Browsing by Author "Karikari, Thomas K."
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Item Associations of 18F‐RO‐948 Tau PET with Fluid AD Biomarkers, Centiloid, and Cognition in the Early AD Continuum(Wiley, 2025-01-09) Shekari, Mahnaz; González Escalante, Armand; Milà-Alomà, Marta; Falcon, Carles; López-Martos, David; Sánchez-Benavides, Gonzalo; Brugulat-Serrat, Anna; Niñerola-Baizán, Aida; Ashton, Nicholas J.; Karikari, Thomas K.; Lantero Rodriguez, Juan; Snellman, Anniina; Day, Theresa A.; Dage, Jeffrey L.; Ortiz-Romero, Paula; Tonietto, Matteo; Borroni, Edilio; Klein, Gregory; Kollmorgen, Gwendlyn; Quijano-Rubio, Clara; Vanmechelen, Eugeen; Minguillón, Carolina; Fauria, Karine; Perissinotti, Andrés; Molinuevo, Jose Luis; Zetterberg, Henrik; Blennow, Kaj; Grau-Rivera, Oriol; Suárez-Calvet, Marc; Gispert, Juan Domingo; Neurology, School of MedicineBackground: Fluid biomarkers provide a convenient way to predict AD pathophysiology. However, few studies have focused on determining associations with tau neurofibrillary tangle pathology in the early preclinical AD continuum, relevant to prevention strategies. Methods: Ninety‐nine cognitively unimpaired individuals from the ALFA+ cohort with valid 18F‐RO‐948 and 18F‐flutemetamol PET, T1‐weighted MRI, cognition, CSF, and plasma biomarkers were included. Participants were initially categorized into AT stages using CSF‐based pre‐established cut‐off values [1]. Regional SUVR of 18F‐RO‐948 PET was calculated in entorhinal(BraakI/II), limbic(BraakIII/IV), and neocortical(BraakV/VI) regions using the inferior cerebellum as reference region as well as with the CenTAURz. Regional positivity thresholds per Braak stage were calculated as the median+2SD of the CSF A‐T‐ group. Amyloid PET was quantified using Centiloids. Pearson correlations were calculated between regional 18F‐RO‐948 SUVRs and AD biomarkers. ROC analyses adjusted for age, sex, and APOE‐ε4 performed to evaluate the capacity of biomarkers in predicting BraakI/IIPositive. Four progressive PET‐derived AT groups were defined using Centiloid and tau PET positivity cut‐offs (A‐T‐, AGZT‐, A+T‐ and A+T+; with A‐ CL<12, 12≤AGZ<38 and A+ CL≥38 [2], and T+ BraakI/II>1.35) and between‐stage differences in z‐scored biomarkers evaluated using a Kruskal‐Wallis tests. Results: Table 1 shows demographic information of participants. Nine(9.09%) participants were BraakI/IIPositive, seven(7.07%) BraakIII/IVPositive and one(1.01%) BraakV/VIPositive. Two BraakIII/IVPositive participants were BraakI/IINegative, deviating from the Braak hierarchical model. CSF biomarker correlations with BraakI/II SUVR (Figure 1‐A) ranged from r=0.24(ttau) to r=0.57(ptau217) and plasma (Figure 1‐B) from r=0.30(ptau217) to r=0.49(ptau181). Correlations survived adding age+sex+APOE‐ε4 in the model (Figure 1‐C&D). CSF ptau181/Aβ42, ptau217 and ptau205 showed an AUC≥0.93 to predict BraakI/IIPositive, and plasma ptau181, ptau181/Aβ42 and ptau217 had an AUC≥0.84. Centiloid positivity threshold for BraakI/IIPositive was 38.14CL. Plasma ptau181, ptau181/Aβ42, and CSF ptau205, ptau217, and ptau235 reached a mean z‐score>2 for the PET‐derived A+T+ group (Figure 2) which was associated with lower cognitive scores for executive function (p=0.03), attention (p=0.05), and the PACC (p=0.01). Conclusion: 18F‐RO‐948 PET conformed to the Braak hierarchical model for most tau‐positive participants. Fluid AD biomarkers showed moderate associations with tau PET SUVR. Plasma biomarkers showed good capacity to predict BraakI/IIPositive and track fibrillary amyloid and tau pathological changes in the early preclinical AD continuum.Item Comparison of Plasma Phosphorylated Tau Species With Amyloid and Tau Positron Emission Tomography, Neurodegeneration, Vascular Pathology, and Cognitive Outcomes(American Medical Association, 2021) Mielke, Michelle M.; Frank, Ryan D.; Dage, Jeffrey L.; Jeromin, Andreas; Ashton, Nicholas J.; Blennow, Kaj; Karikari, Thomas K.; Vanmechelen, Eugene; Zetterberg, Henrik; Algeciras-Schimnich, Alicia; Knopman, David S.; Lowe, Val; Bu, Guojun; Vemuri, Prashanthi; Graff-Radford, Jonathan; Jack, Clifford R., Jr.; Petersen, Ronald C.; Neurology, School of MedicineImportance: Cerebrospinal fluid phosphorylated tau (p-tau) 181, p-tau217, and p-tau231 are associated with neuropathological outcomes, but a comparison of these p-tau isoforms in blood samples is needed. Objective: To conduct a head-to-head comparison of plasma p-tau181 and p-tau231 measured on the single-molecule array (Simoa) platform and p-tau181 and p-tau217 measured on the Meso Scale Discovery (MSD) platform on amyloid and tau positron emission tomography (PET) measures, neurodegeneration, vascular pathology, and cognitive outcomes. Design, setting, and participants: This study included data from the Mayo Clinic Study on Aging collected from March 1, 2015, to September 30, 2017, and analyzed between December 15, 2020, and May 17, 2021. Associations between the 4 plasma p-tau measures and dichotomous amyloid PET, metaregion of interest tau PET, and entorhinal cortex tau PET were analyzed using logistic regression models; the predictive accuracy was summarized using area under the receiver operating characteristic curve (AUROC) statistic. Of 1329 participants without dementia and with p-tau181 and p-tau217 on MSD, 200 participants with plasma p-tau181 and p-tau231 on Simoa and magnetic resonance imaging and amyloid and tau PET data at the same study visit were eligible. Main outcomes and measures: Primary outcomes included amyloid (greater than 1.48 standardized uptake value ratio) and tau PET, white matter hyperintensities, white matter microstructural integrity (fractional anisotropy genu of corpus callosum and hippocampal cingulum bundle), and cognition. Results: Of 200 included participants, 101 (50.5%) were male, and the median (interquartile range [IQR]) age was 79.5 (71.1-84.1) years. A total of 177 were cognitively unimpaired (CU) and 23 had mild cognitive impairment. Compared with amyloid-negative CU participants, among amyloid-positive CU participants, the median (IQR) Simoa p-tau181 measure was 49% higher (2.58 [2.00-3.72] vs 1.73 [1.45-2.13] pg/mL), MSD p-tau181 measure was 53% higher (1.22 [0.91-1.56] vs 0.80 [0.66-0.97] pg/mL), MSD p-tau217 measure was 77% higher (0.23 [0.17-0.34] vs 0.13 [0.09-0.18] pg/mL), and Simoa p-tau231 measure was 49% higher (20.21 [15.60-25.41] vs 14.27 [11.27-18.10] pg/mL). There were no differences between the p-tau species for amyloid PET and tau PET metaregions of interest. However, among CU participants, both MSD p-tau181 and MSD p-tau217 more accurately predicted abnormal entorhinal cortex tau PET than Simoa p-tau181 (MSD p-tau181: AUROC, 0.80 vs 0.70; P = .046; MSD p-tau217: AUROC, 0.81 vs 0.70; P = .04). MSD p-tau181 and p-tau217 and Simoa p-tau181, but not p-tau231, were associated with greater white matter hyperintensity volume and lower white matter microstructural integrity. Conclusions and relevance: In this largely presymptomatic population, these results suggest subtle differences across plasma p-tau species and platforms for the prediction of amyloid and tau PET and magnetic resonance imaging measures of cerebrovascular and Alzheimer-related pathology.Item Longitudinal Associations of Blood Phosphorylated Tau181 and Neurofilament Light Chain With Neurodegeneration in Alzheimer Disease(American Medical Association, 2021) Moscoso, Alexis; Grothe, Michel J.; Ashton, Nicholas J.; Karikari, Thomas K.; Rodríguez, Juan Lantero; Snellman, Anniina; Suárez-Calvet, Marc; Blennow, Kaj; Zetterberg, Henrik; Schöll, Michael; Alzheimer’s Disease Neuroimaging Initiative; Medicine, School of MedicineImportance: Plasma phosphorylated tau at threonine 181 (p-tau181) has been proposed as an easily accessible biomarker for the detection of Alzheimer disease (AD) pathology, but its ability to monitor disease progression in AD remains unclear. Objective: To study the potential of longitudinal plasma p-tau181 measures for assessing neurodegeneration progression and cognitive decline in AD in comparison to plasma neurofilament light chain (NfL), a disease-nonspecific marker of neuronal injury. Design, setting, and participants: This longitudinal cohort study included data from the Alzheimer's Disease Neuroimaging Initiative from February 1, 2007, to June 6, 2016. Follow-up blood sampling was performed for up to 8 years. Plasma p-tau181 measurements were performed in 2020. This was a multicentric observational study of 1113 participants, including cognitively unimpaired participants as well as patients with cognitive impairment (mild cognitive impairment and AD dementia). Participants were eligible for inclusion if they had available plasma p-tau181 and NfL measurements and at least 1 fluorine-18-labeled fluorodeoxyglucose (FDG) positron emission tomography (PET) or structural magnetic resonance imaging scan performed at the same study visit. Exclusion criteria included any significant neurologic disorder other than suspected AD; presence of infection, infarction, or multiple lacunes as detected by magnetic resonance imaging; and any significant systemic condition that could lead to difficulty complying with the protocol. Exposures: Plasma p-tau181 and NfL measured with single-molecule array technology. Main outcomes and measures: Longitudinal imaging markers of neurodegeneration (FDG PET and structural magnetic resonance imaging) and cognitive test scores (Preclinical Alzheimer Cognitive Composite and Alzheimer Disease Assessment Scale-Cognitive Subscale with 13 tasks). Data were analyzed from June 20 to August 15, 2020. Results: Of the 1113 participants (mean [SD] age, 74.0 [7.6] years; 600 men [53.9%]; 992 non-Hispanic White participants [89.1%]), a total of 378 individuals (34.0%) were cognitively unimpaired (CU) and 735 participants (66.0%) were cognitively impaired (CImp). Of the CImp group, 537 (73.1%) had mild cognitive impairment, and 198 (26.9%) had AD dementia. Longitudinal changes of plasma p-tau181 were associated with cognitive decline (CU: r = -0.24, P < .001; CImp: r = 0.34, P < .001) and a prospective decrease in glucose metabolism (CU: r = -0.05, P = .48; CImp: r = -0.27, P < .001) and gray matter volume (CU: r = -0.19, P < .001; CImp: r = -0.31, P < .001) in highly AD-characteristic brain regions. These associations were restricted to amyloid-β-positive individuals. Both plasma p-tau181 and NfL were independently associated with cognition and neurodegeneration in brain regions typically affected in AD. However, NfL was also associated with neurodegeneration in brain regions exceeding this AD-typical spatial pattern in amyloid-β-negative participants. Mediation analyses found that approximately 25% to 45% of plasma p-tau181 outcomes on cognition measures were mediated by the neuroimaging-derived markers of neurodegeneration, suggesting links between plasma p-tau181 and cognition independent of these measures. Conclusions and relevance: Study findings suggest that plasma p-tau181 was an accessible and scalable marker for predicting and monitoring neurodegeneration and cognitive decline and was, unlike plasma NfL, AD specific. The study findings suggest implications for the use of plasma biomarkers as measures to monitor AD progression in clinical practice and treatment trials.Item Over‐Representation of Extremely Wealthy Neighborhood Social Exposomes for Brain Donors within Alzheimer’s Disease Research Center Brain Banks assessed by the Neighborhoods Study(Wiley, 2025-01-09) Kind, Amy J. H.; Bendlin, Barbara B.; Powell, W. Ryan; DeWitt, Amanda; Cheng, Yixuan; Chamberlain, Luke; Sharrow, Jessica; Lyons Boone, Brittney; Abner, Erin L.; Alosco, Michael L.; Apostolova, Liana G.; Bakulski, Kelly M.; Barnes, Lisa L.; Bateman, James R.; Beach, Thomas G.; Bennett, David A.; Brewer, James B.; Carrion, Carmen; Chodosh, Joshua; Craft, Suzanne; Croff, Raina; Fabio, Anthony; Tomaszewski Farias, Sarah; Goldstein, Felicia; Henderson, Victor W.; Karikari, Thomas K.; Kofler, Julia; Kucharska-Newton, Anna M.; Lamar, Melissa; Lanata, Serggio; Lepping, Rebecca J.; Lingler, Jennifer H.; Lockhart, Samuel N.; Mahnken, Jonathan D.; Marsh, Karyn; Meyer, Oanh L.; Miller, Bruce L.; Morris, Jill K.; Neugroschl, Judith A.; O'Connor, Maureen K.; Paulson, Henry L.; Perrin, Richard J.; Pettigrew, Corinne; Pierce, Aimee; Raji, Cyrus A.; Reiman, Eric M.; Risacher, Shannon L.; Rissman, Robert A.; Rodriguez Espinoza, Patricia; Sano, Mary; Saykin, Andrew J.; Serrano, Geidy E.; Soldan, Anja; Sultzer, David L.; Whitmer, Rachel A.; Wisniewski, Thomas; Woltjer, Randall; Zhu, Carolyn W.; Radiology and Imaging Sciences, School of MedicineBackground: Adverse social exposome (indexed by national Area Deprivation Index [ADI] 80‐100 or ‘high ADI’) is linked to structural inequities and increased risk of Alzheimer’s disease neuropathology. Twenty percent of the US population resides within high ADI areas, predominantly in inner cities, tribal reservations and rural areas. The percentage of brain donors from high ADI areas within the Alzheimer’s Disease Research Center (ADRC) brain bank system is unknown. Objective: Determine ADI for brain donors from 21 ADRC sites as part of the on‐going Neighborhoods Study. Methods: All brain donors in participating ADRC sites with NACC neuropathology data and personal identifiers for ADI linkage (N = 8,637) were included (Figure 1). Geocoded donor addresses were linked to time‐concordant ADI percentiles for year of death. Results: Overall, only 5.6% of ADRC brain donors (N = 488) resided in a high ADI (disadvantaged) neighborhood at death. The remaining donors resided in more advantaged neighborhoods, with nearly 40% of donors living in the wealthiest quintile of neighborhoods, and over 300 brain donors originating from the wealthiest 1% of US neighborhoods (Figure 2). Donors from high ADI (disadvantaged) neighborhoods identified as 87% White (n = 424), 11% Black (55), 1% Multiracial (6) and <1% other/unknown race (3), with 1% Hispanic (5). None identified as American Indian/Alaska Native or Native Hawaiian/Pacific Islander/Asian. In comparison, donors from low ADI neighborhoods were 94% White (n = 7680), 3% Black (273), 1% Multiracial (75), <1% American Indian/Alaska Native (11), <1% Native Hawaiian/Pacific Islander/Asian (60), and <1% other/unknown race (50), with 3% Hispanic (230). Sex distribution was similar (54%, 51% female, respectively). Inclusion of high ADI donors varied dramatically across the 21 ADRC brain banks from a low of 0.6% to high of 20% of all a site’s donors (Figure 3). Conclusions: ADI was determined for over 8,600 brain donors in the ADRC system, demonstrating a marked over‐representation of donors from very low ADI (extremely wealthy) neighborhoods, in addition to site‐to‐site variability. This is the first time a comprehensive cross‐sectional social exposome assessment of this nature has been performed, opening windows for additional mechanistic study of the social exposome on brain pathology. Life course ADI assessments are on‐going.Item Plasma and CSF biomarkers in a memory clinic: Head-to-head comparison of phosphorylated tau immunoassays(Wiley, 2023) Ashton, Nicholas J.; Puig-Pijoan, Albert; Milà-Alomà, Marta; Fernández-Lebrero, Aida; García-Escobar, Greta; González-Ortiz, Fernándo; Kac, Przemysław R.; Brum, Wagner S.; Benedet, Andréa L.; Lantero-Rodriguez, Juan; Day, Theresa A.; Vanbrabant, Jeroen; Stoops, Erik; Vanmechelen, Eugeen; Triana-Baltzer, Gallen; Moughadam, Setareh; Kolb, Hartmuth; Ortiz-Romero, Paula; Karikari, Thomas K.; Minguillon, Carolina; Hernández Sánchez, Juan José; Navalpotro-Gómez, Irene; Grau-Rivera, Oriol; Manero, Rosa María; Puente-Periz, Víctor; de la Torre, Rafael; Roquer, Jaume; Dage, Jeff L.; Zetterberg, Henrik; Blennow, Kaj; Suárez-Calvet, Marc; Neurology, School of MedicineIntroduction: Direct comparisons of the main blood phosphorylated tau immunoassays in memory clinic populations are needed to understand possible differences. Methods: In the BIODEGMAR study, 197 participants presenting with cognitive complaints were classified into an Alzheimer's disease (AD) or a non-AD cerebrospinal fluid (CSF) profile group, according to their amyloid beta 42/ phosphorylated tau (Aβ42/p-tau) ratio. We performed a head-to-head comparison of nine plasma and nine CSF tau immunoassays and determined their accuracy to discriminate abnormal CSF Aβ42/p-tau ratio. Results: All studied plasma tau biomarkers were significantly higher in the AD CSF profile group compared to the non-AD CSF profile group and significantly discriminated abnormal CSF Aβ42/p-tau ratio. For plasma p-tau biomarkers, the higher discrimination accuracy was shown by Janssen p-tau217 (r = 0.76; area under the curve [AUC] = 0.96), ADx p-tau181 (r = 0.73; AUC = 0.94), and Lilly p-tau217 (r = 0.73; AUC = 0.94). Discussion: Several plasma p-tau biomarkers can be used in a specialized memory clinic as a stand-alone biomarker to detect biologically-defined AD. Highlights: Patients with an Alzheimer's disease cerebrospinal fluid (AD CSF) profile have higher plasma phosphorylated tau (p-tau) levels than the non-AD CSF profile group. All plasma p-tau biomarkers significantly discriminate patients with an AD CSF profile from the non-AD CSF profile group. Janssen p-tau217, ADx p-tau181, and Lilly p-tau217 in plasma show the highest accuracy to detect biologically defined AD. Janssen p-tau217, ADx p-tau181, Lilly p-tau217, Lilly p-tau181, and UGot p-tau231 in plasma show performances that are comparable to their CSF counterparts.Item Plasma biomarkers combinations for prescreening rapid amyloid accumulation in cognitively unimpaired individuals at‐risk of Alzheimer’s disease(Wiley, 2025-01-09) Contador, José; Milà-Alomà, Marta; Escalante, Armand González; Ashton, Nicholas J.; Shekari, Mahnaz; Ortiz-Romero, Paula; Karikari, Thomas K.; Vanmechelen, Eugeen; Day, Theresa A.; Dage, Jeffrey L.; Zetterberg, Henrik; Gispert, Juan Domingo; Blennow, Kaj; Suarez-Calvet, Marc; Neurology, School of MedicineBackground: Alzheimer’s disease (AD) blood biomarkers alone can detect amyloid‐β (Aβ) pathology in cognitively unimpaired (CU) individuals. We assessed whether combining different plasma biomarkers improves the detection of Aβ‐positivity and identifies rapid amyloid deposition in CU individuals. Method: CU participants from the ALFA+ cohort were included. Among them, 361 had CSF Aβ42/40 and 328 amyloid PET‐scans [194 with two longitudinal scans; mean interval=3.35 (0.56) years]. Plasma Aβ42/40, p‐tau181, p‐tau231, GFAP, NfL (Simoa‐based) and p‐tau217 and t‐tau (MSD‐based) were measured at baseline (Table 1). We used simple and multiple logistic models to estimate Aβ‐positivity (defined as CSF Aβ42/40<0.071 or amyloid‐PET>12 Centiloids) or Aβ accumulation rate (“Fast accumulators” defined as >3 Centiloids/year). The model contained plasma biomarkers and demographics (age and sex) as covariates. We selected as "best model" (BM) that with lowest AIC. We defined parsimonious models as those with an AUC not significantly different (DeLong test) from BM or from each other yet outperforming single biomarkers and/or demographics models (FDR corrected). For the positive agreement closest to 90%, we calculated savings in lumbar punctures and amyloid PET‐scans. Result: For CSF Aβ‐positive detection, BM included plasma Aβ42/40, p‐tau181, p‐tau217, p‐tau231, GFAP and t‐tau (AUC=0.84). All simpler biomarkers combinations included plasma Ab42/40 and p‐tau231 (Table 2A). For PET Ab‐positive detection, BM included plasma Aβ42/40, p‐tau181, p‐tau217, GFAP, NFL and age (AUC=0.88). All simpler biomarkers combinations included plasma Ab42/40 and p‐tau217 (Table 2B). Regarding fast accumulators’ detection, plasma p‐tau217 was the single biomarker with the highest performance (AUC=0.70). BM included plasma Aβ42/40, p‐tau217, p‐tau231 and GFAP (AUC= 0.76). BM and the plasma Aβ42/40, p‐tau217 and GFAP (AUC=0.75) combination were the only models that outperformed the age and sex combination and single biomarkers, except for plasma p‐tau217, Aβ42/40 (AUC=0.69) or GFAP (AUC=0.68) alone (Table 2C). The combination of biomarkers could save up to 11% of lumbar punctures or 44% of amyloid‐PET to detect Ab‐positive CU individuals and 16% amyloid‐PETs to detect fast Aβ‐accumulation compared to the best single plasma biomarker (Table 2). Conclusion: In CU individuals, diverse combinations of plasma biomarkers detect Aβ‐positivity and future Aβ‐accumulation with high accuracy and can lead to substantial cost savings in AD detection.Item Plasma p-tau231 and p-tau217 as state markers of amyloid-β pathology in preclinical Alzheimer's disease(Springer Nature, 2022) Milà-Alomà, Marta; Ashton, Nicholas J.; Shekari, Mahnaz; Salvadó, Gemma; Ortiz-Romero, Paula; Montoliu-Gaya, Laia; Benedet, Andrea L.; Karikari, Thomas K.; Lantero-Rodriguez, Juan; Vanmechelen, Eugeen; Day, Theresa A.; González-Escalante, Armand; Sánchez-Benavides, Gonzalo; Minguillon, Carolina; Fauria, Karine; Molinuevo, José Luis; Dage, Jeffrey L.; Zetterberg, Henrik; Gispert, Juan Domingo; Suárez-Calvet, Marc; Blennow, Kaj; Neurology, School of MedicineBlood biomarkers indicating elevated amyloid-β (Aβ) pathology in preclinical Alzheimer's disease are needed to facilitate the initial screening process of participants in disease-modifying trials. Previous biofluid data suggest that phosphorylated tau231 (p-tau231) could indicate incipient Aβ pathology, but a comprehensive comparison with other putative blood biomarkers is lacking. In the ALFA+ cohort, all tested plasma biomarkers (p-tau181, p-tau217, p-tau231, GFAP, NfL and Aβ42/40) were significantly changed in preclinical Alzheimer's disease. However, plasma p-tau231 reached abnormal levels with the lowest Aβ burden. Plasma p-tau231 and p-tau217 had the strongest association with Aβ positron emission tomography (PET) retention in early accumulating regions and associated with longitudinal increases in Aβ PET uptake in individuals without overt Aβ pathology at baseline. In summary, plasma p-tau231 and p-tau217 better capture the earliest cerebral Aβ changes, before overt Aβ plaque pathology is present, and are promising blood biomarkers to enrich a preclinical population for Alzheimer's disease clinical trials.Item Publisher Correction: Plasma p-tau231 and p-tau217 as state markers of amyloid-β pathology in preclinical Alzheimer's disease(Springer Nature, 2022) Milà-Alomà, Marta; Ashton, Nicholas J.; Shekari, Mahnaz; Salvadó, Gemma; Ortiz-Romero, Paula; Montoliu-Gaya, Laia; Benedet, Andrea L.; Karikari, Thomas K.; Lantero-Rodriguez, Juan; Vanmechelen, Eugeen; Day, Theresa A.; González-Escalante, Armand; Sánchez-Benavides, Gonzalo; Minguillon, Carolina; Fauria, Karine; Molinuevo, José Luis; Dage, Jeffrey L.; Zetterberg, Henrik; Gispert, Juan Domingo; Suárez-Calvet, Marc; Blennow, Kaj; Neurology, School of MedicineThis corrects the article "Plasma p-tau231 and p-tau217 as state markers of amyloid-β pathology in preclinical Alzheimer’s disease" in Nat Med, volume 28 on page 1797.