Browsing by Author "Koeppe, Robert A."

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    Amyloid‐PET in patients with a clinical diagnosis of sporadic early‐ versus late‐onset AD: comparison of the LEADS and ADNI cohorts
    (Wiley, 2025-01-09) Lagarde, Julien; Maiti, Piyush; Schonhaut, Daniel R.; Zhang, Jiaxiuxiu; Soleimani-meigooni, David N.; Zeltzer, Ehud; Windon, Charles; Raya, Maison Abu; Vrillon, Agathe; Hammers, Dustin B.; Dage, Jeffrey L.; Nudelman, Kelly N.; Eloyan, Ani; Koeppe, Robert A.; Landau, Susan M.; Carrillo, Maria C.; Touroutoglou, Alexandra; Vemuri, Prashanthi; Dickerson, Bradford C.; Apostolova, Liana G.; Rabinovici, Gil D.; La Joie, Renaud; LEADS Consortium, Alzheimer’s Disease Neuroimaging Initiative; Neurology, School of Medicine
    Background: Large‐scale studies comparing sporadic early‐onset AD (EOAD, age<65) and late‐onset AD (LOAD, age≥65) are lacking. We compared amyloid‐PET outcomes (positivity rate and amyloid burden) between patients clinically diagnosed with sporadic EOAD vs LOAD, leveraging data from the Longitudinal Early‐Onset AD Study (LEADS) and the Alzheimer’s Disease Neuroimaging Initiative 3 (ADNI3). Method: 731 patients meeting the 2011 NIA‐AA criteria for AD dementia or MCI were included (505 early‐onset from LEADS, 226 late‐onset from ADNI3, Table 1). All participants underwent amyloid‐PET with [18F]Florbetaben or [18F]Florbetapir. Amyloid positivity was centrally determined by a process involving a visual read by a trained expert and PET‐only quantification; in case of a discrepancy, a read from an independent physician acted as a tiebreaker. Logistic regressions in each cohort examined relations between amyloid positivity and age, sex, MMSE and APOE4 genotype. Amyloid burden was independently quantified in Centiloids using an MRI‐based pipeline. Mean Centiloids in LEADS and ADNI were compared with two‐way ANOVA, for visually positive and visually negative scans. Result: Amyloid positivity rate was higher in LEADS (76%) than ADNI (64%, p<0.001, Figure 1A). Lower MMSE and APOE4 genotype increased odds of amyloid positivity in both cohorts, although the APOE4 effect was stronger in ADNI than LEADS (OR=10.1 versus 2.4, p=0.007, Table 2). Amyloid positivity was more common in females across cohorts, but this effect was only statistically significant in LEADS (Table 2). Centiloids were bimodally distributed in both cohorts, although the separation between positive and negative scans was more prominent in LEADS (Figure 1B). Visually positive scans had significantly higher Centiloids in LEADS than in ADNI, whereas no cohort difference was observed for visually negative scans (Figure 1C). Sensitivity analyses showed that this effect was driven by patients with MCI (CDR≤0.5; Figure 1D‐E). Conclusion: The lower amyloid positivity rate in ADNI might be due to AD‐mimicking pathologies being more common at an older age. The higher amyloid burden in early‐onset, amyloid‐positive patients could reflect younger patients being diagnosed later in the disease course compared to typical, late‐onset patients. Alternatively, younger patients might tolerate higher neuropathology burden due to higher brain reserve or fewer co‐pathologies.
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    APOE effect on Alzheimer's disease biomarkers in older adults with significant memory concern
    (Elsevier, 2015-12) Risacher, Shannon L.; Kim, Sungeun; Nho, Kwangsik; Foroud, Tatiana; Shen, Li; Peterson, Ronald C.; Jack Jr, Clifford R.; Beckett, Laurel A.; Aisen, Paul S.; Koeppe, Robert A.; Jagust, William J.; Shaw, Leslie M.; Trojanowski, John Q.; Department of Radiology and Imaging Sciences, IU School of Medicine
    INTRODUCTION: This study assessed apolipoprotein E (APOE) ε4 carrier status effects on Alzheimer's disease imaging and cerebrospinal fluid (CSF) biomarkers in cognitively normal older adults with significant memory concerns (SMC). METHODS: Cognitively normal, SMC, and early mild cognitive impairment participants from Alzheimer's Disease Neuroimaging Initiative were divided by APOE ε4 carrier status. Diagnostic and APOE effects were evaluated with emphasis on SMC. Additional analyses in SMC evaluated the effect of the interaction between APOE and [(18)F]Florbetapir amyloid positivity on CSF biomarkers. RESULTS: SMC ε4+ showed greater amyloid deposition than SMC ε4-, but no hypometabolism or medial temporal lobe (MTL) atrophy. SMC ε4+ showed lower amyloid beta 1-42 and higher tau/p-tau than ε4-, which was most abnormal in APOE ε4+ and cerebral amyloid positive SMC. DISCUSSION: SMC APOE ε4+ show abnormal changes in amyloid and tau biomarkers, but no hypometabolism or MTL neurodegeneration, reflecting the at-risk nature of the SMC group and the importance of APOE in mediating this risk.
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    Association of plasma and cortical beta-amyloid is modulated by APOE ε4 status.
    (Elsevier, 2014-01) Swaminathan, Shanker; Risacher, Shannon L.; Yoder, Karmen K.; West, John D.; Shen, Li; Kim, Sungeun; Inlow, Mark; Foroud, Tatiana; Jagust, William J.; Koeppe, Robert A.; Mathis, Chester A.; Shaw, Leslie M.; Trojanowski, John Q.; Soares, Holly; Aisen, Paul S.; Petersen, Ronald C.; Weiner, Michael W.; Saykin, Andrew J.; Department of Radiology and Imaging Sciences, IU School of Medicine
    Background: APOE ε4’s role as a modulator of the relationship between soluble plasma beta-amyloid (Aβ) and fibrillar brain Aβ measured by Pittsburgh Compound-B positron emission tomography ([11C]PiB PET) has not been assessed. Methods: Ninety-six Alzheimer’s Disease Neuroimaging Initiative participants with [11C]PiB scans and plasma Aβ1-40 and Aβ1-42 measurements at time of scan were included. Regional and voxel-wise analyses of [11C]PiB data were used to determine the influence of APOE ε4 on association of plasma Aβ1-40, Aβ1-42, and Aβ1-40/Aβ1-42 with [11C]PiB uptake. Results: In APOE ε4− but not ε4+ participants, positive relationships between plasma Aβ1-40/Aβ1-42 and [11C]PiB uptake were observed. Modeling the interaction of APOE and plasma Aβ1-40/Aβ1-42 improved the explained variance in [11C]PiB binding compared to using APOE and plasma Aβ1-40/Aβ1-42 as separate terms. Conclusions: The results suggest that plasma Aβ is a potential Alzheimer’s disease biomarker and highlight the importance of genetic variation in interpretation of plasma Aβ levels.
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    Characterization of the heterogeneity of amyloid‐PET‐negative patients with a clinical diagnosis of sporadic early‐onset AD: an FDG‐PET study in the LEADS cohort
    (Wiley, 2025-01-09) Lagarde, Julien; Schonhaut, Daniel R.; Maiti, Piyush; Zhang, Jiaxiuxiu; Soleimani-Meigooni, David N.; Zeltzer, Ehud; Windon, Charles; Hammers, Dustin B.; Dage, Jeffrey L.; Nudelman, Kelly N.; Eloyan, Ani; Koeppe, Robert A.; Carrillo, Maria C.; Touroutoglou, Alexandra; Vemuri, Prashanthi; Dickerson, Bradford C.; Apostolova, Liana G.; Rabinovici, Gil D.; La Joie, Renaud; Neurology, School of Medicine
    Background Diagnosing sporadic early‐onset AD (EOAD, age‐at‐onset<65) is challenging: in the multi‐center Longitudinal Early‐onset Alzheimer’s Disease Study, ∼25% of patients with clinically diagnosed EOAD are amyloid‐PET‐negative. Here we used FDG‐PET to characterize the heterogeneity of hypometabolic profiles in these patients and better identify underlying etiologies. Method Seventy‐four amyloid‐PET‐negative patients with clinical diagnosis of sporadic EOAD (MCI or mild dementia stage) underwent FDG‐PET. Patients were classified as having normal or hypometabolic FDG‐PET based on a data‐driven approach that compared each patient to a group of 61 age‐matched amyloid‐PET‐negative controls using 12 methodological combinations (3 reference regions, 2 voxel‐level thresholds, 2 outlier detection methods). We then assessed clinical and demographic differences between patients with normal versus hypometabolic FDG‐PET, and further compared groups using independent biomarkers of neurodegeneration (structural MRI and fluid biomarkers). Finally, we applied hierarchical clustering to hypometabolic FDG‐PET scans to identify patterns of hypometabolism. Result Thirty‐six amyloid‐negative patients (49%) had hypometabolic FDG‐PET scans. They were older and more severely impaired across most cognitive domains than patients with normal FDG‐PET (Table 1). They also had reduced hippocampal volumes and cortical thickness (Figure 1A), higher plasma and CSF neurofilament light chain (NfL) levels, and elevated plasma GFAP compared to patients with normal FDG‐PET (Figure 1B). In contrast, the latter, who had intermediate cognitive scores between hypometabolic patients and controls, had MRI and fluid biomarker levels in the range of controls (Figure 1). In hypometabolic patients, hierarchical clustering identified four profiles: i) anterior temporal extending to temporo‐parietal and frontal regions (n = 5), ii) anterior temporal and orbitofrontal (n = 11), iii) occipito‐parietal (n = 6), and iv) lateral frontal and parietal (n = 14) (Figure 2). Genetic testing identified two patients with Frontotemporal Lobar Degeneration (FTLD)‐associated pathogenic variants, both considered hypometabolic and assigned to the first (MAPT) and second (c9orf72) metabolic profiles. Conclusion Fifty‐one percent of amyloid‐negative patients had normal FDG‐PET: they had milder clinical impairment, normal MRI measures, and normal NfL values, suggesting non‐neurodegenerative etiologies. Patients with abnormal FDG showed heterogeneous hypometabolic patterns suggestive of multiple etiologies including Lewy body disease, FTLD or corticobasal degeneration. Longitudinal follow‐up to autopsy will ultimately clarify the amyloid‐negative clinical mimics of sporadic EOAD.
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    Comparison of Pittsburgh compound B and florbetapir in cross-sectional and longitudinal studies
    (Elsevier, 2019-02-22) Su, Yi; Flores, Shaney; Wang, Guoqiao; Hornbeck, Russ C.; Speidel, Benjamin; Joseph-Mathurin, Nelly; Vlassenko, Andrei G.; Gordon, Brian A.; Koeppe, Robert A.; Klunk, William E.; Clifford, R. Jack, Jr.; Farlow, Martin R.; Salloway, Stephen; Snider, Barbara J.; Berman, Sarah B.; Roberson, Erik D.; Broschi, Jared; Jimenez-Velazques, Ivonne; van Dyck, Christopher H.; Galasko, Douglas; Yuan, Shauna H.; Jayadev, Suman; Honig, Lawrence S.; Gauthier, Serge; Hsiung, Ging-Yuek R.; Masellis, Mario; Brooks, William S.; Fulham, Michael; Clarnette, Roger; Masters, Colin L.; Wallon, David; Hannequin, Didier; Dubois, Bruno; Pariente, Jeremie; Sanchez-Valle, Raquel; Mummery, Catherine; Ringman, John M.; Bottlaender, Michel; Klein, Gregory; Milosavljevic-Ristic, Smiljana; McDade, Eric; Xiong, Chengjie; Morris, John C.; Bateman, Randall J.; Benzinger, Tammie L.S.; Neurology, School of Medicine
    Introduction: Quantitative in vivo measurement of brain amyloid burden is important for both research and clinical purposes. However, the existence of multiple imaging tracers presents challenges to the interpretation of such measurements. This study presents a direct comparison of Pittsburgh compound B-based and florbetapir-based amyloid imaging in the same participants from two independent cohorts using a crossover design. Methods: Pittsburgh compound B and florbetapir amyloid PET imaging data from three different cohorts were analyzed using previously established pipelines to obtain global amyloid burden measurements. These measurements were converted to the Centiloid scale to allow fair comparison between the two tracers. The mean and inter-individual variability of the two tracers were compared using multivariate linear models both cross-sectionally and longitudinally. Results: Global amyloid burden measured using the two tracers were strongly correlated in both cohorts. However, higher variability was observed when florbetapir was used as the imaging tracer. The variability may be partially caused by white matter signal as partial volume correction reduces the variability and improves the correlations between the two tracers. Amyloid burden measured using both tracers was found to be in association with clinical and psychometric measurements. Longitudinal comparison of the two tracers was also performed in similar but separate cohorts whose baseline amyloid load was considered elevated (i.e., amyloid positive). No significant difference was detected in the average annualized rate of change measurements made with these two tracers. Discussion: Although the amyloid burden measurements were quite similar using these two tracers as expected, difference was observable even after conversion into the Centiloid scale. Further investigation is warranted to identify optimal strategies to harmonize amyloid imaging data acquired using different tracers.
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    Preferential degradation of cognitive networks differentiates Alzheimer's disease from ageing
    (Oxford University Press, 2018-05-01) Chhatwal, Jasmeer P.; Schultz, Aaron P.; Johnson, Keith A.; Hedden, Trey; Jaimes, Sehily; Benzinger, Tammie L S.; Jack, Clifford; Ances, Beau M.; Ringman, John M.; Marcus, Daniel S.; Ghetti, Bernardino; Farlow, Martin R.; Danek, Adrian; Levin, Johannes; Yakushev, Igor; Laske, Christoph; Koeppe, Robert A.; Galasko, Douglas R.; Xiong, Chengjie; Masters, Colin L.; Schofield, Peter R.; Kinnunen, Kirsi M.; Salloway, Stephen; Martins, Ralph N.; McDade, Eric; Cairns, Nigel J.; Buckles, Virginia D.; Morris, John C.; Bateman, Randall; Sperling, Reisa A.; Pathology and Laboratory Medicine, School of Medicine
    Converging evidence from structural, metabolic and functional connectivity MRI suggests that neurodegenerative diseases, such as Alzheimer's disease, target specific neural networks. However, age-related network changes commonly co-occur with neuropathological cascades, limiting efforts to disentangle disease-specific alterations in network function from those associated with normal ageing. Here we elucidate the differential effects of ageing and Alzheimer's disease pathology through simultaneous analyses of two functional connectivity MRI datasets: (i) young participants harbouring highly-penetrant mutations leading to autosomal-dominant Alzheimer's disease from the Dominantly Inherited Alzheimer's Network (DIAN), an Alzheimer's disease cohort in which age-related comorbidities are minimal and likelihood of progression along an Alzheimer's disease trajectory is extremely high; and (ii) young and elderly participants from the Harvard Aging Brain Study, a cohort in which imaging biomarkers of amyloid burden and neurodegeneration can be used to disambiguate ageing alone from preclinical Alzheimer's disease. Consonant with prior reports, we observed the preferential degradation of cognitive (especially the default and dorsal attention networks) over motor and sensory networks in early autosomal-dominant Alzheimer's disease, and found that this distinctive degradation pattern was magnified in more advanced stages of disease. Importantly, a nascent form of the pattern observed across the autosomal-dominant Alzheimer's disease spectrum was also detectable in clinically normal elderly with clear biomarker evidence of Alzheimer's disease pathology (preclinical Alzheimer's disease). At the more granular level of individual connections between node pairs, we observed that connections within cognitive networks were preferentially targeted in Alzheimer's disease (with between network connections relatively spared), and that connections between positively coupled nodes (correlations) were preferentially degraded as compared to connections between negatively coupled nodes (anti-correlations). In contrast, ageing in the absence of Alzheimer's disease biomarkers was characterized by a far less network-specific degradation across cognitive and sensory networks, of between- and within-network connections, and of connections between positively and negatively coupled nodes. We go on to demonstrate that formalizing the differential patterns of network degradation in ageing and Alzheimer's disease may have the practical benefit of yielding connectivity measurements that highlight early Alzheimer's disease-related connectivity changes over those due to age-related processes. Together, the contrasting patterns of connectivity in Alzheimer's disease and ageing add to prior work arguing against Alzheimer's disease as a form of accelerated ageing, and suggest multi-network composite functional connectivity MRI metrics may be useful in the detection of early Alzheimer's disease-specific alterations co-occurring with age-related connectivity changes. More broadly, our findings are consistent with a specific pattern of network degradation associated with the spreading of Alzheimer's disease pathology within targeted neural networks.
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    Reproducibility of Centiloid Values in Real‐World Amyloid PET Data: Comparison of the Imaging Dementia‐Evidence for Amyloid Scanning (IDEAS) to Four Large Research Datasets
    (Wiley, 2025-01-09) Blazhenets, Ganna; Zeltzer, Ehud; Lagarde, Julien; Landau, Susan M.; Koeppe, Robert A.; Carrillo, Maria C.; Dickerson, Bradford C.; Apostolova, Liana G.; Jagust, William J.; Rabinovici, Gil D.; La Joie, Renaud; Alzheimer’s Disease Neuroimaging Initiative (ADNI); Neurology, School of Medicine
    Background: The Centiloid framework was developed to harmonize amyloid‐PET quantification across radiotracers and processing pipelines to facilitate data sharing and merging; it is now widely used across research and clinical trials. As we just completed the quantification of 10,361 amyloid‐PET scans from the largest “real‐world” study of amyloid‐PET (IDEAS) and are about to release the data, we aimed to compare the distribution of IDEAS Centiloid values with other available datasets. Method: In IDEAS, amyloid scans were acquired across 343 facilities and centrally processed at UCSF using a PET‐only pipeline. We also had access to PET data from our own UCSF Alzheimer’s Disease Research Center and the LEADS study. Using the GAAIN platform, we identified two other cohorts with available Centiloids: ADNI and MCSA. For each cohort, we collected Centiloids, demographic, and basic clinical data. Gaussian mixture models (GMM) were fitted to Centiloid values for each cohort, and data‐driven Centiloid cutoffs were calculated as mean + 2SD of the first Gaussian. Finally, we compared Centiloids to PET visual reads (when available) and determined the Centiloid cutoff value maximizing correspondence between visual read and binarized Centiloids based on Cohen’s kappa. Result: The 5 cohorts were heterogeneous in terms of sample characteristics and radiotracers (Table 1). In all cohorts, a two‐Gaussian model was considered the best fit for the data based on the integrated completed likelihood criteria (Figure 1). The first Gaussian peaks were close to zero, with mild variability across studies (from ‐5 in IDEAS to 10 CL in MSCA). The second peak was more heterogeneous across cohorts (from 67 to 102 CL) with a rightward shift in cohorts enriched with clinically impaired patients. Mean Centiloid values in visually negative and positive scans generally matched well with results derived from GMM (Figure 2). Across all cohorts, GMM‐based Centiloid cutoffs tended to be slightly lower (18‐26) compared to those based on visual inspection (25‐31). Conclusion: The availability of Centiloids across cohorts enables a direct comparison of amyloid‐PET results in otherwise different studies. Despite some variability across cohorts and analysis methods, Centiloid cutoffs align well with thresholds from the existing literature.
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    Serum neurofilament light chain levels are associated with white matter integrity in autosomal dominant Alzheimer's disease
    (Elsevier, 2020-08-01) Schultz, Stephanie A.; Strain, Jeremy F.; Adedokun, Adedamola; Wang, Qing; Preische, Oliver; Kuhle, Jens; Flores, Shaney; Keefe, Sarah; Dincer, Aylin; Ances, Beau M.; Berman, Sarah B.; Brickman, Adam M.; Cash, David M.; Chhatwal, Jasmeer; Cruchaga, Carlos; Ewers, Michael; Fox, Nick N.; Ghetti, Bernardino; Goate, Alison; Graff-Radford, Neill R.; Hassenstab, Jason J.; Hornbeck, Russ; Jack, Clifford; Johnson, Keith; Joseph-Mathurin, Nelly; Karch, Celeste M.; Koeppe, Robert A.; Lee, Athene K. W.; Levin, Johannes; Masters, Colin; McDade, Eric; Perrin, Richard J.; Rowe, Christopher C.; Salloway, Stephen; Saykin, Andrew J.; Sperling, Reisa; Su, Yi; Villemagne, Victor L.; Vöglein, Jonathan; Weiner, Michael; Xiong, Chengjie; Fagan, Anne M.; Morris, John C.; Bateman, Randall J.; Benzinger, Tammie L. S.; Jucker, Mathias; Gordon, Brian A.; Pathology and Laboratory Medicine, School of Medicine
    Neurofilament light chain (NfL) is a protein that is selectively expressed in neurons. Increased levels of NfL measured in either cerebrospinal fluid or blood is thought to be a biomarker of neuronal damage in neurodegenerative diseases. However, there have been limited investigations relating NfL to the concurrent measures of white matter (WM) decline that it should reflect. White matter damage is a common feature of Alzheimer's disease. We hypothesized that serum levels of NfL would associate with WM lesion volume and diffusion tensor imaging (DTI) metrics cross-sectionally in 117 autosomal dominant mutation carriers (MC) compared to 84 non-carrier (NC) familial controls as well as in a subset (N = 41) of MC with longitudinal NfL and MRI data. In MC, elevated cross-sectional NfL was positively associated with WM hyperintensity lesion volume, mean diffusivity, radial diffusivity, and axial diffusivity and negatively with fractional anisotropy. Greater change in NfL levels in MC was associated with larger changes in fractional anisotropy, mean diffusivity, and radial diffusivity, all indicative of reduced WM integrity. There were no relationships with NfL in NC. Our results demonstrate that blood-based NfL levels reflect WM integrity and supports the view that blood levels of NfL are predictive of WM damage in the brain. This is a critical result in improving the interpretability of NfL as a marker of brain integrity, and for validating this emerging biomarker for future use in clinical and research settings across multiple neurodegenerative diseases.
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    Sex and APOE ε4 carrier effects on atrophy, amyloid PET, and tau PET burden in early-onset Alzheimer's disease
    (Wiley, 2023) Nemes, Sára; Logan, Paige E.; Manchella, Mohit K.; Mundada, Nidhi S.; La Joie, Renaud; Polsinelli, Angelina J.; Hammers, Dustin B.; Koeppe, Robert A.; Foroud, Tatiana M.; Nudelman, Kelly N.; Eloyan, Ani; Iaccarino, Leonardo; Dorsant-Ardón, Valérie; Taurone, Alexander; Thangarajah, Maryanne; Dage, Jeffery L.; Aisen, Paul; Grinberg, Lea T.; Jack, Clifford R., Jr.; Kramer, Joel; Kukull, Walter A.; Murray, Melissa E.; Rumbaugh, Malia; Soleimani-Meigooni, David N.; Toga, Arthur; 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.; Musiek, Erik; Onyike, Chiadi U.; Riddle, Meghan; Rogalski, Emily; Salloway, Stephen; Sha, Sharon J.; Turner, Raymond S.; Wingo, Thomas S.; Womack, Kyle B.; Wolk, David A.; Rabinovici, Gil D.; Carrillo, Maria C.; Dickerson, Bradford C.; Apostolova, Liana G.; LEADS Consortium; Neurology, School of Medicine
    Introduction: We used sex and apolipoprotein E ε4 (APOE ε4) carrier status as predictors of pathologic burden in early-onset Alzheimer's disease (EOAD). Methods: We included baseline data from 77 cognitively normal (CN), 230 EOAD, and 70 EO non-Alzheimer's disease (EOnonAD) participants from the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS). We stratified each diagnostic group by males and females, then further subdivided each sex by APOE ε4 carrier status and compared imaging biomarkers in each stratification. Voxel-wise multiple linear regressions yielded statistical brain maps of gray matter density, amyloid, and tau PET burden. Results: EOAD females had greater amyloid and tau PET burdens than males. EOAD female APOE ε4 non-carriers had greater amyloid PET burdens and greater gray matter atrophy than female ε4 carriers. EOnonAD female ε4 non-carriers also had greater gray matter atrophy than female ε4 carriers. Discussion: The effects of sex and APOE ε4 must be considered when studying these populations. Highlights: Novel analysis examining the effects of biological sex and apolipoprotein E ε4 (APOE ε4) carrier status on neuroimaging biomarkers among early-onset Alzheimer's disease (EOAD), early-onset non-AD (EOnonAD), and cognitively normal (CN) participants. Female sex is associated with greater pathology burden in the EOAD cohort compared to male sex. The effect of APOE ε4 carrier status on pathology burden was the most impactful in females across all cohorts.
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    The role of apolipoprotein E (APOE) genotype in early mild cognitive impairment (E-MCI)
    (Frontiers Media, 2013-04-01) Risacher, Shannon L.; Kim, Sungeun; Shen, Li; Nho, Kwangsik; Foroud, Tatiana; Green, Robert C.; Petersen, Ronald C.; Jack, Clifford R., Jr.; Aisen, Paul S.; Koeppe, Robert A.; Jagust, William J.; Shaw, Leslie M.; Trojanowski, John Q.; Weiner, Michael W.; Saykin, Andrew J.; Alzheimer’s Disease Neuroimaging Initiative (ADNI); Radiology and Imaging Sciences, School of Medicine
    Objective: Our goal was to evaluate the association of APOE with amyloid deposition, cerebrospinal fluid levels (CSF) of Aβ, tau, and p-tau, brain atrophy, cognition and cognitive complaints in E-MCI patients and cognitively healthy older adults (HC) in the ADNI-2 cohort. Methods: Two-hundred and nine E-MCI and 123 HC participants from the ADNI-2 cohort were included. We evaluated the impact of diagnostic status (E-MCI vs. HC) and APOE ε4 status (ε4 positive vs. ε4 negative) on cortical amyloid deposition (AV-45/Florbetapir SUVR PET scans), brain atrophy (structural MRI scans processed using voxel-based morphometry and Freesurfer version 5.1), CSF levels of Aβ, tau, and p-tau, and cognitive performance and complaints. Results: E-MCI participants showed significantly impaired cognition, higher levels of cognitive complaints, greater levels of tau and p-tau, and subcortical and cortical atrophy relative to HC participants (p < 0.05). Cortical amyloid deposition and CSF levels of Aβ were significantly associated with APOE ε4 status but not E-MCI diagnosis, with ε4 positive participants showing more amyloid deposition and lower levels of CSF Aβ than ε4 negative participants. Other effects of APOE ε4 status on cognition and CSF tau levels were also observed. Conclusions: APOE ε4 status is associated with amyloid accumulation and lower CSF Aβ, as well as increased CSF tau levels in early prodromal stages of AD (E-MCI) and HC. Alternatively, neurodegeneration, cognitive impairment, and increased complaints are primarily associated with a diagnosis of E-MCI. These findings underscore the importance of considering APOE genotype when evaluating biomarkers in early stages of disease.