Gene E Alexander
Professor, BIO5 Institute
Professor, Evelyn F Mcknight Brain Institute
Professor, Neuroscience - GIDP
Professor, Physiological Sciences - GIDP
Professor, Psychiatry
Professor, Psychology
Primary Department
Department Affiliations
(520) 626-1704
Work Summary
My research focuses on advancing our understanding of how and why aging impacts the brain and associated cognitive abilities. I use neuroimaging scans of brain function and structure together with measures of cognition and health status to identify those factors that influence brain aging and the risk for Alzheimer's disease. My work also includes identifying how health and lifestyle interventions can help to delay or prevent the effects of brain aging and Alzheimer's disease.
Research Interest
Dr. Alexander is Professor in the Departments of Psychology and Psychiatry, the Evelyn F. McKnight Brain Institute, and the Neuroscience and Physiological Sciences Graduate Interdisciplinary Programs of the University of Arizona. He is Director of the Brain Imaging, Behavior and Aging Lab, a member of the Internal Scientific Advisory Committee for the Arizona Alzheimer’s Consortium, and a member of the Scientific Advisory Board for the Arizona Evelyn F. McKnight Brain Institute. He received his post-doctoral training in neuroimaging and neuropsychology at Columbia University Medical Center and the New York State Psychiatric Institute. Prior to coming to Arizona, Dr. Alexander was Chief of the Neuropsychology Unit in the Laboratory of Neurosciences in the Intramural Research Program at the National Institute on Aging. Dr. Alexander has over 20 years experience as a neuroimaging and neuropsychology researcher in the study of aging and age-related neurodegenerative disease. He is a Fellow of the Association for Psychological Science and the American Psychological Association (Division 40) Society for Clinical Neuropsychology. His research has been supported by grants from the National Institutes of Health, the Evelyn F. McKnight Brain Research Foundation, the State of Arizona, and the Alzheimer’s Association. He uses structural and functional magnetic resonance imaging (MRI) and positron emission tomography (PET) combined with measures of cognition and behavior to investigate the effects of multiple health and lifestyle factors on the brain changes associated with aging and the risk for Alzheimer’s disease. Keywords: "Aging/Age-Related Disease", "Brain Imaging", "Cognitive Neurosicence", "Alzheimer's Disease"


Caselli, R. J., Dueck, A. C., Osborne, D., Sabbagh, M. N., Connor, D. J., Ahern, G. L., Baxter, L. C., Rapcsak, S. Z., Shi, J., Woodruff, B. K., E., D., Snyder, C. H., Alexander, G. E., Rademakers, R., & Reiman, E. M. (2009). Longitudinal modeling of age-related memory decline and the APOE ε4 effect. New England Journal of Medicine, 361(3), 255-263.

PMID: 19605830;PMCID: PMC2928998;Abstract:

BACKGROUND: The APOE ε4 allele is associated with the risk of late-onset Alzheimer's disease. The age at which memory decline diverges among persons who are homozygous for the APOE ε4 allele, those who are heterozygous for the allele, and noncarriers is unknown. METHODS: Using local advertisements, we recruited cognitively normal subjects between the ages of 21 and 97 years, who were grouped according to their APOE ε4 status. We then followed the subjects with longitudinal neuropsychological testing. Anyone in whom mild cognitive impairment or dementia developed during follow-up was excluded. We compared the rates of decline in predetermined cognitive measures between carriers and noncarriers of the APOE ε4 allele, using a mixed model for longitudinal change with age. RESULTS: We analyzed 815 subjects: 317 APOE ε4 carriers (79 who were homozygous for the APOE ε4 allele and 238 who were heterozygous) and 498 noncarriers. Carriers, as compared with noncarriers, were generally younger (mean age, 58.0 vs. 61.4 years; P

Cohen, R. A., & Alexander, G. E. (2017). Using the Telephone Interview for Cognitive Status and Telephone Montreal Cognitive Assessment for Evaluating Vascular Cognitive Impairment: Promising Call or Put on Hold?. Stroke, 48(11), 2919-2921.
Alexander, G. E., Chen, K., Pietrini, P., Rapoport, S. I., & Reiman, E. M. (2002). Longitudinal PET evaluation of cerebral metabolic decline in dementia: A potential outcome measure in Alzheimer's disease treatment studies. American Journal of Psychiatry, 159(5), 738-745.

PMID: 11986126;Abstract:

Objective: It is well established that regional cerebral metabolic rates for glucose assessed by [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) in patients with Alzheimer's disease in the mental resting state (eyes and ears covered) provide a sensitive, in vivo metabolic index of Alzheimer's disease dementia. Few studies, however, have evaluated longitudinal declines in regional cerebral glucose metabolism in patients with dementia caused by Alzheimer's disease. In addition, the available studies have not used recently developed brain mapping algorithms to characterize the progression of Alzheimer's disease throughout the brain, and none considered the statistical power of regional cerebral glucose metabolism in testing the ability of treatments to attenuate the progression of dementia. Method: The authors used FDG PET and a brain mapping algorithm to investigate cross-sectional reductions in regional cerebral glucose metabolism, longitudinal decline in regional cerebral glucose metabolism after a 1-year follow-up, and the power of this method to evaluate treatments for Alzheimer's disease in patients with mild to moderate dementia. PET scans were initially acquired in 14 patients with Alzheimer's disease and 34 healthy comparison subjects of similar age and sex. Repeat scans were obtained in the patients 1 year later. Power analyses for voxels showing maximal decline over the 1-year period in regional cerebral glucose metabolism (mg/100 g per minute) were computed to estimate the sample sizes needed to detect a significant treatment response in a 1-year, double-blind, placebo-controlled treatment study. Results: The patients with Alzheimer's disease had significantly lower glucose metabolism than healthy comparison subjects in parietal, temporal, occipital, frontal, and posterior cingulate cortices. One year later, the patients with Alzheimer's disease had significant declines in glucose metabolism in parietal, temporal, frontal, and posterior cingulate cortices. Using maximal glucose metabolism reductions in the left frontal cortex, we estimated that as few as 36 patients per group would be needed to detect a 33% treatment response with one-tailed significance of p≤0.005 and 80% power in a 1-year, double-blind, placebo-controlled treatment study. Conclusions: These findings indicate that brain metabolism as assessed by FDG PET during mental rest is a sensitive marker of disease progression in Alzheimer's disease over a 1-year period. These findings also support the feasibility of using FDG PET as an outcome measure to test the ability of treatments to attenuate the progression of Alzheimer's disease.

Hampel, H., Teipel, S. J., Alexander, G. E., Horwitz, B., Teichberg, D., Schapiro, M. B., & Rapoport, S. I. (1998). Corpus callosum atrophy is a possible indicator of region- and cell type-specific neuronal degeneration in Alzheimer disease: A magnetic resonance imaging analysis. Archives of Neurology, 55(2), 193-198.

PMID: 9482361;Abstract:

Background: Pathological studies in Alzheimer disease indicate the specific loss of layer III and V large pyramidal neurons in association cortex. These neurons give rise to long corticocortical connections within and between the cerebral hemispheres. Objectives: To evaluate the corpus callosum as an in vivo marker for cortical neuronal loss. Method: Using a new imaging technique, we measured region-specific corpus callosum atrophy in patients with Alzheimer disease and correlated the changes with neuropsychological functioning. Total cross-sectional area of the corpus callosum and areas of 5 callosal subregions were measured on mid-sagittal magnetic resonance imaging scans of 14 patients with Alzheimer disease (mean age, 64.4 years; Mini-Mental State Examination score, 11.4) and 22 healthy age- and sex-matched control subjects (mean age, 66.6 years; Mini-Mental State Examination score, 29.8). All subjects had minimal white matter changes. Results: The total callosal area was significantly reduced in the patients with Alzheimer disease, with the greatest changes in the rostrum and splenium and relative sparing of the callosal body. Regional callosal atrophy correlated significantly with cognitive impairment in the patients with Alzheimer disease, but not with age or the white matter hyperintensities score. Conclusions: Callosal atrophy in patients with Alzheimer disease with only minimal white matter changes may indicate loss of callosal efferent neurons in corresponding regions of the cortex. Because these neurons are a subset of corticocortical projecting neurons, region-specific callosal atrophy may serve as a marker of progressive neo-cortical disconnection in Alzheimer disease.

Protas, H. D., Chen, K., B., J., Fleisher, A. S., Alexander, G. E., Lee, W., Bandy, D., J., M., Mosconi, L., Buckley, S., Truran-Sacrey, D., Schuff, N., Weiner, M. W., Caselli, R. J., & Reiman, E. M. (2013). Posterior cingulate glucose metabolism, hippocampal glucose metabolism, and hippocampal volume in cognitively normal, late-middle-aged persons at 3 levels of genetic risk for alzheimer disease. JAMA Neurology, 70(3), 320-325.

PMID: 23599929;PMCID: PMC3745014;Abstract:

Objective: To characterize and compare measurements of the posterior cingulate glucose metabolism, the hippocampal glucose metabolism, and hippocampal volume so as to distinguish cognitively normal, late-middleaged persons with 2, 1, or 0 copies of the apolipoprotein E (APOE) e4 allele, reflecting 3 levels of risk for lateonset Alzheimer disease. Design: Cross-sectional comparison of measurements of cerebral glucose metabolism using 18F-fluorodeoxyglucose positron emission tomography and measurements of brain volume using magnetic resonance imaging in cognitively normal e4 homozygotes, e4 heterozygotes, and noncarriers. Setting: Academic medical center. Participants: A total of 31 e4 homozygotes, 42 e4 heterozygotes, and 76 noncarriers, 49 to 67 years old, matched for sex, age, and educational level. Main Outcome Measures: The measurements of posterior cingulate and hippocampal glucose metabolism were characterized using automated region-of-interest algorithms and normalized for whole-brain measurements. The hippocampal volume measurements were characterized using a semiautomated algorithm and normalized for total intracranial volume. Results: Although there were no significant differences among the 3 groups of participants in their clinical ratings, neuropsychological test scores, hippocampal volumes (P=.60), or hippocampal glucose metabolism measurements (P = .12), there were significant group differences in their posterior cingulate glucose metabolism measurements (P=.001). The APOE e4 gene dose was significantly associated with posterior cingulate glucose metabolism (r=0.29, P=.0003), and this association was significantly greater than those with hippocampal volume or hippocampal glucose metabolism (P<.05 determined="" by="" use="" of="" pairwise="" fisher="" z="" tests="" conclusions:="" although="" our="" findings="" may="" depend="" in="" part="" on="" the="" analysis="" algorithms="" used="" they="" suggest="" that="" a="" reduction="" posterior="" cingulate="" glucose="" metabolism="" precedes="" hippocampal="" volume="" or="" cognitively="" normal="" persons="" at="" increased="" genetic="" risk="" for="" alzheimer="" disease.="" american="" medical="" association.="" all="" rights="" reserved.="">