Mapping the effect of APOE ε4 on gray matter loss in Alzheimer's disease in vivo

LENITEM Laboratory of Epidemiology, Neuroimaging and Telemedicine, IRCCS Centro San Giovanni di Dio - FBF, Brescia, Italy.
NeuroImage (Impact Factor: 6.36). 05/2009; 45(4):1090-8. DOI: 10.1016/j.neuroimage.2009.01.009
Source: PubMed


Previous studies suggest that in Alzheimer's disease (AD) the Apolipoprotein E (APOE) epsilon4 allele is associated with greater vulnerability of medial temporal lobe structures. However, less is known about its effect on the whole cortical mantle. Here we aimed to identify APOE-related patterns of cortical atrophy in AD using an advanced computational anatomy technique. We studied 15 AD patients carriers (epsilon4+, age: 72+/-10 SD years, MMSE: 20+/-3 SD) and 14 non-carriers (epsilon4-, age: 69+/-9, MMSE: 20+/-5) of the epsilon4 allele and compared them to 29 age-and-sex matched controls (age: 70+/-9, MMSE: 28+/-1). Each subject underwent a clinical evaluation, a neuropsychological battery, and high-resolution MRI. UCLA's cortical pattern matching technique was used to identify regions of local cortical atrophy. epsilon4+ and epsilon4- patients showed similar performance on neuropsychological tests (p>.05, t-test). Diffuse cortical atrophy was detected for both epsilon4+ (p=.0001, permutation test) and epsilon4- patients (p=.0001, permutation test) relative to controls, and overall gray matter loss was about 15% in each patients group. Differences in gray matter loss between carriers and non-carriers mapped to the temporal cortex and right occipital pole (20% greater loss in carriers) and to the posterior cingulate, left orbitofrontal and dorsal fronto-parietal cortex (5-15% greater loss in non-carriers). APOE effect in AD was not significant (p>.74, ANOVA), but a significant APOE by region (temporal vs fronto-parietal cortex) interaction was detected (p=.002, ANOVA), in both early and late-onset patients (p<.05, ANOVA). We conclude that the epsilon4 allele modulates disease phenotype in AD, being associated with a pattern of differential temporal and fronto-parietal vulnerability.

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    • "The faster cognitive decline in early onset patients, particularly when they are APOE E4 negative may be related to location of neural damage. It is conceivable that genetic characteristics drive distribution of pathology, and in fact, APOE E4 negative patients have been shown to have more frontal and parietal atrophy, while APOE positive E4 patients had more temporal/hippocampal atrophy (Geroldi et al., 1999; Pievani et al., 2009). Moreover, in an earlier study by our group, we have shown that APOE E4 negative AD patients with an early onset were at higher risk for more global brain atrophy than older APOE E4 positive patients who had more pronounced hippocampal atrophy (Sluimer et al., 2008). "
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    ABSTRACT: Age at onset and APOE E4-genotype have been shown to influence clinical manifestation of Alzheimer's disease (AD). We investigated rate of decline in specific cognitive domains according to age at onset and APOE E4-genotype in patients with AD. 199 patients with probable AD underwent at least two annual neuropsychological assessments. Patients were classified according to age-at-onset (≤65 years vs >65 years) and APOE genotype (positive vs negative). The neuropsychological test battery compromised tests for memory, language, attention, executive and visuo-spatial functioning. For each domain compound z-scores were calculated, based on the baseline performance of patients. Average duration of follow-up was 1.5±1 years. We used linear mixed models (LMM) to estimate effects of age, APOE and age⁎APOE on cognitive decline over time. At baseline, patients were 65±8 years, 98(49%) were female and MMSE was 22±4. LMM showed that early onset patients declined faster on executive functioning (β±SE:-0.09±0.06) than late onset patients, but age was not related to decline in the other cognitive domains. APOE E4 negative patients declined faster on language than APOE E4 positive patients (β±SE:-0.1±0.06). When we took age and APOE genotype into account simultaneously, we found that compared to late onset-E4 positive patients, early onset-E4 negative patients declined faster on language (β±SE:-0.36±0.1), attention (β±SE:-0.42±0.1), executive (β±SE:-0.41±0.1) and visuo-spatial functioning (β±SE:-0.43±0.1). Late onset-E4 negative and early onset-E4 positive patients showed intermediate rates of decline. We found no differences in decline on memory. We found that patients who develop AD despite absence of the two most important risk factors, show steepest cognitive decline on non-memory cognitive domains. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.
    European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 03/2015; 25(7). DOI:10.1016/j.euroneuro.2015.03.014 · 4.37 Impact Factor
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    • "To adjust for variations in local smoothness of the probability maps, we conducted a correction for non-stationarity with SPM8. Additional voxel-based region-of-interest (ROI) analyses were performed for the hippocampus, which is known to be affected at early stages of AD and to be essential for memory consolidation, as well as for regions previously shown to be differentially affected in APOE E4 carriers and non-carriers converting to AD, i.e., medial occipital cortex, superior frontal, and posterior parietal cortex at p < 0.05 voxel-level FWE-corrected [3] [4] [22]. FWE-corrections based on Gaussian random field theory were applied as implemented in SPM8. "
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    ABSTRACT: Background: The E4 isoform of the APOE genotype is the most significant genetic risk factor for sporadic Alzheimer's disease (AD) and has recently been found to modulate disease expression in patients with AD. Objective: To investigate APOE-dependent cognitive and structural phenotypes in subjects with mild cognitive impairment who converted to AD within the following three years. Methods: Subjects converting to AD (n = 63) were compared to a control group with stable mild cognitive impairment (n = 131). Clinical, neuropsychological, and MRI data were obtained by the German Dementia Competence Network. Subgroups of converting and stable APOE E4 carriers and non-carriers were investigated longitudinally with MRI to examine structural correlates of conversion. Voxel-based morphometry was applied to investigate gray matter distribution. Results: At baseline, executive performance correlated with global and bilateral prefrontal gray matter volume and predicted conversion only among non-carriers. Converting carriers and non-carriers presented distinct patterns of brain atrophy on longitudinal analysis, in line with a dissociation between more pronounced occipital atrophy in carriers and more frontoparietal volume loss in non-carriers at follow-up. Conclusions: The current findings suggest that in APOE E4 non-carriers with AD, executive dysfunction is closely linked to frontal gray matter atrophy and predictive of progression to dementia. The results are consistent with APOE genotype-dependent profiles of structural damage and cognitive decline in patients with imminent conversion to AD.
    Journal of Alzheimer's disease: JAD 07/2013; 37(2). DOI:10.3233/JAD-130326 · 4.15 Impact Factor
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    • "The exclusion criteria for the patients were: abnormal laboratory tests, evidence of depression or disthymia, substance abuse that could interfere with cognitive functioning, or any other major systemic, psychiatric, or neurological illnesses. Subjects included in this work overlap to a great extent with the group investigated in our previous study (Pievani et al., 2009). Given that the former patient groups differed for sex and education, and APOE4 carriers were on average three years older than non-carriers, an additional group of newly admitted AD patients was included so as to obtain a closer matching with regard to these variables. "
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    ABSTRACT: Prior studies reported that the hippocampal volume is smaller in Alzheimer's disease patients carrying the Apolipoprotein E ε4 allele (APOE4) versus patients who are non-carriers of this allele. This effect however has not been detected consistently, possibly because of the regionally-specific involvement of the hippocampal formation in Alzheimer's disease. The aim of this study was to analyze the local effect of APOE4 on hippocampal atrophy in Alzheimer's disease patients. Using high-resolution T1-weighted images we investigated 14 patients heterozygous for the ε4 allele (age 72±8 SD years; MMSE 20±4 SD) and 14 patients not carrying the ε4 allele (age 71±10; MMSE 20±5 SD), and 28 age-, sex-, and education-matched controls (age 71±8; MMSE 29±1 SD). The hippocampal formation was outlined with manual tracing and 3D parametric surface models were created for each subject. Radial atrophy was assessed on the whole hippocampal surface using the UCLA mapping technique. E4 carriers and non-carriers did not differ in their level of impairment in global cognition (p=0.91, Mann-Whitney test) or memory (p>0.29). Hippocampal surface analysis showed the typical pattern of CA1 and subicular tissue atrophy in both ε4-carriers and non-carriers compared with controls (e4 carriers: p<0.0002; ε4 non-carriers: p<0.01, permutation test). The left hippocampal volume was significantly smaller in ε4-carriers than non-carriers (p=0.044, Mann-Whitney test), the effect of APOE4 mapping to the subicular/CA1 region (p=0.041, permutation test). Differences were not statistically significant in the right hippocampus (p>0.20, permutation test). These findings show that hippocampal atrophy is greater in APOE4 carriers in regions typically affected by pathology. APOE4 may affect the structural expression of Alzheimer's disease.
    NeuroImage 04/2011; 55(3):909-19. DOI:10.1016/j.neuroimage.2010.12.081 · 6.36 Impact Factor
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