Reiman, E. M., Webster, J. A., Myers, A. J., Hardy, J., Dunckley, T., Zismann, V. L., Joshipura, K. D., Pearson, J. V., Hu-Lince, D., Huentelman, M., Craig, D. W., Coon, K. D., Liang, W. S., Herbert, R. H., Beach, T., Rohrer, K. C., Zhao, A. S., Leung, D., Bryden, L., , Marlowe, L., et al. (2007). GAB2 Alleles Modify Alzheimer's Risk in APOE ε4 Carriers. Neuron, 54(5), 713-720.
PMID: 17553421;PMCID: PMC2587162;Abstract:
The apolipoprotein E (APOE) ε4 allele is the best established genetic risk factor for late-onset Alzheimer's disease (LOAD). We conducted genome-wide surveys of 502,627 single-nucleotide polymorphisms (SNPs) to characterize and confirm other LOAD susceptibility genes. In ε4 carriers from neuropathologically verified discovery, neuropathologically verified replication, and clinically characterized replication cohorts of 1411 cases and controls, LOAD was associated with six SNPs from the GRB-associated binding protein 2 (GAB2) gene and a common haplotype encompassing the entire GAB2 gene. SNP rs2373115 (p = 9 × 10-11) was associated with an odds ratio of 4.06 (confidence interval 2.81-14.69), which interacts with APOE ε4 to further modify risk. GAB2 was overexpressed in pathologically vulnerable neurons; the Gab2 protein was detected in neurons, tangle-bearing neurons, and dystrophic neuritis; and interference with GAB2 gene expression increased tau phosphorylation. Our findings suggest that GAB2 modifies LOAD risk in APOE ε4 carriers and influences Alzheimer's neuropathology. © 2007 Elsevier Inc. All rights reserved.
Krasuski, J. S., Alexander, G. E., Horwitz, B., Daly, E. M., Murphy, D. G., Rapoport, S. I., & Schapiro, M. B. (1998). Volumes of medial temporal lobe structures in patients with Alzheimer's disease and mild cognitive impairment (and in healthy controls). Biological Psychiatry, 43(1), 60-68.
PMID: 9442345;Abstract:
Background: The clinical diagnosis of Alzheimer's disease (AD) can be difficult to make in early stages of disease. Structural neuroimaging offers a potential tool in the clinical diagnosis of AD with mild cognitive impairment. Postmortem studies indicate that early neuropathology in AD occurs in medial temporal lobe limbic structures. Magnetic resonance imaging (MRI) studies that assessed these volumes in mildly impaired AD patients remain inconclusive. Methods: Using MRI, we measured volumes of left and right hippocampus, amygdala, and anterior and posterior parahippocampal gyrus (PHG) in 13 AD patients with mild cognitive impairment, defined as ≤ 20 on the Mini-Mental State Exam, and in 21 healthy age- and sex-matched controls. Results: The AD patients had smaller medial temporal lobe volumes, except for the right anterior PHG. Discriminant function analysis using MRI volumes produced 94% correct group classification. Conclusions: These results show that in mildly impaired AD patients atrophy is present in medial temporal lobe structures; that MRI volumes of the anterior PHG, which contains entorhinal cortex, are reduced, but the amygdala and hippocampal volumes show greater reduction; and that discriminant function analysis using all volumes as predictors can correctly classify a high proportion of individuals.
Caselli, R. J., Reiman, E. M., E., D., Hutton, M. L., Hentz, J. G., Hoffman-Snyder, C., Woodruff, B. K., Alexander, G. E., & Osborne, D. (2007). Cognitive domain decline in healthy apolipoprotein E ε4 homozygotes before the diagnosis of mild cognitive impairment. Archives of Neurology, 64(9), 1306-1311.
PMID: 17846270;Abstract:
Background: Memory declines more rapidly with age in apolipoprotein E (APOE) ε4 carriers than in APOE ε4 noncarriers, and APOE ε4 homozygotes' cognitive performances correlate with stressors. These changes could represent presymptomatic disease in some, despite their youth. Objective: To show that presymptomatic APOE ε4 homozygotes experience greater psychometric decline at a younger age than APOE ε4 heterozygotes and noncarriers before the diagnosis of mild cognitive impairment (MCI) and Alzheimer disease (AD). Design: Prospective observational study Setting: Academic medical center. Participants: A total of 43 APOE ε4 homozygotes, 59 APOE ε4 heterozygotes, and 112 APOE ε4 noncarriers aged 50 to 69 years were cognitively healthy and matched at entry according to age, educational level, and sex. Intervention: Neuropsychological battery given every 2 years. Main Outcome Measures: Predefined test and cognitive domain decline criteria applied to consecutive epochs. Results: Of 214 participants, 48 showed no decline on any test, 126 showed decline on only 1 test in 1 or more domains, and 40 showed decline on 2 or more tests in 1 or more domains. Cognitive domain decline occurred in 4 of 10 APOE ε4 homozygotes 60 years and older at entry (40.0%) compared with 5 of 66 APOE ε4 heterozygotes and noncarriers (7.6%) (P=.02) and was more predictive of subsequent decline than nondomain decline (17 of 24 [70.8%] vs 29 of 70 [41.4%]; P=.01). Decline on any memory test was predictive of further decline (P.001), as was memory domain decline (P=.006) in all genetic subgroups. Seven participants developed MCI (in 6) or AD (in 1), of whom 5 were APOE ε4 homozygotes (P=.008). Retrospective comparison showed that those who experienced multidomain, memory, and language domain decline had lower spatial and memory scores at entry than those who experienced no decline. Conclusions: APOE ε4 homozygotes in their 60s have higher rates of cognitive domain decline than APOE ε4 heterozygotes or noncarriers before the diagnosis of MCI and AD, thus confirming and characterizing the existence of a pre-MCI state in this genetic subset. ©2007 American Medical Association. All rights reserved.
Bizon, J. L., Foster, T. C., Alexander, G. E., & Glisky, E. L. (2012). Characterizing cognitive aging of working memory and executive function in animal models. Frontiers in Aging Neuroscience, 4, 19.
Teipel, S. J., Bayer, W., Alexander, G. E., Bokde, A. L., Zebuhr, Y., Teichberg, D., Müller-Spahn, F., Schapiro, M. B., Möller, H., Rapoport, S. I., & Hampel, H. (2003). Regional pattern of hippocampus and corpus callosum atrophy in Alzheimer's disease in relation to dementia severity: Evidence for early neocortical degeneration. Neurobiology of Aging, 24(1), 85-94.
PMID: 12493554;Abstract:
We used volumetric MRI and analysis of areas under receiver operating characteristic (ROC) curves to directly compare the extent of hippocampus-amygdala formation (HAF) and corpus callosum atrophy in patients with Alzheimer's disease (AD) in different clinical stages of dementia. Based on neuropathological studies, we hypothesized that HAF atrophy, representing allocortical neuronal degeneration, would precede atrophy of corpus callosum, representing loss of neocortical association neurons, in early AD. HAF and corpus callosum sizes were significantly reduced in 27 AD patients (37% and 16%, respectively) compared to 28 healthy controls. In mildly- and moderately-demented AD patients, the ROC derived index of atrophy was greater for HAF volume than for total corpus callosum area. The index of atrophy of posterior corpus callosum was not significantly different from HAF at mild, moderate or severe stages of dementia. In conclusion, these findings suggest a characteristic regional pattern of allocortical and neocortical neurodegeneraton in AD. Our data indicate that neuronal loss in parietotemporal cortex (represented by atrophy of corpus callosum splenium) may occur simultaneously with allocortical neurodegeneration in mild AD. Moreover, ROC analysis may provide a statistical framework to determine atrophy patterns of different brain structures in neurodegenerative diseases in vivo. © 2002 Elsevier Science Inc. All rights reserved.
