Browsing by Author "Carrillo, Maria C."
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Item Advancements in APOE and dementia research: Highlights from the 2023 AAIC Advancements: APOE conference(Wiley, 2024) Kloske, Courtney M.; Belloy, Michael E.; Blue, Elizabeth E.; Bowman, Gregory R.; Carrillo, Maria C.; Chen, Xiaoying; Chiba-Falek, Ornit; Davis, Albert A.; Di Paolo, Gilbert; Garretti, Francesca; Gate, David; Golden, Lesley R.; Heinecke, Jay W.; Herz, Joachim; Huang, Yadong; Iadecola, Costantino; Johnson, Lance A.; Kanekiyo, Takahisa; Karch, Celeste M.; Khvorova, Anastasia; Koppes-den Hertog, Sascha J.; Lamb, Bruce T.; Lawler, Paige E.; Le Guen, Yann; Litvinchuk, Alexandra; Liu, Chia-Chen; Mahinrad, Simin; Marcora, Edoardo; Marino, Claudia; Michaelson, Danny M.; Miller, Justin J.; Morganti, Josh M.; Narayan, Priyanka S.; Naslavsky, Michel S.; Oosthoek, Marlies; Ramachandran, Kapil V.; Ramakrishnan, Abhirami; Raulin, Ana-Caroline; Robert, Aiko; Saleh, Rasha N. M.; Sexton, Claire; Shah, Nilomi; Shue, Francis; Sible, Isabel J.; Soranno, Andrea; Strickland, Michael R.; Tcw, Julia; Thierry, Manon; Tsai, Li-Huei; Tuckey, Ryan A.; Ulrich, Jason D.; van der Kant, Rik; Wang, Na; Wellington, Cheryl L.; Weninger, Stacie C.; Yassine, Hussein N.; Zhao, Na; Bu, Guojun; Goate, Alison M.; Holtzman, David M.; Neurology, School of MedicineIntroduction: The apolipoprotein E gene (APOE) is an established central player in the pathogenesis of Alzheimer's disease (AD), with distinct apoE isoforms exerting diverse effects. apoE influences not only amyloid-beta and tau pathologies but also lipid and energy metabolism, neuroinflammation, cerebral vascular health, and sex-dependent disease manifestations. Furthermore, ancestral background may significantly impact the link between APOE and AD, underscoring the need for more inclusive research. Methods: In 2023, the Alzheimer's Association convened multidisciplinary researchers at the "AAIC Advancements: APOE" conference to discuss various topics, including apoE isoforms and their roles in AD pathogenesis, progress in apoE-targeted therapeutic strategies, updates on disease models and interventions that modulate apoE expression and function. Results: This manuscript presents highlights from the conference and provides an overview of opportunities for further research in the field. Discussion: Understanding apoE's multifaceted roles in AD pathogenesis will help develop targeted interventions for AD and advance the field of AD precision medicine. Highlights: APOE is a central player in the pathogenesis of Alzheimer's disease. APOE exerts a numerous effects throughout the brain on amyloid-beta, tau, and other pathways. The AAIC Advancements: APOE conference encouraged discussions and collaborations on understanding the role of APOE.Item Advancements in Immunity and Dementia Research: Highlights from the 2023 AAIC Advancements: Immunity Conference(Wiley, 2025) Kloske, Courtney M.; Mahinrad, Simin; Barnum, Christopher J.; Batista, Andre F.; Bradshaw, Elizabeth M.; Butts, Brittany; Carrillo, Maria C.; Chakrabarty, Paramita; Chen, Xiaoying; Craft, Suzanne; Da Mesquita, Sandro; Dabin, Luke C.; Devanand, Davangere; Duran-Laforet, Violeta; Elyaman, Wassim; Evans, Elizabeth E.; Fitzgerald-Bocarsly, Patricia; Foley, Kate E.; Harms, Ashley S.; Heneka, Michael T.; Hong, Soyon; Huang, Yu-Wen A.; Jackvony, Stephanie; Lai, Laijun; Le Guen, Yann; Lemere, Cynthia A.; Liddelow, Shane A.; Martin-Peña, Alfonso; Orr, Anna G.; Quintana, Francisco J.; Ramey, Grace D.; Rexach, Jessica E.; Rizzo, Stacey J. S.; Sexton, Claire; Tang, Alice S.; Torrellas, Jose G.; Tsai, Andy P.; van Olst, Lynn; Walker, Keenan A.; Wharton, Whitney; Tansey, Malú Gámez; Wilcock, Donna M.; Medical and Molecular Genetics, School of MedicineThe immune system is a key player in the onset and progression of neurodegenerative disorders. While brain resident immune cell-mediated neuroinflammation and peripheral immune cell (eg, T cell) infiltration into the brain have been shown to significantly contribute to Alzheimer's disease (AD) pathology, the nature and extent of immune responses in the brain in the context of AD and related dementias (ADRD) remain unclear. Furthermore, the roles of the peripheral immune system in driving ADRD pathology remain incompletely elucidated. In March of 2023, the Alzheimer's Association convened the Alzheimer's Association International Conference (AAIC), Advancements: Immunity, to discuss the roles of the immune system in ADRD. A wide range of topics were discussed, such as animal models that replicate human pathology, immune-related biomarkers and clinical trials, and lessons from other fields describing immune responses in neurodegeneration. This manuscript presents highlights from the conference and outlines avenues for future research on the roles of immunity in neurodegenerative disorders. HIGHLIGHTS: The immune system plays a central role in the pathogenesis of Alzheimer's disease. The immune system exerts numerous effects throughout the brain on amyloid-beta, tau, and other pathways. The 2023 AAIC, Advancements: Immunity, encouraged discussions and collaborations on understanding the role of the immune system.Item Alzheimer’s Disease Polygenic Risk in the LEADS Cohort(Wiley, 2025-01-03) Nudelman, Kelly N.; Pentchev, Julian V.; Jackson, Trever; Eloyan, Ani; Dage, Jeffrey L.; Foroud, Tatiana M.; Hammers, Dustin B.; Carrillo, Maria C.; Dickerson, Bradford C.; Rabinovici, Gil D.; Apostolova, Liana G.; LEADS Consortium; Medical and Molecular Genetics, School of MedicineBackground: Currently, it is unclear to what extent late‐onset Alzheimer’s disease (AD) risk variants contribute to early‐onset AD (EOAD). One method to clarify the contribution of late‐onset AD genetic risk to EOAD is to investigate the association of AD polygenic risk scores (PRS) with EOAD. We hypothesize that in the Longitudinal Early‐Onset Alzheimer’s Disease Study (LEADS), EOAD participants will have greater PRS than early‐onset amyloid‐negative cognitively‐impaired participants (EOnonAD) and controls, and investigate the association of AD PRS with age of disease onset (AoO) and cognitive performance. Methods: GWAS data was generated for LEADS participants, including those with EOAD, EOnonAD, and controls, with the Illumina Global Screening Array. A PRS was calculated using the 31 SNPs and weights published previously by Desikan et al. (2017) for LEADS participants with imputed GWAS data (N = 369). Logistic regression models including age, sex, PRS, and genetic ancestry principal components were tested to identify predictors of EOAD (N = 210) vs. EOnonAD (N = 69) and controls (N = 89). ANCOVA models were used to assess group differences in PRS scores. Kaplan‐Meier regression was used to assess differences in EOAD AoO for tertile‐binned PRS groups. Within EOAD, pre‐calculated cognitive domain scores for speed and attention, working memory, episodic memory, language, and visuospatial performance were assessed for correlation with PRS. Results: The AD PRS was a predictor of EOAD (p = 0.014), with the model explaining 10.5% of variance (X2 = 40.971, p<0.001). EOAD participants had higher PRS scores (mean = 0.0012, standard deviation (SD) = 0.015) compared to EOnonAD and controls (mean = ‐0.0018, SD = 0.015) (F = 6.602, p = 0.011). Survival analysis indicated no significant differences in EOAD AoO between PRS groups (X2 = 3.396, p = 0.183). In the EOAD group, PRS was associated with cognitive scores for speed and attention (r = 0.204, p = 0.007), language (r = 0.230, p = 0.002), and visuospatial performance (r = 0.166, p = 0.037). Conclusions: In the LEADS cohort, AD PRS is a predictor for EOAD, and is associated with cognitive performance, but does not predict EOAD AoO. This suggests that while late onset AD‐associated genetic variants contribute to disease risk and processes, they do not account for a large portion of disease risk, and do not explain differences in disease AoO in the LEADS cohort.Item Amyloid and tau-PET in early-onset AD: Baseline data from the Longitudinal Early-onset Alzheimer's Disease Study (LEADS)(Wiley, 2023) Cho, Hanna; Mundada, Nidhi S.; Apostolova, Liana G.; Carrillo, Maria C.; Shankar, Ranjani; Amuiri, Alinda N.; Zeltzer, Ehud; Windon, Charles C.; Soleimani-Meigooni, David N.; Tanner, Jeremy A.; Heath, Courtney Lawhn; Lesman-Segev, Orit H.; Aisen, Paul; Eloyan, Ani; Lee, Hye Sun; Hammers, Dustin B.; Kirby, Kala; Dage, Jeffrey L.; Fagan, Anne; Foroud, Tatiana; Grinberg, Lea T.; Jack, Clifford R.; Kramer, Joel; Kukull, Walter A.; Murray, Melissa E.; Nudelman, Kelly; Toga, Arthur; Vemuri, Prashanthi; Atri, Alireza; Day, Gregory S.; Duara, Ranjan; Graff-Radford, Neill R.; Honig, Lawrence S.; Jones, David T.; Masdeu, Joseph; Mendez, Mario; Musiek, Erik; Onyike, Chiadi U.; Riddle, Meghan; Rogalski, Emily J.; Salloway, Stephen; Sha, Sharon; Turner, Raymond Scott; Wingo, Thomas S.; Wolk, David A.; Koeppe, Robert; Iaccarino, Leonardo; Dickerson, Bradford C.; La Joie, Renaud; Rabinovici, Gil D.; LEADS Consortium; Neurology, School of MedicineIntroduction: We aimed to describe baseline amyloid-beta (Aβ) and tau-positron emission tomograrphy (PET) from Longitudinal Early-onset Alzheimer's Disease Study (LEADS), a prospective multi-site observational study of sporadic early-onset Alzheimer's disease (EOAD). Methods: We analyzed baseline [18F]Florbetaben (Aβ) and [18F]Flortaucipir (tau)-PET from cognitively impaired participants with a clinical diagnosis of mild cognitive impairment (MCI) or AD dementia aged < 65 years. Florbetaben scans were used to distinguish cognitively impaired participants with EOAD (Aβ+) from EOnonAD (Aβ-) based on the combination of visual read by expert reader and image quantification. Results: 243/321 (75.7%) of participants were assigned to the EOAD group based on amyloid-PET; 231 (95.1%) of them were tau-PET positive (A+T+). Tau-PET signal was elevated across cortical regions with a parietal-predominant pattern, and higher burden was observed in younger and female EOAD participants. Discussion: LEADS data emphasizes the importance of biomarkers to enhance diagnostic accuracy in EOAD. The advanced tau-PET binding at baseline might have implications for therapeutic strategies in patients with EOAD. Highlights: 72% of patients with clinical EOAD were positive on both amyloid- and tau-PET. Amyloid-positive patients with EOAD had high tau-PET signal across cortical regions. In EOAD, tau-PET mediated the relationship between amyloid-PET and MMSE. Among EOAD patients, younger onset and female sex were associated with higher tau-PET.Item 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 MedicineBackground: 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.Item Association Between Age and Cognitive Severity in Early‐Onset AD: Extension of preliminary findings in the Longitudinal Early‐Onset Alzheimer’s Disease Study (LEADS)(Wiley, 2025-01-03) Hammers, Dustin B.; Eloyan, Ani; Taurone, Alexander; Thangarajah, Maryanne; Kirby, Kala; Wong, Bonnie; Dage, Jeffrey L.; Nudelman, Kelly N.; Carrillo, Maria C.; Rabinovici, Gil D.; Dickerson, Bradford C.; Apostolova, Liana G.; LEADS Consortium; Neurology, School of MedicineBackground: Widespread cognitive impairments have previously been documented in Early‐Onset Alzheimer’s Disease (EOAD) relative to cognitively normal (CN) same‐aged peers or those with cognitive impairment without amyloid pathology (Early‐Onset non‐Alzheimer’s Disease; EOnonAD; Hammers et al., 2023). Prior preliminary work has similarly observed worse cognitive performance being associated with earlier ages in EOAD participants enrolled in the Longitudinal Early‐Onset Alzheimer’s Disease Study (LEADS; Apostolova et al., 2019). It is unclear, however, if these age effects are seen across early‐onset conditions, and whether cognitive discrepancies among diagnostic groups are uniform across the age spectrum. The objective of the current study is to more‐extensively examine the impact of age‐at‐baseline on cognition within LEADS, with emphasis placed on the influence of diagnostic group on these associations. Method: Expanded cross‐sectional baseline cognitive data from 573 participants (CN, n = 97; EOAD, n = 364; EOnonAD, n = 112) enrolled in the LEADS study (aged 40‐64) were analyzed. Multiple linear regression analyses were conducted to investigate associations between age‐at‐baseline and cognition for each diagnostic group – and their interaction among diagnoses – controlling for gender, education, APOE ε4 status, and disease severity. Result: See Table 1 for demographic characteristics of our sample. Linear regression showed a significant interaction effect for the cognitive domain of Executive Functioning (p = .002). Specifically, while the EOAD group displayed a positive relationship between age‐at‐baseline and Executive Functioning performance (β = 0.08, p = .02; Figure 1), the CN group displayed a negative relationship (β = ‐0.04, p = .008) and the EOnonAD group displayed no relationship (β = ‐0.01, p = .50). A similar main‐effect for age was observed for the EOAD group when examining Visuospatial Skills (β = 0.12, p = .04), however no other age effects were evident across other diagnostic groups or cognitive domains (Episodic Memory, Language, or Speed/Attention; Table 2). Conclusion: Building off preliminary work, our results suggest that executive functioning may be disproportionately impacted earlier in the disease course in participants with EOAD relative to other diagnostic groups. This finding appears to be unique to executive functioning, as it was absent in other cognitive domains and remained after accounting for disease severity. This highlights the need for further investigation into executive dysfunction early in the course of EOAD.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 inflammation co-localizes highly with tau in mild cognitive impairment due to early-onset Alzheimer's disease(Oxford University Press, 2025) Appleton, Johanna; Finn, Quentin; Zanotti-Fregonara, Paolo; Yu, Meixiang; Faridar, Alireza; Nakawah, Mohammad O.; Zarate, Carlos; Carrillo, Maria C.; Dickerson, Bradford C.; Rabinovici, Gil D.; Apostolova, Liana G.; Masdeu, Joseph C.; Pascual, Belen; Neurology, School of MedicineBrain inflammation, with an increased density of microglia and macrophages, is an important component of Alzheimer's disease and a potential therapeutic target. However, it is incompletely characterized, particularly in patients whose disease begins before the age of 65 years and, thus, have few co-pathologies. Inflammation has been usefully imaged with translocator protein (TSPO) PET, but most inflammation PET tracers cannot image subjects with a low-binder TSPO rs6971 genotype. In an important development, participants with any TSPO genotype can be imaged with a novel tracer, 11C-ER176, that has a high binding potential and a more favourable metabolite profile than other TSPO tracers currently available. We applied 11C-ER176 to detect brain inflammation in mild cognitive impairment (MCI) caused by early-onset Alzheimer's disease. Furthermore, we sought to correlate the brain localization of inflammation, volume loss, elevated amyloid-β (Aβ)and tau. We studied brain inflammation in 25 patients with early-onset amnestic MCI (average age 59 ± 4.5 years, 10 female) and 23 healthy controls (average age 65 ± 6.0 years, 12 female), both groups with a similar proportion of all three TSPO-binding affinities. 11C-ER176 total distribution volume (VT), obtained with an arterial input function, was compared across patients and controls using voxel-wise and region-wise analyses. In addition to inflammation PET, most MCI patients had Aβ (n = 23) and tau PET (n = 21). For Aβ and tau tracers, standard uptake value ratios were calculated using cerebellar grey matter as region of reference. Regional correlations among the three tracers were determined. Data were corrected for partial volume effect. Cognitive performance was studied with standard neuropsychological tools. In MCI caused by early-onset Alzheimer's disease, there was inflammation in the default network, reaching statistical significance in precuneus and lateral temporal and parietal association cortex bilaterally, and in the right amygdala. Topographically, inflammation co-localized most strongly with tau (r = 0.63 ± 0.24). This correlation was higher than the co-localization of Aβ with tau (r = 0.55 ± 0.25) and of inflammation with Aβ (0.43 ± 0.22). Inflammation co-localized least with atrophy (-0.29 ± 0.26). These regional correlations could be detected in participants with any of the three rs6971 TSPO polymorphisms. Inflammation in Alzheimer's disease-related regions correlated with impaired cognitive scores. Our data highlight the importance of inflammation, a potential therapeutic target, in the Alzheimer's disease process. Furthermore, they support the notion that, as shown in experimental tissue and animal models, the propagation of tau in humans is associated with brain inflammation.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.