Study of the utility and impact of a plasma p‐tau181 Alzheimer's biomarker (SUITABLE).

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Learn more: PMC Disclaimer | PMC Copyright Notice Alzheimers Dement (N Y) . 2026 Mar 13;12(1):e70207. doi: 10.1002/trc2.70207 Study of the utility and impact of a plasma p‐tau181 Alzheimer's biomarker (SUITABLE) Kyra O'Brien 1, 2, ✉ , Cameron Coykendall 1 , Kristin Harkins 3 , Xingmei Wang 4 , Abigail Perelman 5 , Megan Zhang 6 , Jason Karlawish 1, 2, 3, 7 Author information Article notes Copyright and License information 1 Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA 2 Leonard Davis Institute of Health Economics, University of Pennsylvania, Philadelphia, Pennsylvania, USA 3 Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA 4 Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA 5 Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA 6 College of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, USA 7 Department of Medical Ethics and Health Policy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA * Correspondence , Kyra O'Brien, Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. Email: kyra.o'brien@pennmedicine.upenn.edu ✉ Corresponding author. Revised 2025 Nov 20; Received 2025 Oct 22; Accepted 2025 Dec 14; Collection date 2026 Jan-Mar. © 2026 The Author(s). Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. PMC Copyright notice PMCID: PMC13238866  PMID: 42254757 Abstract INTRODUCTION Blood‐based Alzheimer's disease (AD) biomarkers are increasingly used in clinical care, but there are few real‐world studies of their clinical utility. We evaluated the impact of plasma phosphorylated tau at threonine 181 (p‐tau181) on the diagnosis and management of patients with cognitive impairment in a memory clinic. METHODS Dementia specialists referred patients for plasma p‐tau181 testing during clinical care. We used surveys and chart review to assess the impact of plasma p‐tau181 testing on clinical care and patient and care partner wellbeing. We assessed co‐primary outcomes of (1) change in diagnostic confidence before vs after testing, (2) change in diagnosis, and (3) change in management. A diagnosis or management change of greater than 30% was considered to be clinically significant. Secondary and exploratory outcomes included impact of plasma p‐tau181 testing on the use of additional diagnostics and impact on patient and care partner psychological wellbeing, health behaviors, and future planning. RESULTS One hundred patients completed plasma p‐tau181 testing; 81% had an elevated result, and 19% had a non‐elevated result. Clinician diagnostic confidence averaged 1.43 points higher after p‐tau181 testing (95% confidence interval [CI] 1.02 to 1.84, p < 0.0001). After testing, 27.7% (95% CI 18.9% to 36.4%, p = 0.31) of patients had a change in management and 17.2% of patients had a change in diagnosis – significantly lower than the 30% threshold (95% CI 9.5% to 24.9%, p = 0.004). Patients with elevated results were less likely to have a diagnosis changed after testing than those with non‐elevated results (OR 0.08 [95% CI 0.01 to 0.47], p = 0.005). A non‐elevated result was associated with decreased use of amyloid positron emission tomography (PET) (odds ratio [OR] 0.25 [95% CI 0.07 to 0.86], p = 0.028). Patients with an elevated result had higher anxiety at 2 to 3 months after disclosure ( p = 0.01). DISCUSSION Non‐elevated plasma p‐tau181 results impacted the diagnosis and use of amyloid PET imaging in a memory clinic. There was increased anxiety in patients after testing, affirming the need for post‐disclosure psychological support. Keywords: Alzheimer's disease, blood‐based biomarkers, clinical utility, p‐tau181 Highlights Plasma p‐tau181 testing increased clinician diagnostic confidence. Non‐elevated plasma p‐tau181 results may reduce the use of amyloid PET scans. There was not severe emotional distress after learning one's p‐tau181 result. Plasma p‐tau181 did not impact care planning or health‐promoting behaviors. 1. BACKGROUND In the last few years, spurred in part by the emergence of amyloid‐targeting therapies (ATTs), 1 , 2 several imaging and biofluid diagnostic biomarkers of Alzheimer's disease (AD) have become available for clinical use. Although amyloid positron emission tomography (PET) and cerebrospinal fluid (CSF) AD biomarkers have shown good diagnostic accuracy 3 , 4 , 5 and clinical utility in diverse patient populations, 6 , 7 they have shortcomings. They are not widely accessible, especially in rural or under‐resourced clinical settings, 8 and not simple to either administer or undergo. 9 , 10 Blood‐based biomarkers hold great promise to address these shortcomings. Some blood‐based AD biomarkers offer equivalent diagnostic accuracy to spinal fluid AD biomarkers, 11 , 12 , 13 , 14 , 15 , 16 and are a more accessible, less invasive method of AD biomarker testing. 17 One of these biomarkers is plasma phosphorylated‐tau181 (p‐tau181), a downstream indicator of cerebral amyloid deposition. It has good correlation with PET and CSF biomarkers, reliably differentiates between AD and other neurodegenerative disorders, 16 , 18 and predicts clinical progression from mild cognitive impairment (MCI) to dementia due to AD. 19 , 20 It is one example of validated blood‐based AD biomarkers that measure amyloid, neurodegeneration, and tau species. 21 , 22 There are ample validation studies of p‐tau181 and other blood‐based AD biomarkers. What's needed are studies of the clinical utility of blood‐based AD biomarkers, including their impact on the pathway to diagnose AD, medical management and patient and care partner wellbeing. Evidence of clinical utility will promote their clinical adoption. 23 To fill this gap, we conducted a prospective observational study of the utility and impact of plasma p‐tau181 Alzheimer's biomarkers (SUITABLE) in a memory clinic. 2. METHODS We used a prospective observational design to evaluate the clinical impact of a plasma p‐tau181 AD biomarker in a memory clinic. This study was approved by the University of Pennsylvania Institutional Review Board (protocol number 853264). 2.1. Study recruitment Patients were referred to the study by Penn Memory Center dementia specialists. Clinicians received information on the performance of the blood‐based AD biomarker used for this study, the LucentAD plasma p‐tau181 assay. This test was selected due to its having one of the highest sensitivities of plasma AD biomarkers available at the time the study was conducted. Clinicians were informed of the eligibility criteria and were instructed to use their clinical judgment when referring patients for plasma p‐tau181 testing. Patients were eligible to participate if they had a syndromic diagnosis of MCI or dementia and no prior biomarker‐based AD diagnosis. Patients were required to participate with a study partner who could provide consent if the patient was unable and act as a reliable informant. Patients could be granted an exception to the study partner requirement if the referring physician confirmed the patient could consent to study procedures. Patients and their study partners received education about what the p‐tau181 test measured, the limitations of the test – including inability to rule out other causes of cognitive decline – and its potential psychosocial impact prior to testing. 2.2. Plasma p‐tau181 testing and return of results Patients underwent venipuncture to provide 5 to 8 mL blood for p‐tau181 testing. Blood samples were centrifuged at 2°C to 8°C and shipped to Quanterix for testing. The Quanterix assay, LucentAD plasma p‐tau181, differentiated CSF biomarker‐confirmed (amyloid beta (Aβ) 42 and p‐tau181) AD cases from cognitively normal controls (unknown biomarker status) with a sensitivity of 97.3% and a specificity of 52.8% at a cutoff of 14.2 pg/mL. 24 Practically, this assay is a reliable rule‐out test for brain amyloidosis but not a reliable confirmatory test. The research coordinator shared the result with the patient's referring physician via an electronic health record (EHR) message. Plasma p‐tau181 results were then returned to the participants by their referring physician. Clinicians did not receive a script to help facilitate results return. RESEARCH IN CONTEXT Systematic review : Several studies evaluated the performance of various blood‐based AD biomarkers, but the clinical utility of these tests has not been well characterized. Amyloid PET scans have been shown to significantly impact patient care and influence patient and care partner wellbeing and health‐related behaviors, but few studies have examined the impact of blood‐based AD biomarkers on patient care. Interpretation : A plasma p‐tau181 test was associated with higher diagnostic confidence and moderated use of amyloid PET scans in a memory clinic. Mild increased anxiety was reported in patients at 2 to 3 months after the return of results. Future directions : Our findings demonstrate partial clinical utility of a plasma p‐tau181 assay in a memory center, without major adverse effects on patient and care partner wellbeing. Future work should examine the clinical utility of blood‐based AD biomarkers with higher specificity in both primary and specialty care settings. 2.3. Data collection Primary and secondary diagnoses, diagnostic confidence, use of additional diagnostic testing, and medical management were assessed through electronic questionnaires completed by physicians prior to the return of the result and within 1 month following the return of the result. Surveys were distributed through the Research Electronic Data Capture (REDCap) platform. 25 These data were supplemented with information gathered by retrospective chart review 1 to 2 months after the results were returned. Changes in psychosocial outcomes for patients and their study partners were assessed using electronic REDCap surveys or by telephone prior to, 1 to 2 weeks after, and 2 to 3 months after results were returned. 2.4. Clinical care measures In the electronic questionnaires (both before and after results were returned), physicians were asked to indicate the primary and secondary suspected diagnoses and rate their confidence in each diagnosis using a 10‐point Likert‐type scale (1 = not at all confident, 10 = extremely confident). In the pretesting survey, physicians indicated what testing they would order if the plasma p‐tau181 test were not available. In the post‐testing survey, clinicians indicated what additional diagnostic tests they planned to order. In both surveys, they were asked whether safety and care planning considerations had been discussed with the patient. Through retrospective chart review, we identified all diagnostic testing ordered; medications ordered, modified, or discontinued; and referrals made at the time of or within 1 month of result return. 2.5. Patient and care partner measures Prior to receiving the result, patients and their study partners completed questionnaires collecting demographic information and assessing anxiety and depression symptoms via the Patient‐Reported Outcomes Measurement Information System (PROMIS) Anxiety Short Form 26 and the Patient Health Questionnaire‐9 (PHQ‐9), 27 respectively. Within 1 to 2 weeks following the return of the p‐tau181 result, participants again completed the PROMIS Anxiety and PHQ‐9 surveys, in addition to a questionnaire assessing the psychological impact of receiving the result (Impact of Event Scale–Revised; IES‐R) 28 and their understanding of the result and its utility. Two to three months after receiving the results, participants completed the PROMIS Anxiety, PHQ‐9, and IES‐R surveys with additional questionnaires assessing behavior and lifestyle changes made after learning their plasma p‐tau181 results. If the participant was unable to complete the questionnaires themselves, their study partner could assist them. The study partner also completed these questionnaires separately from the patient. 2.6. Outcomes The three co‐primary outcomes were (1) change in patient management after p‐tau181 testing, defined as one or more of (a) stopping, starting, or modifying a medication for cognitive and/or behavioral symptoms; (b) counseling on safety and future planning; or (c) referring to another specialty; (2) change in the primary etiologic diagnosis; and (3) change in clinician diagnostic confidence before versus after testing. Secondary outcomes included (1) change in the use of additional diagnostic testing, such as amyloid PET or CSF biomarkers before versus after testing; (2) change in patient and study partner anxiety, depression, and psychological impact measures before versus after testing; and (3) proportion of individuals who engaged in lifestyle modification, future planning, or health‐promoting behaviors after testing. We also explored patient and study partner understanding of the p‐tau181 result and the perceived usefulness of the result. 2.7. Statistical analysis Analyses were completed using SAS software (copyright © 2025 SAS Institute Inc., Cary, NC, USA). We used descriptive statistics, mean, and standard deviation for continuous data and counts and percentages for categorical data, to summarize the demographics of the patients who participated and their responses to the understanding and utility of results questions. We used paired t ‐tests to compare pre‐ and post‐test diagnostic confidence. We used proportions testing to evaluate significant changes in primary diagnosis and management. We defined a clinically significant change as impacting more than 30% of patients tested, a threshold that has been used in similar studies of amyloid PET clinical utility, based on an assessment plan for determining Medicare coverage for PET scans. 6 , 7 , 29 Given no guidance exists on an appropriate threshold for clinical utility to use for blood tests, we used the same cutoff used in the amyloid PET studies. We then used logistic regression to assess for differences in the change in management and change in diagnosis outcomes associated with an elevated versus non‐elevated plasma p‐tau181 result, adjusting for sex, age, race, and education. We evaluated the same for the diagnostic confidence outcome using a generalized linear model, again adjusting for sex, age, race, and education. Anxiety and depression scales were evaluated using generalized estimating equations (GEE), adjusted for sex, age, race, and education. The IES was assessed using t ‐tests to compare against a score of 33, at or above which indicates probable significant psychological impact. We used McNemar tests to evaluate for significant changes in the use of amyloid PET, metabolic PET, and CSF biomarkers after plasma p‐tau181 testing. We used binomial logistic regression to evaluate the lifestyle modification, future planning, and health‐promoting behavior outcomes. 2.8. Safety monitoring The study team monitored adverse events using scheduled telephone outreach at 1 to 3 days and 2 to 3 months after the results were returned. An adverse event was defined as a patient or study partner IES‐R score ≥24, PHQ‐9 score ≥10, or PROMIS anxiety score ≥70 – indicating significant post‐results return stress, depression, or anxiety, respectively. The study primary investigator (PI) reviewed adverse events and coordinated additional support through the clinical team. 3. RESULTS One hundred thirty‐four Penn Memory Center patients were referred for plasma p‐tau181 testing. Of those, 14 declined, 15 could not be reached or did not respond to follow‐up attempts, and five were ineligible. The remaining 100 individuals consented to participate and completed a blood draw; 91 patients had a study partner. Ninety‐four patients and 87 study partners completed baseline surveys, and 98 baseline clinician surveys were completed. Ninety‐seven patients had their plasma p‐tau181 results returned, 48 via clinic visit (in person or telemedicine), 48 via telephone, and one via EHR message. Ninety‐one post‐testing clinician surveys were completed. Seventy patient surveys and 69 study partner surveys were completed at 2 to 3 months after testing (Figure 1 ). Table 1 summarizes characteristics of the patients who received plasma p‐tau181 testing and their study partners. Patients were on average 70.6 ± 8.8 years old and predominantly White (77%) and non‐Hispanic (91%). Fifty‐two percent were female, and 67% had at least a college education. Nine percent of patients participated without a study partner. Most study partners were patients’ spouses (62.6%), and 29.7% were patients’ adult children. FIGURE 1. Open in a new tab SUITABLE study recruitment and retention. TABLE 1. Participant characteristics. Characteristic Patients ( N = 100) Study partners ( N = 91) Sex, n (%) Female 52 (52) 49 (53.9) Male 44 (44) 38 (41.8) Did not respond 4 (4) 4 (4.4) Age in years, mean (SD) 70.6 (8.8) 61.1 (15.7) Race, n (%) Asian 6 (6) 6 (6.6) Black or African American 8 (8) 6 (6.6) White 77 (77) 75 (82.4) Multiple 1 (1) 0 (0) Other/Did not respond 8 (8) 4 (4.4) Ethnicity, n (%) Hispanic or Latino 5 (5) 4 (4.4) Non‐Hispanic or Latino 91 (91) 84 (92.3) Did not respond 4 (4) 3 (3.3) Education, n (%) Some college or less 27 (27) 16 (17.6) College or more 67 (67) 71 (78.0) Did not respond 6 (6) 4 (4.4) Income, n (%) $99,999 or less 28 (28) 15 (16.5) $100,000 or more 51 (51) 62 (68.1) Did not respond 21 (21) 14 (15.4) Participated with study partner, n (%) Yes 91 (91) No 9 (9) Relationship to patient, n (%) Spouse 57 (62.6) Adult child 27 (29.7) Sibling 1 (1.1) Other 3 (3.3) Did not respond 3 (3.3) Plasma p‐tau181 result, n (%) < 14.2 (not elevated) 19 (19) ≥ 14.2 (elevated) 81 (81) Open in a new tab Abbreviations: p‐tau181, tau phosphorylated at threonine 181; SD, standard deviation. 3.1. Clinical diagnosis and management outcomes Twenty‐eight patients (28%) had a change in management after plasma p‐tau181 testing (Table 2 ). This did not exceed the 30% threshold for clinically significant change ( p = 0.33). There was no difference in the likelihood of having a change in management with an elevated versus non‐elevated plasma p‐tau181 result (adjusted odds ratio [OR] 1.27, 95% confidence interval [CI] 0.32 to 5.06, p = 0.74). Of the 93 patients for whom post‐testing clinician surveys were completed, 16 (17.2%) had a change in primary diagnosis after plasma p‐tau181 testing, significantly less than the 30% threshold ( p = 0.004). Patients with an elevated result were less likely to have a change in diagnosis compared to patients with a non‐elevated result (adjusted OR 0.08, 95% CI 0.01 to 0.47, p = 0.005). Figure 2 depicts the changes in primary diagnosis across elevated and non‐elevated p‐tau181 results. Clinician diagnostic confidence significantly increased after plasma p‐tau181 testing (mean difference 1.43, 95% CI 1.02 to 1.84, p < 0.0001). The change in diagnostic confidence for elevated results was lower compared to non‐elevated results ( β = −1.15, 95% CI −2.32 to 0.03, p = 0.057), but this was not significant. TABLE 2. Clinical care and use of diagnostic testing. Outcome Elevated p‐tau181 ( N = 77) a Not elevated p‐tau181 ( N = 16) a Adjusted OR or estimate (95% CI) b p ‐value Diagnostic confidence– Mean (SD) −1.15 (−2.32, 0.03) 0.057 Before 5.80 (1.80) 6.00 (1.41) After 7.01 (1.96) 8.25 (1.53) Primary diagnosis change, n (%) 11 (14.29) 5 (31.25) 0.08 (0.01, 0.48) 0.0053 Management change, n (%) 24 (29.63) 4 (21.05) 1.32 (0.33, 5.28) 0.70 Metabolic PET use, n (%) 3.54 (0.32, 39.3) 0.30 Before 8 (9.88) 0 (0) After 1 (1.23) 1 (5.26) Amyloid PET use, n (%) 0.25 (0.07, 0.86) 0.028 Before 36 (44.44) 12 (63.16) After 11 (13.58) 1 (5.26) CSF testing use, n (%) 1.53 (0.37, 6.38) 0.56 Before 15 (18.52) 3 (15.79) After 15 (18.52) 0 (0) Open in a new tab a N = 93 for completed pre‐ and post‐testing clinician surveys. b Logistic regression or generalized linear model adjusted for sex, age, race, and education. Abbreviations: CSF, cerebrospinal fluid; PET, positron emission tomography;:p‐tau181, tau phosphorylated at threonine 181; SD, standard deviation. FIGURE 2. Open in a new tab Primary diagnosis before and after plasma p‐tau181 testing. (A) Primary diagnosis change before and after p‐tau181 testing for an elevated p‐tau181 result. (B) Primary diagnosis change before and after p‐tau181 testing for a non‐elevated p‐tau181 result. AD, Alzheimer's disease; FTD, frontotemporal dementia; LBD, Lewy body dementia; LATE, limbic‐predominant age‐related TDP‐43 encephalopathy; Vasc, vascular cognitive impairment; Non‐degen, non‐neurodegenerative. Before plasma p‐tau181 testing, clinicians reported they would use spinal fluid biomarkers for 18% of patients if the plasma biomarker was not available. After receiving the p‐tau181 results, clinicians recommended spinal fluid biomarker testing for 15% of patients. This difference was not significant ( χ 2 = 0.33, p = 0.70). For amyloid PET scans, clinicians reported they would order this test for 48% of patients if plasma p‐tau181 testing was not available. After receiving the p‐tau181 results, significantly fewer patients (12%) had an amyloid PET scan ordered ( χ 2 = 28.17, p < 0.0001). Clinicians indicated they would use metabolic PET scans for 8% of patients beforep‐tau181 testing, and 2% of patients had this test ordered after p‐tau181 testing ( χ 2 = 3.6, p = 0.0045). Logistic regression showed no difference in change in the use of spinal fluid biomarkers for elevated versus non‐elevated plasma p‐tau181 results (adjusted OR = 1.48, 95% CI 0.35 to 6.14, p = 0.59), but an elevated result was less likely to result in a change in the use of amyloid PET compared to a non‐elevated result (adjusted OR 0.26, 95% CI 0.08 to 0.90, p = 0.034). 3.2. Patient and study partner impact At 1 to 2 weeks after the results were returned, the median patient IES‐R score was 6 (interquartile range [IQR] 12.5), and it was 2 (IQR 10.75) 2 to 3 months after the results were returned. The median study partner IES‐R score was 6 (IQR 13) 1 to 2 weeks after the results were returned and 4 (IQR 8) 2 to 3 months after the results were returned. The average IES‐R scores were significantly below the threshold (≥33) for possible post‐traumatic stress related to results return ( p < 0.0001 for patients and study partners at both post‐results return time points). Table 3 shows PROMIS Anxiety and PHQ‐9 scores across patients and study partners, stratified by elevated versus non‐elevated plasma p‐tau181 result. GEE models showed no change in depression scores for patients and study partners or for study partner anxiety scores at each post‐results return visit. Patient anxiety scores were higher at the 2‐ to 3‐month visit for those with an elevated p‐tau181 result (estimate 4.04, 95% CI 0.80 to 7.29, p = 0.015). TABLE 3. Patient and study partner wellbeing. Patients Study partners Measure Elevated p‐tau181 ( N = 78) a Non‐elevated p‐tau181 ( N = 16) b p ‐value c Elevated p‐tau181 ( N = 73) d Non‐elevated p‐tau181 ( N = 13) e p ‐value c PROMIS Anxiety ‐ median (IQR) Baseline 16 (10.75) 15.5 (8.75) 0.87 12 (8) 14 (10) 0.53 1 to 2 weeks after result return 14.5 (12) 16 (9) 0.87 13 (8) 18 (12.5) 0.45 2 to 3 months after result return 14 (12) 13 (9) 0.01 12 (8) 16.5 (8.25) 0.16 PHQ‐9, median (IQR) Baseline 3 (5) 5.5 (6.5) 0.43 1 (3) 3 (3) 0.33 1 to 2 weeks after results return 3 (5.75) 6 (4) 0.71 1 (3) 3 (3.5) 0.36 2 to 3 months after results return 3 (5) 4 (5.75) 0.81 1 (3) 4 (3.5) 0.16 IES‐R, median (IQR) 1 to 2 weeks after results return 5.5 (12) 7 (15) 0.35 6 (13) 1.5 (3.75) 0.85 2 to 3 months after results return 2 (11.5) 0 (3.5) 0.04 4 (8.5) 2.5 (7.5) 0.52 Open in a new tab a N = 78 at baseline, N = 70 at 1 to 2 weeks after results return, and N = 71 at 2 to 3 months after results return. b N = 16 at baseline, N = 13 at 1 to 2 weeks after results return, and N = 13 at 2–3 months after results return. c Generalized estimating equation with p‐tau181 result (elevated or not elevated), visit, and interaction as fixed effects, adjusted for sex, age, race, and education. d N = 73 at baseline, N = 65 at 1 to 2 weeks after results return, and N = 67 at 2–3 months after results return. e N = 13 at baseline, N = 11 at 1 to 2 weeks after results return, and N = 10 at 2 to 3 months after results return. Abbreviations: IES, impact of events scale; IQR, interquartile range; PHQ, patient health questionnaire; PROMIS, patient‐reported outcomes measurement information system. No difference was found in the number of health behavior, future planning, living arrangement, or employment and lifestyle changes made or considered between those with an elevated versus non‐elevated plasma p‐tau181 result (Table 4 ). TABLE 4. Health behaviors and future planning. Domain Elevated p‐tau181 result ( N = 70) Not elevated p‐tau181 result ( N = 11) Adjusted OR (95% CI) a p ‐value Health behavior changes, median (IQR) 2.5 (4) 5 (6) 0.94 (0.56, 1.58) 0.82 Future planning changes, median (IQR) 1 (5) 0 (5) 1.82 (0.98, 3.36) 0.06 Living arrangement changes, median (IQR) 0 (1) 0 (1) 1.47 (0.57, 3.82) 0.43 Employment and lifestyle changes, median (IQR) 1.5 (4) 4 (6) 0.78 (0.46, 1.31) 0.34 Open in a new tab a Binomial logistic regression adjusted for age, sex, race, and education Abbreviations: CI, confidence interval; IQR, interquartile range; OR, odds ratio; p‐tau181, tau phosphorylated at threonine 181. 3.3. Results comprehension and perceived utility As above, an elevated plasma p‐tau181 result is not reliable enough to confirm the presence of AD pathology, but a non‐elevated result is sufficient to rule out AD pathology. We asked patients and their study partners about their understanding of the test result. Of the 71 patients with an elevated plasma p‐tau181 result who responded to the 2‐ to 3‐month survey, 50.7% correctly recalled whether the result was elevated or non‐elevated, compared to 81.8% correct recall in the 11 patients with a non‐elevated p‐tau181 level. Of the 67 study partners of patients with elevated p‐tau181 who completed the 2‐ to 3‐month survey, 62.7% correctly recalled the result, compared to 80% of the 10 responding study partners of patients with a non‐elevated result. Patients with an elevated result had variable interpretation of the result: 25.4% believed the result indicated their changes in cognition were more likely due to AD, 16.9% believed the result indicated their changes in cognition were less likely due to AD, and 57.7% were unsure. Seventy‐two percent of patients with a non‐elevated result believed it indicated their cognitive changes were less likely due to AD, and 27% were unsure. A higher proportion of study partners (47.8%) felt an elevated result indicated greater likelihood that AD was the cause of the patient's symptoms, 20.9% thought AD was less likely the cause, and 31.3% were unsure. Eighty0 percent of study partners felt the non‐elevated result meant that AD was less likely the cause of the patient's symptoms, and 20% were unsure. Overall, 47.6% of patients and 58.4% of study partners felt the plasma p‐tau181 result was useful. For patients, 42.3% of those with an elevated result and 81.8% of those with a non‐elevated result found the test to be useful. For study partners, 58.2% of those whose loved ones received an elevated result, and 60.0% of those whose loved ones received a non‐elevated result found the test to be useful. 3.4. Adverse events Twenty patients (17 with an elevated result and three with a non‐elevated result) and 15 study partners (13 for patients with an elevated result and two for patients with a non‐elevated result) experienced significant emotional or psychological distress after learning the plasma p‐tau181 result. The majority of these patients (90%) and study partners (73%) had mild distress, and the remainder had moderate distress. No patients or study partners experienced severe distress after learning the plasma p‐tau181 result. 4. DISCUSSION This prospective observational study examined the clinical utility of a plasma p‐tau181 biomarker in a memory center. Of the 100 patients enrolled, 81 had an elevated plasma p‐tau181 result. Plasma p‐tau181 testing increased diagnostic confidence but was not associated with a clinically significant change in diagnosis or patient management. A non‐elevated plasma p‐tau181 result was more likely to be associated with a change in diagnosis and reduction in the use of amyloid PET. Patients and study partners had varied emotional responses to learning the p‐tau181 result. Higher anxiety was seen in patients with an elevated p‐tau181 result at 2 to 3 months after the results were returned compared to those with non‐elevated results. No differences were seen between study partners of patients with elevated versus non‐elevated results. There were no differences in adoption of health, lifestyle, or employment changes for elevated versus non‐elevated results. Patient and study partners’ understanding and rating of utility of the plasma p‐tau181 result was greater for non‐elevated results, which is expected given the high sensitivity and low specificity of the test. These findings provide valuable insights into the clinical implementation of plasma AD biomarkers in specialty memory centers. Several studies have examined the clinical utility of amyloid PET, 6 , 7 , 30 including the Imaging Dementia—Evidence for Amyloid Scanning (IDEAS) study, which showed that amyloid PET resulted in a change in diagnosis in over 60% of cases and a change in diagnosis in 35.6% of cases. 6 There are few studies examining the clinical utility of blood‐based AD biomarkers. A survey‐based study of the clinical utility of the PrecivityAD2 blood test (C2N Diagnostics, St. Louis, MO, USA) found that the test increased clinician diagnostic confidence, guided ATT treatment decisions, and/or modulated use of amyloid PET scans in 75% of cases. 31 We found a lesser impact of plasma p‐tau181 on diagnostics and management in our center compared to the impact of amyloid PET and the PrecivityAD2 blood test, likely due to the low specificity of the plasma p‐tau181 assay. However, given the high sensitivity of the test, we appropriately observed a significant association between a non‐elevated result and a change in primary diagnosis and in the use of amyloid PET. Our findings support the hypothesis that blood‐based AD biomarkers could yield cost savings from reduction in use of amyloid PET. 32 To our knowledge, this is the first study to evaluate the impact of learning a blood‐based AD biomarker result on patients and their care partners. Several studies have examined individuals’ reactions to learning their or their loved ones’ amyloid PET results in cognitively impaired and unimpaired individuals. 33 , 34 , 35 , 36 , 37 , 38 Though severe emotional disturbance is rare, patients and their families can experience increased anxiety with knowledge of an elevated or positive AD biomarker result, as we observed in our patient cohort at 2 to 3 months after disclosure. Our findings are consistent with what has been shown in studies of returning amyloid PET results. Some individuals may experience mild or moderate increases in psychological distress after disclosure. This emphasizes the need for pretest education and post‐results return support when using blood‐based AD biomarkers. 39 Our study has several limitations. The prevalence of AD in our memory center is much higher compared to a general neurology or primary care setting. Hence, we had a low proportion of non‐elevated plasma p‐tau181 results. We also could not use an elevated result as confirmation of the presence of brain amyloid due to the low specificity (and therefore high false positive rate). While these findings suggest that a low specificity assay is less useful in a specialized memory center, they are not generalizable to clinical settings where the prevalence of AD is lower. A high‐performing rule‐out test may have greater clinical utility in a setting with low AD prevalence. The plasma p‐tau181 assay used for this study has a specificity below what is recommended for use as a triaging test in specialty care settings. 40 , 41 Additionally, in the months after this study was conducted, plasma p‐tau217 assays were shown to have the highest performance for detection of cerebral amyloid and thus are now favored over p‐tau181 assays. 12 Recent guidelines recommend triaging blood‐based AD biomarker tests have a sensitivity of ≥90% and a specificity ≥75%, and confirmatory tests must have both a specificity and sensitivity ≥90%. Additional studies are needed to examine the impact of blood tests with higher specificity, such as high‐performing p‐tau217 assays, in both primary and specialty care. Our study is further limited by loss to follow‐up at the post‐results return time points. This reduced our ability to detect significant impacts on psychological wellbeing, particularly at the 2‐ to 3‐month timepoint, and on lifestyle modification and future planning. We also did not collect data on what information was shared with the patient and their study partner during the p‐tau181 result return visit conducted by their referring clinician. Thus, it is difficult to interpret the patient's and family's understanding and perceived utility of the results. Additionally, cognitive impairment may have impeded a patient's recall or understanding of their p‐tau181 biomarker result. In future studies, standardizing delivery of biomarker test results – such as through self‐guided modules – in addition to providing pretest education, as was done in this study, can support assessment of test understanding and perceived utility. Despite these limitations, we demonstrated that plasma p‐tau181 testing impacted both diagnostic confidence and the diagnostic evaluation in a specialty setting. Further demonstration of blood‐based AD biomarkers’ clinical utility may support their adoption in primary and specialty care settings and build evidence to support insurance coverage of these tests. CONFLICT OF INTEREST STATEMENT Dr. O'Brien has received honoraria from Eli Lilly. Dr. Karlawish has served as a consultant for Biogen and was on the advisory board for Linus Health. The other authors have nothing to disclose. CONSENT STATEMENT All human subjects provided informed consent. Supporting information Supporting Information TRC2-12-e70207-s001.pdf (1.1MB, pdf) ACKNOWLEDGMENTS Dr. O'Brien has received honoraria from Eli Lilly. Dr. Karlawish has served as a consultant for Biogen and was on the advisory board for Linus Health. The other authors have nothing to disclose. The authors thank Quanterix Corporation for providing the plasma p‐tau181 assay. This work was supported by the University of Pennsylvania Institute on Aging Joseph A. Brennan Research Scholar Award. REFERENCES 1. 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