Browsing by Author "Toga, Arthur W."
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Item 2014 Update of the Alzheimer's Disease Neuroimaging Initiative: A review of papers published since its inception(Elsevier, 2016-06-01) Weiner, Michael W.; Veitch, Dallas P.; Aisen, Paul S.; Beckett, Laurel A.; Cairns, Nigel J.; Cedarbaum, Jesse; Green, Robert C.; Harvey, Danielle; Jack, Clifford R.; Jagust, William; Luthman, Johan; Morris, John C.; Petersen, Ronald C.; Saykin, Andrew J.; Shaw, Leslie; Shen, Li; Schwarz, Adam; Toga, Arthur W.; Trojanowski, John Q.; Alzheimer’s Disease Neuroimaging Initiative; Radiology and Imaging Sciences, School of MedicineThe Alzheimer's Disease Neuroimaging Initiative (ADNI) is an ongoing, longitudinal, multicenter study designed to develop clinical, imaging, genetic, and biochemical biomarkers for the early detection and tracking of Alzheimer's disease (AD). The initial study, ADNI-1, enrolled 400 subjects with early mild cognitive impairment (MCI), 200 with early AD, and 200 cognitively normal elderly controls. ADNI-1 was extended by a 2-year Grand Opportunities grant in 2009 and by a competitive renewal, ADNI-2, which enrolled an additional 550 participants and will run until 2015. This article reviews all papers published since the inception of the initiative and summarizes the results to the end of 2013. The major accomplishments of ADNI have been as follows: (1) the development of standardized methods for clinical tests, magnetic resonance imaging (MRI), positron emission tomography (PET), and cerebrospinal fluid (CSF) biomarkers in a multicenter setting; (2) elucidation of the patterns and rates of change of imaging and CSF biomarker measurements in control subjects, MCI patients, and AD patients. CSF biomarkers are largely consistent with disease trajectories predicted by β-amyloid cascade (Hardy, J Alzheimer's Dis 2006;9(Suppl 3):151-3) and tau-mediated neurodegeneration hypotheses for AD, whereas brain atrophy and hypometabolism levels show predicted patterns but exhibit differing rates of change depending on region and disease severity; (3) the assessment of alternative methods of diagnostic categorization. Currently, the best classifiers select and combine optimum features from multiple modalities, including MRI, [(18)F]-fluorodeoxyglucose-PET, amyloid PET, CSF biomarkers, and clinical tests; (4) the development of blood biomarkers for AD as potentially noninvasive and low-cost alternatives to CSF biomarkers for AD diagnosis and the assessment of α-syn as an additional biomarker; (5) the development of methods for the early detection of AD. CSF biomarkers, β-amyloid 42 and tau, as well as amyloid PET may reflect the earliest steps in AD pathology in mildly symptomatic or even nonsymptomatic subjects and are leading candidates for the detection of AD in its preclinical stages; (6) the improvement of clinical trial efficiency through the identification of subjects most likely to undergo imminent future clinical decline and the use of more sensitive outcome measures to reduce sample sizes. Multimodal methods incorporating APOE status and longitudinal MRI proved most highly predictive of future decline. Refinements of clinical tests used as outcome measures such as clinical dementia rating-sum of boxes further reduced sample sizes; (7) the pioneering of genome-wide association studies that leverage quantitative imaging and biomarker phenotypes, including longitudinal data, to confirm recently identified loci, CR1, CLU, and PICALM and to identify novel AD risk loci; (8) worldwide impact through the establishment of ADNI-like programs in Japan, Australia, Argentina, Taiwan, China, Korea, Europe, and Italy; (9) understanding the biology and pathobiology of normal aging, MCI, and AD through integration of ADNI biomarker and clinical data to stimulate research that will resolve controversies about competing hypotheses on the etiopathogenesis of AD, thereby advancing efforts to find disease-modifying drugs for AD; and (10) the establishment of infrastructure to allow sharing of all raw and processed data without embargo to interested scientific investigators throughout the world.Item The Alzheimer's Disease Neuroimaging Initiative 3: Continued innovation for clinical trial improvement(Elsevier, 2017-05) Weiner, Michael W.; Veitch, Dallas P.; Aisen, Paul S.; Beckett, Laurel A.; Cairns, Nigel J.; Green, Robert C.; Harvey, Danielle; Jack, Clifford R., Jr.; Jagust, William; Morris, John C.; Petersen, Ronald C.; Salazar, Jennifer; Saykin, Andrew J.; Shaw, Leslie M.; Toga, Arthur W.; Trojanowski, John Q.; Radiology and Imaging Sciences, School of MedicineINTRODUCTION: The overall goal of the Alzheimer's Disease Neuroimaging Initiative (ADNI) is to validate biomarkers for Alzheimer's disease (AD) clinical trials. ADNI-3, which began on August 1, 2016, is a 5-year renewal of the current ADNI-2 study. METHODS: ADNI-3 will follow current and additional subjects with normal cognition, mild cognitive impairment, and AD using innovative technologies such as tau imaging, magnetic resonance imaging sequences for connectivity analyses, and a highly automated immunoassay platform and mass spectroscopy approach for cerebrospinal fluid biomarker analysis. A Systems Biology/pathway approach will be used to identify genetic factors for subject selection/enrichment. Amyloid positron emission tomography scanning will be standardized using the Centiloid method. The Brain Health Registry will help recruit subjects and monitor subject cognition. RESULTS: Multimodal analyses will provide insight into AD pathophysiology and disease progression. DISCUSSION: ADNI-3 will aim to inform AD treatment trials and facilitate development of AD disease-modifying treatments.Item Anxiety in late life depression is associated with poorer performance across multiple cognitive domains(Cambridge University Press, 2024) Kryza-Lacombe, Maria; Kassel, Michelle T.; Insel, Philip S.; Rhodes, Emma; Bickford, David; Burns, Emily; Butters, Meryl A.; Tosun, Duygu; Aisen, Paul; Raman, Rema; Saykin, Andrew J.; Toga, Arthur W.; Jack, Clifford R., Jr.; Weiner, Michael W.; Nelson, Craig; Radiology and Imaging Sciences, School of MedicineObjective: Anxiety is a common comorbid feature of late-life depression (LLD) and is associated with poorer global cognitive functioning independent of depression severity. However, little is known about whether comorbid anxiety is associated with a domain-specific pattern of cognitive dysfunction. We therefore examined group differences (LLD with and without comorbid anxiety) in cognitive functioning performance across multiple domains. Method: Older adults with major depressive disorder (N = 228, ages 65-91) were evaluated for anxiety and depression severity, and cognitive functioning (learning, memory, language, processing speed, executive functioning, working memory, and visuospatial functioning). Ordinary least squares regression adjusting for age, sex, education, and concurrent depression severity examined anxiety group differences in performance on tests of cognitive functioning. Results: Significant group differences emerged for confrontation naming and visuospatial functioning, as well as for verbal fluency, working memory, and inhibition with lower performance for LLD with comorbid anxiety compared to LLD only, controlling for depression severity. Conclusions: Performance patterns identified among older adults with LLD and comorbid anxiety resemble neuropsychological profiles typically seen in neurodegenerative diseases of aging. These findings have potential implications for etiological considerations in the interpretation of neuropsychological profiles.Item Anxiety in Late Life Depression: Associations with Brain Volume, Amyloid Beta, White Matter Lesions, Cognition, and Functional Ability(Elsevier, 2024) Kryza-Lacombe, Maria; Kassel, Michelle T.; Insel, Philip S.; Rhodes, Emma; Bickford, David; Burns, Emily; Butters, Meryl A.; Tosun, Duygu; Aisen, Paul; Raman, Rema; Landau, Susan; Saykin, Andrew J.; Toga, Arthur W.; Jack, Clifford R., Jr.; Koeppe, Robert; Weiner, Michael W.; Nelson, Craig; Mackin, R. Scott; Radiology and Imaging Sciences, School of MedicineObjectives: Late-life depression (LLD) is common and frequently co-occurs with neurodegenerative diseases of aging. Little is known about how heterogeneity within LLD relates to factors typically associated with neurodegeneration. Varying levels of anxiety are one source of heterogeneity in LLD. We examined associations between anxiety symptom severity and factors associated with neurodegeneration, including regional brain volumes, amyloid beta (Aβ) deposition, white matter disease, cognitive dysfunction, and functional ability in LLD. Participants and measurements: Older adults with major depression (N = 121, Ages 65-91) were evaluated for anxiety severity and the following: brain volume (orbitofrontal cortex [OFC], insula), cortical Aβ standardized uptake value ratio (SUVR), white matter hyperintensity (WMH) volume, global cognition, and functional ability. Separate linear regression analyses adjusting for age, sex, and concurrent depression severity were conducted to examine associations between anxiety and each of these factors. A global regression analysis was then conducted to examine the relative associations of these variables with anxiety severity. Results: Greater anxiety severity was associated with lower OFC volume (β = -68.25, t = -2.18, p = .031) and greater cognitive dysfunction (β = 0.23, t = 2.46, p = .016). Anxiety severity was not associated with insula volume, Aβ SUVR, WMH, or functional ability. When examining the relative associations of cognitive functioning and OFC volume with anxiety in a global model, cognitive dysfunction (β = 0.24, t = 2.62, p = .010), but not OFC volume, remained significantly associated with anxiety. Conclusions: Among multiple factors typically associated with neurodegeneration, cognitive dysfunction stands out as a key factor associated with anxiety severity in LLD which has implications for cognitive and psychiatric interventions.Item Association analysis of rare variants near the APOE region with CSF and neuroimaging biomarkers of Alzheimer's disease(Springer Nature, 2017-05-24) Nho, Kwangsik; Kim, Sungeun; Horgusluoglu, Emrin; Risacher, Shannon L.; Shen, Li; Kim, Dokyoon; Lee, Seunggeun; Foroud, Tatiana; Shaw, Leslie M.; Trojanowski, John Q.; Aisen, Paul S.; Petersen, Ronald C.; Jack, Clifford R., Jr.; Weiner, Michael W.; Green, Robert C.; Toga, Arthur W.; Saykin, Andrew J.; Radiology and Imaging Sciences, School of MedicineBACKGROUND: The APOE ε4 allele is the most significant common genetic risk factor for late-onset Alzheimer's disease (LOAD). The region surrounding APOE on chromosome 19 has also shown consistent association with LOAD. However, no common variants in the region remain significant after adjusting for APOE genotype. We report a rare variant association analysis of genes in the vicinity of APOE with cerebrospinal fluid (CSF) and neuroimaging biomarkers of LOAD. METHODS: Whole genome sequencing (WGS) was performed on 817 blood DNA samples from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Sequence data from 757 non-Hispanic Caucasian participants was used in the present analysis. We extracted all rare variants (MAF (minor allele frequency) < 0.05) within a 312 kb window in APOE's vicinity encompassing 12 genes. We assessed CSF and neuroimaging (MRI and PET) biomarkers as LOAD-related quantitative endophenotypes. Gene-based analyses of rare variants were performed using the optimal Sequence Kernel Association Test (SKAT-O). RESULTS: A total of 3,334 rare variants (MAF < 0.05) were found within the APOE region. Among them, 72 rare non-synonymous variants were observed. Eight genes spanning the APOE region were significantly associated with CSF Aβ1-42 (p < 1.0 × 10-3). After controlling for APOE genotype and adjusting for multiple comparisons, 4 genes (CBLC, BCAM, APOE, and RELB) remained significant. Whole-brain surface-based analysis identified highly significant clusters associated with rare variants of CBLC in the temporal lobe region including the entorhinal cortex, as well as frontal lobe regions. Whole-brain voxel-wise analysis of amyloid PET identified significant clusters in the bilateral frontal and parietal lobes showing associations of rare variants of RELB with cortical amyloid burden. CONCLUSIONS: Rare variants within genes spanning the APOE region are significantly associated with LOAD-related CSF Aβ1-42 and neuroimaging biomarkers after adjusting for APOE genotype. These findings warrant further investigation and illustrate the role of next generation sequencing and quantitative endophenotypes in assessing rare variants which may help explain missing heritability in AD and other complex diseases.Item Autosomal dominant and sporadic late onset Alzheimer's disease share a common in vivo pathophysiology(Oxford University Press, 2022) Morris, John C.; Weiner, Michael; Xiong, Chengjie; Beckett, Laurel; Coble, Dean; Saito, Naomi; Aisen, Paul S.; Allegri, Ricardo; Benzinger, Tammie L. S.; Berman, Sarah B.; Cairns, Nigel J.; Carrillo, Maria C.; Chui, Helena C.; Chhatwal, Jasmeer P.; Cruchaga, Carlos; Fagan, Anne M.; Farlow, Martin; Fox, Nick C.; Ghetti, Bernardino; Goate, Alison M.; Gordon, Brian A.; Graff-Radford, Neill; Day, Gregory S.; Hassenstab, Jason; Ikeuchi, Takeshi; Jack, Clifford R.; Jagust, William J.; Jucker, Mathias; Levin, Johannes; Massoumzadeh, Parinaz; Masters, Colin L.; Martins, Ralph; McDade, Eric; Mori, Hiroshi; Noble, James M.; Petersen, Ronald C.; Ringman, John M.; Salloway, Stephen; Saykin, Andrew J.; Schofield, Peter R.; Shaw, Leslie M.; Toga, Arthur W.; Trojanowski, John Q.; Vöglein, Jonathan; Weninger, Stacie; Bateman, Randall J.; Buckles, Virginia D.; Dominantly Inherited Alzheimer Network; Alzheimer’s Disease Neuroimaging and Initiative; Neurology, School of MedicineThe extent to which the pathophysiology of autosomal dominant Alzheimer's disease corresponds to the pathophysiology of 'sporadic' late onset Alzheimer's disease is unknown, thus limiting the extrapolation of study findings and clinical trial results in autosomal dominant Alzheimer's disease to late onset Alzheimer's disease. We compared brain MRI and amyloid PET data, as well as CSF concentrations of amyloid-β42, amyloid-β40, tau and tau phosphorylated at position 181, in 292 carriers of pathogenic variants for Alzheimer's disease from the Dominantly Inherited Alzheimer Network, with corresponding data from 559 participants from the Alzheimer's Disease Neuroimaging Initiative. Imaging data and CSF samples were reprocessed as appropriate to guarantee uniform pipelines and assays. Data analyses yielded rates of change before and after symptomatic onset of Alzheimer's disease, allowing the alignment of the ∼30-year age difference between the cohorts on a clinically meaningful anchor point, namely the participant age at symptomatic onset. Biomarker profiles were similar for both autosomal dominant Alzheimer's disease and late onset Alzheimer's disease. Both groups demonstrated accelerated rates of decline in cognitive performance and in regional brain volume loss after symptomatic onset. Although amyloid burden accumulation as determined by PET was greater after symptomatic onset in autosomal dominant Alzheimer's disease than in late onset Alzheimer's disease participants, CSF assays of amyloid-β42, amyloid-β40, tau and p-tau181 were largely overlapping in both groups. Rates of change in cognitive performance and hippocampal volume loss after symptomatic onset were more aggressive for autosomal dominant Alzheimer's disease participants. These findings suggest a similar pathophysiology of autosomal dominant Alzheimer's disease and late onset Alzheimer's disease, supporting a shared pathobiological construct.Item Baseline neuropsychiatric symptoms and psychotropic medication use midway through data collection of the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS) cohort(Wiley, 2023) Polsinelli, Angelina J.; Wonderlin, Ryan J.; Hammers, Dustin B.; Pena Garcia, Alex; Eloyan, Anii; Taurone, Alexander; Thangarajah, Maryanne; Beckett, Laurel; Gao, Sujuan; Wang, Sophia; Kirby, Kala; Logan, Paige E.; Aisen, Paul; Dage, Jeffrey L.; Foroud, Tatiana; Griffin, Percy; Iaccarino, Leonardo; Kramer, Joel H.; Koeppe, Robert; Kukull, Walter A.; La Joie, Renaud; Mundada, Nidhi S.; Murray, Melissa E.; Nudelman, Kelly; Soleimani-Meigooni, David N.; Rumbaugh, Malia; Toga, Arthur W.; Touroutoglou, Alexandra; Vemuri, Prashanthi; Atri, Alireza; Day, Gregory S.; Duara, Ranjan; Graff-Radford, Neill R.; Honig, Lawrence S.; Jones, David T.; Masdeu, Joseph; Mendez, Mario F.; Womack, Kyle; Musiek, Erik; Onyike, Chiadi U.; Riddle, Meghan; Rogalski, Emily; Salloway, Steven; Sha, Sharon J.; Turner, Raymond S.; Wingo, Thomas S.; Wolk, David A.; Carrillo, Maria C.; Dickerson, Bradford C.; Rabinovici, Gil D.; Apostolova, Liana G.; LEADS Consortium; Neurology, School of MedicineIntroduction: We examined neuropsychiatric symptoms (NPS) and psychotropic medication use in a large sample of individuals with early-onset Alzheimer's disease (EOAD; onset 40-64 years) at the midway point of data collection for the Longitudinal Early-onset Alzheimer's Disease Study (LEADS). Methods: Baseline NPS (Neuropsychiatric Inventory - Questionnaire; Geriatric Depression Scale) and psychotropic medication use from 282 participants enrolled in LEADS were compared across diagnostic groups - amyloid-positive EOAD (n = 212) and amyloid negative early-onset non-Alzheimer's disease (EOnonAD; n = 70). Results: Affective behaviors were the most common NPS in EOAD at similar frequencies to EOnonAD. Tension and impulse control behaviors were more common in EOnonAD. A minority of participants were using psychotropic medications, and use was higher in EOnonAD. Discussion: Overall NPS burden and psychotropic medication use were higher in EOnonAD than EOAD participants. Future research will investigate moderators and etiological drivers of NPS, and NPS differences in EOAD versus late-onset AD. Keywords: early-onset Alzheimer's disease; early-onset dementia; mild cognitive impairment; neuropharmacology; neuropsychiatric symptoms; psychotropic medications.Item Brain volumetric deficits in MAPT mutation carriers: a multisite study(Wiley, 2021) Chu, Stephanie A.; Flagan, Taru M.; Staffaroni, Adam M.; Jiskoot, Lize C.; Deng, Jersey; Spina, Salvatore; Zhang, Liwen; Sturm, Virginia E.; Yokoyama, Jennifer S.; Seeley, William W.; Papma, Janne M.; Geschwind, Dan H.; Rosen, Howard J.; Boeve, Bradley F.; Boxer, Adam L.; Heuer, Hilary W.; Forsberg, Leah K.; Brushaber, Danielle E.; Grossman, Murray; Coppola, Giovanni; Dickerson, Bradford C.; Bordelon, Yvette M.; Faber, Kelley; Feldman, Howard H.; Fields, Julie A.; Fong, Jamie C.; Foroud, Tatiana; Gavrilova, Ralitza H.; Ghoshal, Nupur; Graff-Radford, Neill R.; Hsiung, Ging-Yuek Robin; Huey, Edward D.; Irwin, David J.; Kantarci, Kejal; Kaufer, Daniel I.; Karydas, Anna M.; Knopman, David S.; Kornak, John; Kramer, Joel H.; Kukull, Walter A.; Lapid, Maria I.; Litvan, Irene; Mackenzie, Ian R. A.; Mendez, Mario F.; Miller, Bruce L.; Onyike, Chiadi U.; Pantelyat, Alexander Y.; Rademakers, Rosa; Ramos, Eliana Marisa; Roberson, Erik D.; Tartaglia, Maria Carmela; Tatton, Nadine A.; Toga, Arthur W.; Vetor, Ashley; Weintraub, Sandra; Wong, Bonnie; Wszolek, Zbigniew K.; ARTFL/LEFFTDS Consortium; Van Swieten, John C.; Lee, Suzee E.; Medical and Molecular Genetics, School of MedicineObjective: MAPT mutations typically cause behavioral variant frontotemporal dementia with or without parkinsonism. Previous studies have shown that symptomatic MAPT mutation carriers have frontotemporal atrophy, yet studies have shown mixed results as to whether presymptomatic carriers have low gray matter volumes. To elucidate whether presymptomatic carriers have lower structural brain volumes within regions atrophied during the symptomatic phase, we studied a large cohort of MAPT mutation carriers using a voxelwise approach. Methods: We studied 22 symptomatic carriers (age 54.7 ± 9.1, 13 female) and 43 presymptomatic carriers (age 39.2 ± 10.4, 21 female). Symptomatic carriers' clinical syndromes included: behavioral variant frontotemporal dementia (18), an amnestic dementia syndrome (2), Parkinson's disease (1), and mild cognitive impairment (1). We performed voxel-based morphometry on T1 images and assessed brain volumetrics by clinical subgroup, age, and mutation subtype. Results: Symptomatic carriers showed gray matter atrophy in bilateral frontotemporal cortex, insula, and striatum, and white matter atrophy in bilateral corpus callosum and uncinate fasciculus. Approximately 20% of presymptomatic carriers had low gray matter volumes in bilateral hippocampus, amygdala, and lateral temporal cortex. Within these regions, low gray matter volumes emerged in a subset of presymptomatic carriers as early as their thirties. Low white matter volumes arose infrequently among presymptomatic carriers. Interpretation: A subset of presymptomatic MAPT mutation carriers showed low volumes in mesial temporal lobe, the region ubiquitously atrophied in all symptomatic carriers. With each decade of age, an increasing percentage of presymptomatic carriers showed low mesial temporal volume, suggestive of early neurodegeneration.Item Cerebrospinal fluid biomarkers in the Longitudinal Early-onset Alzheimer's Disease Study(Wiley, 2023) Dage, Jeffrey L.; Eloyan, Ani; Thangarajah, Maryanne; Hammers, Dustin B.; Fagan, Anne M.; Gray, Julia D.; Schindler, Suzanne E.; Snoddy, Casey; Nudelman, Kelly N. H.; Faber, Kelley M.; Foroud, Tatiana; Aisen, Paul; Griffin, Percy; Grinberg, Lea T.; Iaccarino, Leonardo; Kirby, Kala; Kramer, Joel; Koeppe, Robert; Kukull, Walter A.; La Joie, Renaud; Mundada, Nidhi S.; Murray, Melissa E.; Rumbaugh, Malia; Soleimani-Meigooni, David N.; Toga, Arthur W.; Touroutoglou, Alexandra; Vemuri, Prashanthi; Atri, Alireza; Beckett, Laurel A.; Day, Gregory S.; Graff-Radford, Neill R.; Duara, Ranjan; Honig, Lawrence S.; Jones, David T.; Masdeu, Joseph C.; Mendez, Mario F.; Musiek, Erik; Onyike, Chiadi U.; Riddle, Meghan; Rogalski, Emily; Salloway, Stephen; Sha, Sharon J.; Turner, Raymond S.; Wingo, Thomas S.; Wolk, David A.; Womack, Kyle B.; Carrillo, Maria C.; Dickerson, Bradford C.; Rabinovici, Gil D.; Apostolova, Liana G.; LEADS Consortium; Neurology, School of MedicineIntroduction: One goal of the Longitudinal Early Onset Alzheimer's Disease Study (LEADS) is to define the fluid biomarker characteristics of early-onset Alzheimer's disease (EOAD). Methods: Cerebrospinal fluid (CSF) concentrations of Aβ1-40, Aβ1-42, total tau (tTau), pTau181, VILIP-1, SNAP-25, neurogranin (Ng), neurofilament light chain (NfL), and YKL-40 were measured by immunoassay in 165 LEADS participants. The associations of biomarker concentrations with diagnostic group and standard cognitive tests were evaluated. Results: Biomarkers were correlated with one another. Levels of CSF Aβ42/40, pTau181, tTau, SNAP-25, and Ng in EOAD differed significantly from cognitively normal and early-onset non-AD dementia; NfL, YKL-40, and VILIP-1 did not. Across groups, all biomarkers except SNAP-25 were correlated with cognition. Within the EOAD group, Aβ42/40, NfL, Ng, and SNAP-25 were correlated with at least one cognitive measure. Discussion: This study provides a comprehensive analysis of CSF biomarkers in sporadic EOAD that can inform EOAD clinical trial design.Item Common folate gene variant, MTHFR C677T, is associated with brain structure in two independent cohorts of people with mild cognitive impairment(Elsevier, 2012-10-04) Rajagopalan, Priya; Jahanshad, Neda; Stein, Jason L.; Hua, Xue; Madsen, Sarah K.; Kohannim, Omid; Hibar, Derrek P.; Toga, Arthur W.; Jack, Clifford R., Jr.; Saykin, Andrew J.; Green, Robert C.; Weiner, Michael W.; Bis, Joshua C.; Kuller, Lewis H.; Riverol, Mario; Becker, James T.; Lopez, Oscar L.; Thompson, Paul M.; Alzheimer's Disease Neuroimaging Initiative (ADNI); Cardiovascular Health Study (CHS); Radiology and Imaging Sciences, School of MedicineA commonly carried C677T polymorphism in a folate-related gene, MTHFR, is associated with higher plasma homocysteine, a well-known mediator of neuronal damage and brain atrophy. As homocysteine promotes brain atrophy, we set out to discover whether people carrying the C677T MTHFR polymorphism which increases homocysteine, might also show systematic differences in brain structure. Using tensor-based morphometry, we tested this association in 359 elderly Caucasian subjects with mild cognitive impairment (MCI) (mean age: 75 ± 7.1 years) scanned with brain MRI and genotyped as part of Alzheimer's Disease Neuroimaging Initiative. We carried out a replication study in an independent, non-overlapping sample of 51 elderly Caucasian subjects with MCI (mean age: 76 ± 5.5 years), scanned with brain MRI and genotyped for MTHFR, as part of the Cardiovascular Health Study. At each voxel in the brain, we tested to see where regional volume differences were associated with carrying one or more MTHFR 'T' alleles. In ADNI subjects, carriers of the MTHFR risk allele had detectable brain volume deficits, in the white matter, of up to 2-8% per risk T allele locally at baseline and showed accelerated brain atrophy of 0.5-1.5% per T allele at 1 year follow-up, after adjusting for age and sex. We replicated these brain volume deficits of up to 5-12% per MTHFR T allele in the independent cohort of CHS subjects. As expected, the associations weakened after controlling for homocysteine levels, which the risk gene affects. The MTHFR risk variant may thus promote brain atrophy by elevating homocysteine levels. This study aims to investigate the spatially detailed effects of this MTHFR polymorphism on brain structure in 3D, pointing to a causal pathway that may promote homocysteine-mediated brain atrophy in elderly people with MCI.