability and for defining new therapeutic algorithms.
References
1. Van der Flier WM, Schoonenboom SNM, Pijnenburg YAL, Fox NC, Scheltens P. The effect of APOE genotype on clinical phenotype in Alzheimer Disease. Neurology 2006; 67:526-527.
2. McKhann G, Drachman D, Folstein M, et al. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 1984; 34(7):939-44.
3. Borroni B, Grassi M, Costanzi C, et al. APOE genotype and cholesterol levels in Lewy Body Dementia and Alzheimer Disease: investigating genotype-phenotype effect on disease risk. Am J Ger Psychiatry in press.
4. Reiman EM, Caselli RJ, Yun LS, et al. Preclinical evidence of Alzheimer’s disease in persons homozygous for the epsilon 4 allelle of apolipoprotein E. New Eng J Med 1996; 334:752-758.
Disclosure: The authors report no conflicts of interest.

Reply from the Authors 19 September 2006

Wiesje M van der Flier,
VU Medical Center
PO Box 7057, 1007 MB Amsterdam, the Netherlands,
Niki SM Schoonenboom, Yolande AL Pijnenburg, Nick C Fox, and Philip Scheltens.
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Re: Reply from the Authors

wm.vdflier{at}vumc.nl Wiesje M van der Flier, et al.

We thank Borroni et al for their interest. Although prototypically characterized by memory impairment and forgetfulness, patients with AD can also present with other types of initial cognitive deficits, such as apraxia, agnosia, or dyscalculia. Although less prevalent, the nonmemory type of AD accounted for almost 30% of our cohort of patients with younger onset AD. Drs. Borroni et al extend our findings, as they describe a remarkably comparable proportion of this clinical phenotype in a cohort of late-onset patients.
The appreciation of differences in clinical phenotype parallels new directions in the studies of brain changes underlying AD. Traditionally, the hippocampus has been the focus of AD research. Sophisticated image analysis methods, such as voxel based morphometry, allow for the search for brain abnormalities without a priori hypothesis regarding the location of these abnormalities. Remarkably, both MRI and PET studies have shown abnormalities in the biparietal regions in AD which are deemed important for the cognitive deficits as observed in AD patients with a nonmemory presentation. [5-7]
Our findings that the clinical phenotype is associated with APOE genotype provides further evidence supporting the hypothesis that genetic make-up directs the location of Alzheimer-type pathology. It has been suggested that APOE e4 is associated with reduced dendritic density in the hippocampal area. [8] Conversely, other genotypes may be related to abnormalities more posteriorly. Further studies inlcuding imaging are needed to explore this possibility.
References
5. Silverman DH, Small GW, Chang CY, et al. Positron emission tomography in evaluation of dementia: Regional brain metabolism and long-term outcome. JAMA 2001; 286:2120-2127.
6. Karas GB, Scheltens P, Rombouts SA, et al. Global and local gray matter loss in mild cognitive impairment and Alzheimer's disease. Neuroimage 2004;2:708-716.
7. Johnson NA, Jahng GH, Weiner MW, Miller et al. Pattern of cerebral hypoperfusion in Alzheimer disease and mild cognitive impairment measured with arterial spin-labeling MR imaging: initial experience. Radiology 2005; 234:851-859.
8. Ji Y, Gong Y, Gan W, Beach T, Holtzman DM, Wisniewski T. Apolipoprotein E isoform-specific regulation of dendritic spine morphology in apolipoprotein E transgenic mice and Alzheimer's disease patients. Neuroscience 2003; 122:305-315.
Disclosure: The authors report no conflicts of interest.