Key Points
Question
Does earlier disclosure of blood-based biomarkers improve etiologic diagnostic certainty and clinical management in patients evaluated for cognitive symptoms in a memory clinic?
Findings
In this randomized clinical trial including 220 participants, earlier disclosure of plasma phosphorylated tau at threonine 217 (p-tau217) and neurofilament light chain increased etiologic diagnostic certainty and was associated with earlier initiation of symptomatic Alzheimer disease treatment, fewer planned follow-up neuropsychological reassessments, and more planned discharge to primary care. Earlier disclosure was not associated with increased anxiety, depressive symptoms, perceived stress, or worse quality of life.
Meaning
Earlier integration of blood-based biomarkers into memory clinic workflows increases etiologic diagnostic certainty and supports earlier and more targeted clinical management without increasing psychological distress.
This randomized clinical trial evaluates whether earlier disclosure of plasma phosphorylated tau at threonine 217 and neurofilament light chain affects diagnostic certainty and clinical management.
Abstract
Importance
Blood-based biomarkers show high performance for detecting Alzheimer disease (AD) pathology, but evidence on their impact on diagnostic certainty, clinical management, and emotional outcomes in routine care is limited.
Objective
To determine whether earlier disclosure of plasma phosphorylated tau at threonine 217 (p-tau217) and neurofilament light chain (NfL) increases etiologic diagnostic certainty, influences clinical management, and affects emotional outcomes in individuals evaluated for cognitive symptoms.
Design, Setting, and Participants
This was a prospective randomized clinical trial conducted at a single memory clinic in Spain between February and October 2024, with 9 months of follow-up. Consecutive new outpatients with subjective cognitive decline (SCD), mild cognitive impairment (MCI), or mild dementia without a prior etiologic diagnosis were enrolled. Of 265 eligible participants, 220 were randomized to earlier disclosure of blood-based biomarkers at the 3-month visit or delayed disclosure at the 9-month visit.
Intervention
Disclosure of blood-based biomarkers for AD pathology (p-tau217) and neurodegeneration (NfL) to the treating neurologist and participant, alongside standard clinical evaluation.
Main Outcomes and Measures
The primary outcome was the proportion of participants achieving a very high-confidence etiologic diagnosis (≥90%). Secondary outcomes included changes in clinical management and emotional outcomes (anxiety, depression, perceived stress, and quality of life).
Results
Among the 220 randomized participants (median [IQR] age, 73 [68-78] years; 123 [55.9%] women), baseline diagnoses were SCD (100 [45.5%]), MCI (68 [30.9%]), and mild dementia (52 [23.6%]). At 3 months, a very high-confidence etiologic diagnosis was achieved in 56 of 112 participants in the earlier-disclosure arm (50.0%) compared with 5 of 108 in the delayed-disclosure arm (4.6%) (P < .001). Diagnostic certainty converged after disclosure in both arms, except among participants with MCI, in whom higher certainty persisted in the earlier-disclosure arm. Earlier disclosure was associated with more frequent initiation of symptomatic AD treatment (16/112 [14.3%] vs 5/108 [4.6%]; difference, 9.7; 95% CI, 1.8 to 17.8; P = .01), fewer planned follow-up neuropsychological reassessments for diagnostic clarification (34/112 [30.4%] vs 57/108 [52.8%]; difference, −22.4; 95% CI, −34.4 to −9.4; P < .001), and more planned discharge from the memory clinic to primary care (35/112 [31.3%] vs 13/108 [12.0%]; difference, 19.2; 95% CI, 8.4 to 29.5; P < .001). Earlier disclosure was not associated with worse emotional outcomes.
Conclusions and Relevance
In this randomized clinical trial, earlier disclosure of blood-based biomarkers increased etiologic diagnostic certainty and led to earlier, targeted clinical management without increasing emotional distress. These findings support the integration of blood-based biomarkers into memory clinic diagnostic pathways.
Trial Registration
ClinicalTrials.gov Identifier: NCT06246019
Introduction
Accurate etiologic diagnosis in patients presenting to memory clinics remains challenging. Clinical evaluation is indispensable, but has limited accuracy compared with neuropathologic confirmation, and diagnostic uncertainty may delay counseling, therapeutic decisions, and access to clinical trials. Cerebrospinal fluid (CSF) and amyloid positron emission tomography (PET) biomarkers are the reference standards for detecting Alzheimer disease (AD) pathology, but their use is limited by cost, perceived invasiveness, and scalability.
Blood-based biomarkers have emerged as accurate tools for the in vivo detection of AD pathology. Plasma phosphorylated tau at threonine 217 (p-tau217) consistently shows the highest accuracy for identifying AD pathology and is correlated with CSF and PET. Plasma neurofilament light chain (NfL), although not specific for AD, may provide complementary information regarding neurodegeneration. These advances have led to consensus recommendations and clinical practice guidance on the use of blood-based biomarkers in specialized care settings.
However, diagnostic performance alone does not establish clinical utility. Evidence remains limited regarding whether blood-based biomarkers improve outcomes relevant to clinicians and patients, such as diagnostic certainty, management decisions, and emotional responses to biomarker disclosure. Large pragmatic studies of amyloid PET implementation, such as the Imaging Dementia—Evidence for Amyloid Scanning (IDEAS) study and the Amyloid Imaging to Prevent Alzheimer’s Disease Diagnostic and Patient Management Study (AMYPAD-DPMS), demonstrated that biomarker disclosure can meaningfully influence diagnostic confidence and clinical management, underscoring the importance of evaluating clinical impact beyond diagnostic accuracy. A perspective warned that implementation of blood-based biomarkers in clinical practice may be premature without data on patient-relevant outcomes. To date, several studies have evaluated their use as part of diagnostic workups in memory clinics, with most reporting increased diagnostic confidence or changes in management but without randomized designs or concurrent control groups.
The Clinical Impact of the Novel Alzheimer’s Blood-Based Biomarkers (PLASMAR) trial aimed to address this evidence gap using a prospective randomized design to compare earlier vs delayed disclosure of blood-based biomarkers in patients presenting with cognitive symptoms in a memory clinic of a public hospital. We hypothesized that earlier disclosure would increase etiologic diagnostic certainty, influence clinical management, and not worsen patient-reported emotional outcomes.
Methods
Ethical Considerations
All participants provided written informed consent. The study protocol was approved by the clinical research ethics committee of Hospital del Mar and was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines.
Study Design
PLASMAR was a prospective, single-center randomized clinical trial evaluating the clinical impact of blood-based biomarkers in a memory clinic. The trial was registered at ClinicalTrials.gov (NCT06246019) before enrollment and is reported in accordance with the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline. The full protocol and statistical analysis plan are available in Supplement 1.
Setting and Participants
All consecutive new outpatients presenting with cognitive or behavioral complaints at the Cognitive and Behavioral Neurology Unit, Hospital del Mar, Barcelona, Spain, were screened for eligibility between February 13 and October 16, 2024 (Figure 1). Participants who met predefined inclusion criteria (eTable 1 in Supplement 2) were invited to participate. The target sample size was 200 evaluable participants (100 per group), based on the primary end point of the proportion of participants achieving a very high-confidence etiologic diagnosis at visit 1 and assuming a 2-sided α of .05 and 80% power. Recruitment continued beyond this target to account for anticipated attrition (eMethods in Supplement 2).
Figure 1. CONSORT Flow Diagram.
Some individuals had more than 1 reason for ineligibility; therefore, the sum of reported reasons may exceed the number of participants who did not meet the eligibility criteria. The 220 randomized participants constituted the prespecified intention-to-treat population used for all primary, secondary, and exploratory analyses. Sensitivity analyses of the primary outcome were performed in the per-protocol population (n = 170) and yielded results consistent with those of the intention-to-treat analyses (eTable 5 in Supplement 2). eTable 2 in Supplement 2 summarizes the demographic and clinical characteristics of the consented, intention-to-treat, and per-protocol populations. Visit 1 was at 3-month follow-up and visit 2 at 9-month follow-up. AD indicates Alzheimer disease; GDS, Global Deterioration Scale.
Study Visits, Procedures, and Randomization
Participants attended up to 4 visits: screening, baseline, and follow-up visits at 3 months (visit 1) and 9 months (visit 2). Visit 1 had an allowable window of ±1 month. Visit 2 occurred no earlier than 9 months after baseline, with an allowable window of up to 2 additional months to accommodate routine clinical scheduling while preserving temporal separation between the earlier- and delayed-disclosure arms. The study was embedded within the routine diagnostic pathway of the memory clinic, and all participants were evaluated according to the unit’s predefined standard-of-care protocols (eMethods in Supplement 2). Before visit 1, all participants underwent standard clinical evaluation, including neurological assessment, formal neuropsychological assessment, structural neuroimaging (computed tomography or magnetic resonance imaging), and laboratory testing to exclude reversible causes of cognitive impairment. Etiologic investigations, including lumbar puncture for CSF biomarkers, amyloid PET, fluorodeoxyglucose PET, or additional neuropsychological reassessments, were requested when clinically indicated at the discretion of the treating neurologist. Study-specific procedures comprised blood-based biomarker sampling, structured questionnaires, standardized follow-up, and randomized disclosure timing. The schedule of study visits and timing of biomarker disclosure is shown in eFigure 1 in Supplement 2.
At screening, eligibility was confirmed, written informed consent was obtained, and venous blood was collected for plasma p-tau217 and NfL measurements. The baseline visit occurred within 12 weeks of screening and was concurrent with the screening visit if the standard-of-care diagnostic evaluation was available (119/220 [54.1%] screening and baseline visit conducted at the same time). At baseline, participants were randomized in a 1:1 ratio to either the earlier-disclosure or delayed-disclosure arm using a computer-based minimization algorithm. The algorithm balanced sex, treating neurologist, and plasma p-tau217 category. Because plasma p-tau217 was included in the algorithm, p-tau217 measurements were required before randomization (eMethods in Supplement 2). Blood-based biomarker results were disclosed to the treating neurologist and the participant at visit 1 in the earlier-disclosure arm and at visit 2 in the delayed-disclosure arm. All treating neurologists, study personnel, patients, and study partners were blinded to blood-based biomarker results until the assigned disclosure visit, except for the study coordinator (L.D.M.; Supplement 2). Detailed information on clinical assessments, questionnaires, blood-based biomarker measurements, cutoffs, and disclosure procedures is provided in the eMethods in Supplement 2.
Outcomes
Outcomes were prespecified in the study protocol (Supplement 1) and ClinicalTrials.gov registration. The primary outcome was the proportion of participants achieving a very high-confidence etiologic diagnosis (≥90%), as assessed by the treating neurologist at visit 1 (primary comparison), with reassessment at visit 2 to evaluate convergence after disclosure. Secondary outcomes included changes in etiologic diagnosis, clinician-rated diagnostic certainty, clinician-estimated probabilities of AD or another neurodegenerative disease as the cause of symptoms, clinical management (including therapeutic decisions and clinician-reported intended management [planned diagnostic investigations, planned follow-up, and discharge from the memory clinic]), and participant-reported emotional outcomes. Subgroup and stratified analyses were exploratory.
Statistical Analysis
The primary analyses were conducted in the intention-to-treat population, defined as all randomized participants (Figure 1). Analyses followed the prespecified statistical analysis plan, with deviations described in Supplement 1.
Baseline characteristics were summarized using medians with IQRs for continuous variables, and counts with percentages for categorical variables. Between-arm comparisons used Wilcoxon rank sum tests for continuous variables and χ2 or Fisher exact tests for categorical variables.
For the primary outcome, the prespecified between-arm comparison was conducted at visit 1, corresponding to blood-based biomarker disclosure in the earlier-disclosure arm and nondisclosure in the delayed-disclosure arm, using Fisher exact tests. Diagnostic certainty was also evaluated at visit 2 and after disclosure in both arms (visit 1 for earlier disclosure and visit 2 for delayed disclosure) to assess temporal changes and convergence. Prespecified exploratory subgroup analyses by baseline clinical syndrome (SCD, MCI, mild dementia) and biomarker category (plasma p-tau217: low, intermediate, or high likelihood; NfL: low or high likelihood) used the same approach. Changes in diagnostic certainty as a continuous variable were compared between arms using 2-sample t tests.
Secondary outcomes included clinical management (therapeutic decisions and clinician-reported intended management) and participant-reported emotional outcomes. Between-arm differences were assessed at visit 1 using Fisher exact tests for categorical variables. Within-arm changes in participant-reported emotional scales between consecutive visits were assessed using Wilcoxon signed-rank tests, and between-arm differences in change scores using Wilcoxon rank sum tests.
All statistical tests were 2-sided, with P < .05 considered statistically significant. No adjustment was made for multiple comparisons. Analyses were performed using R version 4.4.2 (R Foundation).
Results
Baseline Characteristics of the Study Population
A total of 384 individuals were prospectively and consecutively screened for eligibility, 265 met eligibility criteria, and 229 provided written informed consent and were enrolled (Figure 1). Nine participants lacked available plasma p-tau217 results; the remaining 220 (96.1%) were randomized and comprised the intention-to-treat population. Reasons for ineligibility, declining participation, and noncompletion of protocol-defined follow-up are summarized in Figure 1.
Baseline characteristics are summarized in Table 1. The median (IQR) age was 73 (68-78) years; 123 [55.9%] were women and 97 [44.1%] were men. At baseline, 100 (45.5%) had SCD, 68 (30.9%) had MCI, and 52 (23.6%) had mild dementia. Baseline characteristics and biomarker categories were well balanced between the earlier- (n = 112) and delayed-disclosure (n = 108) arms and were similar across the intention-to-treat population, per-protocol population, and consented participants not included in the per-protocol population (eTable 2 in Supplement 2).
Table 1. Baseline Characteristics of the Participants.
| Characteristica | Total randomized cohort (N = 220) | Earlier disclosure (n = 112) | Delayed disclosure (n = 108) | P valueb |
|---|---|---|---|---|
| Age, median (IQR), y | 73 (68-78) | 73 (68-78) | 74 (68-77) | .98 |
| Sex, No. (%) | ||||
| Male | 97 (44.1) | 50 (44.6) | 47 (43.5) | .97 |
| Female | 123 (55.9) | 62 (55.4) | 61 (56.5) | |
| Race and ethnicity, No. (%) | ||||
| Latin American | 19 (8.6) | 11 (9.8) | 8 (7.4) | .82 |
| White European | 197 (89.5) | 99 (88.4) | 98 (90.7) | |
| Otherc | 4 (1.8) | 2 (0.9) | 2 (0.9) | |
| Education, median (IQR), y | 8 (6-12) | 8 (6-12) | 8 (6-12) | .98 |
| Family history of dementia, No. (%) | 84 (38.2) | 43 (38.4) | 41 (38.0) | .97 |
| Clinical syndrome at baseline, No. (%) | ||||
| SCD | 100 (45.5) | 47 (42.0) | 53 (49.1) | .48 |
| MCI | 68 (30.9) | 38 (33.9) | 30 (27.8) | |
| Mild dementia | 52 (23.6) | 27 (24.1) | 25 (23.1) | |
| Likelihood of AD according to blood p-tau217 levels, No. (%) | ||||
| Low | 123 (55.9) | 62 (55.4) | 61 (56.5) | .42 |
| Intermediate | 31 (14.1) | 13 (11.6) | 18 (16.7) | |
| High | 66 (30.0) | 37 (33.0) | 29 (26.9) | |
| Likelihood of ND according to blood NfL levels, No. (%) | ||||
| Low | 183 (83.2) | 88 (78.6) | 95 (88.0) | .06 |
| High | 37 (16.8) | 24 (21.4) | 13 (12.0) | |
| Kidney function | ||||
| eGFR (CKD-EPI), median (IQR), mL/min/1.73 m2 | 80 (64-88) | 80 (67-87) | 78 (63-88) | .67 |
| Creatinine, median (IQR), mg/dL | 0.85 (0.71-1.01) | 0.85 (0.74-0.99) | 0.85 (0.69-1.05) | .99 |
Abbreviations: AD, Alzheimer disease; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; eGFR, estimated glomerular filtration rate; MCI, mild cognitive impairment; ND, neurodegenerative disease; NfL, neurofilament light chain; p-tau217, phosphorylated tau at threonine 217; SCD, subjective cognitive decline.
Additional clinical characteristics, including comorbidities and medication use, are presented in eTable 4 in Supplement 2. Baseline characteristics of the per-protocol population (n = 170) are presented in eTable 2 in Supplement 2.
Between-arm comparisons were performed using Wilcoxon rank sum tests for continuous variables and χ2 or Fisher exact tests for categorical variables, as appropriate.
Including other (not specified) and unreported/unknown, consolidated owing to small numbers.
Baseline biomarker categories by clinical diagnosis are summarized in eTable 3 in Supplement 2. Based on plasma p-tau217, high likelihood of AD pathology was more frequent among participants with baseline AD working diagnoses, whereas low likelihood of AD pathology was common among participants with SCD or nonneurodegenerative working diagnoses.
Median (IQR) time from baseline to visit 1 was 100.5 (91-113) days in the earlier-disclosure arm and 105 (91-113) days in the delayed-disclosure arm (P = .89). Median (IQR) time from baseline to visit 2 was 273.5 (273-287) days and 274 (273-283) days, respectively (P = .84). Additional clinical characterization is provided in eTable 4 in Supplement 2.
Primary Outcomes: Etiologic Diagnosis Certainty
At visit 1, corresponding to biomarker disclosure in the earlier-disclosure arm, the proportion of participants with a very high-confidence etiologic diagnosis (≥90%) was significantly higher in the earlier-disclosure arm than in the delayed-disclosure arm (56/112 [50.0%] vs 5/108 [4.6%], respectively; P < .001) (Figure 2A). No between-arm differences were observed at baseline (earlier disclosure: 6/112 [5.4%] vs delayed disclosure: 5/108 [4.6%]; P > .99) or at visit 2 (earlier disclosure: 65/112 [58.0%] vs delayed disclosure: 57/108 [52.8%]; P = .43). After disclosure in both arms (visit 1, earlier disclosure; visit 2, delayed disclosure), the proportion achieving a very high-confidence etiologic diagnosis was similar (earlier disclosure: 56/112 [50.0%] vs delayed disclosure: 57/108 [52.8%]; P = .68) (Table 2). Sensitivity analyses of the primary outcome in the per-protocol population (n = 170) yielded results consistent with the intention-to-treat analyses (eTable 5 in Supplement 2).
Figure 2. Box Plots Showing Diagnostic Certainty and Clinician-Estimated Probability of Alzheimer Disease and Neurodegenerative Disease by Study Arm Across Visits.
A, Clinician-rated diagnostic certainty for the selected etiologic diagnosis. B, Clinician-estimated probability that Alzheimer disease was the underlying cause of symptoms. C, Clinician-estimated probability that a neurodegenerative disease was the underlying cause of symptoms across Clinical Impact of the Novel Alzheimer's Blood-Based Biomarkers (PLASMAR) study visits. Very high-confidence etiologic diagnosis was defined as clinician-rated certainty ≥90% (dotted line). Diagnostic certainty was rated on a scale from 50% to 100%, with 50% representing maximum uncertainty and 100% complete certainty; clinician-estimated probabilities were rated on a scale from 0% to 100%. Analyses were conducted in the intention-to-treat population (n = 220). Between-arm comparisons were performed using Fisher exact tests.
aP < .001.
Table 2. Proportion of Participants Achieving a Very High-Confidence Etiologic Diagnosis (≥90%) by Study Arm, Time Point, and Prespecified Stratifications.
| Outcome/stratification | Between-arm comparison time | Earlier disclosure (n = 112) | Delayed disclosure (n = 108) | P valuea |
|---|---|---|---|---|
| Overall etiologic diagnosis, No. (%) | Baseline | 6 (5.4) | 5 (4.6) | >.99 |
| 3 mo | 56 (50.0) | 5 (4.6) | <.001 | |
| 9 mo | 65 (58.0) | 57 (52.8) | .43 | |
| Postdisclosure: earlier (3 mo) vs delayed (9 mo) | 56 (50.0) | 57 (52.8) | .68 | |
| Stratified by baseline clinical syndrome, No./total No. (%) | ||||
| SCD (n = 100) | 3 mo | 22/47 (46.8) | 4/53 (7.5) | <.001 |
| MCI (n = 68) | 3 mo | 23/38 (60.5) | 1/30 (3.3) | <.001 |
| Mild dementia (n = 52) | 3 mo | 11/27 (40.7) | 0/25 (0.0) | <.001 |
| Stratified by plasma p-tau217 category, No./total No. (%) | ||||
| Low likelihood of AD pathology (n = 123) | 3 mo | 38/62 (61.3) | 3/61 (4.9) | <.001 |
| Intermediate likelihood of AD pathology (n = 31) | 3 mo | 1/13 (7.7) | 2/18 (11.1) | >.99 |
| High likelihood of AD pathology (n = 66) | 3 mo | 17/37 (45.9) | 0/29 (0.0) | <.001 |
| Stratified by plasma NfL category, No./total No. (%) | ||||
| Low likelihood of ND (n = 183) | 3 mo | 48/88 (54.5) | 4/95 (4.2) | <.001 |
| High likelihood of ND (n = 37) | 3 mo | 8/24 (33.3) | 1/13 (7.7) | .13 |
Abbreviations: AD, Alzheimer disease; MCI, mild cognitive impairment; ND, neurodegenerative disease; NfL, neurofilament light chain; p-tau217, phosphorylated tau at threonine 217; SCD, subjective cognitive decline.
All subgroup comparisons were performed using data from the same time point (3 months after baseline). Between-arm comparisons were performed using Fisher exact tests.
Stratifying by baseline clinical syndrome, the visit 1 between-arm difference was observed consistently in participants with SCD (n = 100, earlier disclosure: 22/47 [46.8%] vs delayed disclosure: 4/53 [7.5%]; P < .001), MCI (n = 68, earlier disclosure: 23/38 [60.5%] vs delayed disclosure: 1/30 [3.3%]; P < .001), and mild dementia (n = 52, earlier disclosure: 11/27 [40.7%] vs delayed disclosure: 0/25 [0.0%]; P < .001). At visit 2, a significant between-arm difference persisted only among participants with MCI (earlier disclosure: 26/35 [74.3%] vs delayed disclosure: 13/28 [46.4%]; P = .04). No other between-arm differences were observed across clinical syndromes after each arm’s disclosure.
Stratification by AD pathology (determined by plasma p-tau217) showed that, at visit 1, the proportion of participants achieving a very high-confidence etiologic diagnosis was higher in the earlier-disclosure arm among those classified as having a low likelihood of AD pathology (n = 123, earlier disclosure: 38/62 [61.3%] vs delayed disclosure: 3/61 [4.9%]; P < .001) and high likelihood of AD pathology (n = 66, earlier disclosure: 17/37 [45.9%] vs delayed disclosure: 0/29 [0.0%]; P < .001), but not among those with intermediate likelihood (n = 31, earlier disclosure: 1/13 [7.7%] vs delayed disclosure: 2/18 [11.1%]; P > .99). No between-arm differences were observed at baseline, at visit 2, or after disclosure in each arm.
When stratified by neurodegeneration biomarker (plasma NfL), a visit 1 between-arm difference in the proportion of very high diagnostic certainty was observed only in participants classified as low likelihood of neurodegeneration (n = 183, earlier disclosure: 48/88 [54.5%] vs delayed disclosure: 4/95 [4.2%]; P < .001), with no difference in the high likelihood group, although this subgroup was small (n = 37, earlier disclosure: 8/24 [33.3%] vs delayed disclosure: 1/13 [7.7%], P = .13). No between-arm differences were observed at baseline, at visit 2, or after disclosure in each arm (Table 2).
Next, we examined the proportion of participants reaching ≥90% clinician-estimated probability of AD or neurodegenerative disease as the underlying etiology. At visit 1, this proportion was higher in the earlier-disclosure arm than in the delayed-disclosure arm (AD: earlier disclosure: 17/112 [15.2%] vs delayed disclosure: 0/108 [0.0%]; neurodegenerative disease: earlier disclosure: 21/112 [18.8%] vs delayed disclosure: 3/108 [2.8%]; P < .001 for both) (Figure 2B and C). These differences were not observed after disclosure in both groups. Detailed subgroup and continuous analyses are provided in eTables 6-9 in Supplement 2. Exploratory analyses stratified by median age showed generally consistent findings across younger and older participants (eTable 8 in Supplement 2).
Changes in the Etiologic Diagnosis
We examined the proportion of participants whose etiologic diagnosis changed between visits. Diagnoses were classified as AD, non-AD neurodegenerative disease, or nonneurodegenerative disease. At visit 1, diagnostic reclassification occurred more frequently in the earlier-disclosure arm than in the delayed-disclosure arm (24/103 [23.3%] vs 7/100 [7.0%], respectively; P = .002). Among participants with an initial diagnosis of AD (n = 72), reclassification was also more frequent in the earlier-disclosure arm vs the delayed-disclosure arm (11/36 [30.6%] vs 2/31 [6.5%], respectively; P = .01). No between-arm differences were observed among participants with an initial diagnosis other than AD (eFigure 2 in Supplement 2).
Changes in Clinical Management
At visit 1, therapeutic decisions differed between study arms (eFigure 3A in Supplement 2). Compared with participants in the delayed-disclosure arm, those in the earlier-disclosure arm more frequently initiated symptomatic AD pharmacologic treatment (earlier disclosure: 16/112 [14.3%] vs delayed disclosure: 5/108 [4.6%]; difference, 9.7; 95% CI, 1.8 to 17.8; P = .01) and were referred to cognitive stimulation therapy (earlier disclosure: 51/112 [45.5%] vs delayed disclosure: 33/108 [30.6%]; P = .03). Consideration for participation in clinical trials with disease-targeting therapy (DTT) was also more frequent in the earlier-disclosure arm, although the difference was not significant (earlier disclosure: 5/112 [4.5%] vs delayed disclosure: 0/108 [0.0%]; P = .06).
Clinician-reported intended follow-up plans also differed (eFigure 3B in Supplement 2): earlier disclosure was associated with more discharge to primary care (earlier disclosure: 35/112 [31.3%] vs delayed disclosure: 13/108 [12.0%]; difference, 19.2; 95% CI, 8.4 to 29.5; P < .001), whereas participants in the delayed-disclosure arm more frequently had follow-up neuropsychological reassessments planned (earlier disclosure: 34/112 [30.4%] vs delayed disclosure: 57/108 [52.8%]; difference, −22.4; 95% CI, −34.4 to −9.4; P < .001) (eTable 10 and eFigure 3B in Supplement 2). At visit 2, and after disclosure in each arm, no between-arm differences in therapeutic decisions or clinical management were observed (eTables 11 and 12 in Supplement 2).
Exploratory stratified analyses at visit 1 showed generally consistent patterns across clinical syndromes and biomarker profiles (eFigure 3C-F and eTables 13.1 and 13.2 in Supplement 2). Among participants with SCD and MCI, earlier disclosure was associated with more planned discharge to primary care (SCD: earlier disclosure: 19/47 [40.4%] vs delayed disclosure: 10/53 [18.9%]; P = .03; MCI: earlier disclosure: 11/38 [28.9%] vs delayed disclosure: 0/30 [0.0%]; P = .002) and fewer planned follow-up neuropsychological assessments for diagnostic clarification (SCD: earlier disclosure: 14/47 [29.8%] vs delayed disclosure: 35/53 [66.0%]; P < .001; MCI: earlier disclosure: 11/38 [28.9%] vs delayed disclosure: 19/30 [63.3%]; P = .01). Among participants with SCD, earlier disclosure was associated with more referrals to cognitive stimulation therapy (earlier disclosure: 10/47 [21.3%] vs delayed disclosure: 2/53 [3.8%]; P = .01) and more planned lumbar punctures for CSF AD biomarkers (earlier disclosure: 5/47 [10.6%] vs delayed disclosure: 0/53 [0.0%]; P = .02). Among participants with MCI or mild dementia, initiation of symptomatic AD treatment was more frequent in the earlier-disclosure arm, although the differences were not statistically significant (MCI, earlier disclosure: 7/38 [18.4%] vs delayed disclosure: 2/30 [6.7%], P = .28; mild dementia, earlier disclosure: 9/27 [33.3%] vs delayed disclosure: 3/25 [12.0%], P = .10) (eTable 13.1 in Supplement 2). When both cognitively impaired groups were considered together, the difference reached statistical significance (earlier disclosure: 16/65 [24.6%] vs delayed disclosure: 5/55 [9.1%]; P = .03).
Similar patterns were observed across biomarker profiles (eTable 13.2 in Supplement 2). Among participants with a low likelihood of AD pathology (p-tau217), those in the earlier-disclosure arm had higher rates of planned discharge (earlier disclosure: 28/62 [45.2%] vs delayed disclosure: 8/61 [13.1%]; P < .001), whereas those in the delayed-disclosure arm had more frequently planned follow-up neuropsychological assessments for diagnostic clarification (earlier disclosure: 17/62 [27.4%] vs delayed disclosure: 37/61 [60.7%]; P < .001). Among participants with a high likelihood of AD, initiation of symptomatic AD pharmacologic treatment was more frequent in the earlier-disclosure arm (earlier disclosure: 15/37 [40.5%] vs delayed disclosure: 1/29 [3.4%]; P < .001), as well as referral to cognitive stimulation therapy (earlier disclosure: 28/37 [75.7%] vs delayed disclosure: 13/29 [44.8%]; P = .02) (eTable 13.2 in Supplement 2).
Emotional Outcomes
Emotional outcomes were analyzed within the intention-to-treat population using available questionnaire data; sample sizes varied by instrument and comparison (eTable 14 in Supplement 2). The emotional outcome analysis outline is shown in eFigure 4 in Supplement 2, baseline characteristics are reported in eTable 14 in Supplement 2, and changes in emotional outcomes are summarized in Table 3.
Table 3. Emotional Outcomes in Participants by Study Arm and Time Pointa.
| Outcomeb | Time point/comparisonc | Earlier disclosure | Delayed disclosure | P valued |
|---|---|---|---|---|
| HADS summary score, median (IQR)e | Baseline (n = 211) | 10.5 (6.0 to 15.0) | 11.0 (6.0 to 15.0) | .99 |
| Change from baseline to V1 (n = 135) | −1.5 (−5.8 to 2.0) | −1.0 (−6.0 to 3.0) | .78 | |
| Change from V1 to V2 (n = 94) | −1.0 (−3.0 to 2.0) | −1.0 (−6.0 to 2.0) | .33 | |
| PSS score, median (IQR)f | Baseline (n = 202) | 18.0 (12.0 to 27.0) | 18.5 (11.0 to 26.3) | .79 |
| Change from baseline to V1 (n = 129) | −4.0 (−8.0 to 1.0) | 4.0 (0.0 to 11.0) | <.001 | |
| Change from V1 to V2 (n = 85) | −2.0 (−8.0 to 5.0) | −3.5 (−7.8 to 4.0) | .70 | |
| EQ-5D-5L level-sum score, median (IQR)g | Baseline (n = 205) | 8.0 (6.0 to 11.0) | 7.5 (6.0 to 10.0) | .82 |
| Change from baseline to V1 (n = 134) | −0.5 (−2.0 to 1.0) | −1.0 (−3.0 to 1.0) | .33 | |
| Change from V1 to V2 (n = 89) | 0.0 (−2.0 to 1.0) | 0.0 (−1.0 to 2.0) | .68 | |
| EQ-5D-5L analog scale score, median (IQR)h | Baseline (n = 205) | 65.0 (50.0 to 80.0) | 70.0 (50.0 to 80.0) | .68 |
| Change from baseline to V1 (n = 134) | 0.0 (−15.0 to 20.0) | 5.0 (−5.0 to 18.7) | .08 | |
| Change from V1 to V2 (n = 89) | 0.0 (−10.0 to 10.0) | 0.0 (−20.0 to 10.0) | .54 |
Abbreviations: EQ-5D-5L, European Quality of Life 5-Dimension Questionnaire; HADS, Hospital Anxiety and Depression Scale; PSS, Perceived Stress Scale; V1, visit 1 (3 mo); V2, visit 2 (9 mo).
Data are from the randomized population and include participant-reported outcomes only.
Analyses of change required questionnaire completion at both time points being compared; therefore, sample sizes differ across comparisons.
Change from baseline to V1 and change from V1 to V2 show within-participant change scores between consecutive visits.
P values compare distribution at baseline and of change scores between randomized groups using Wilcoxon rank sum tests. Within-arm changes over time were assessed using Wilcoxon signed-rank tests.
HADS consists of anxiety and depression subscales; the summary score ranges from 0 to 42 (0-21 for each subscale), with higher scores indicating greater anxiety or depressive symptom burden.
PSS assesses perceived stress (range, 0-56; higher scores indicate greater perceived stress).
The EQ-5D-5L level-sum score is the sum of the 5-dimension levels (range, 5-25; lower scores indicate fewer health problems).
The EQ-5D visual analog scale ranges from 0 to 100, with higher scores indicating better self-rated health.
For anxiety and depressive symptoms (Hospital Anxiety and Depression Scale Summary score: range, 0-42; higher scores indicate greater anxiety or depressive symptoms; n = 211), scores decreased between baseline and visit 1 in both study arms, reaching statistical significance only in the earlier-disclosure arm (earlier disclosure: median [IQR] change, –1.5 [–5.8 to 2.0] points; P = .003; delayed disclosure: median [IQR] change, –1.0 [–6.0 to 3.0] points; P = .07); however, change scores did not differ between groups. No between-arm differences were observed at visit 2 or after disclosure in both arms.
For perceived stress (Perceived Stress Scale score: range, 0-56; higher scores indicate greater perceived stress; n = 202), scores decreased in the earlier-disclosure arm (median [IQR] change, −4.0 [–8.0 to 1.0] points; P < .001), and increased in the delayed-disclosure arm (median [IQR] change, 4.0 [0.0 to 11.0] points; P < .001) between baseline and visit 1, resulting in a significant between-arm difference in Perceived Stress Scale score change at visit 1 (P < .001). No between-arm differences were observed at visit 2 or after disclosure in both arms.
Health-related quality of life (European Quality of Life 5-Dimension [EQ-5D] descriptive system summed score: range, 5–25; lower scores indicate better self-reported health; n = 205) showed small changes across visits in both study arms (earlier disclosure: median [IQR] change from baseline to visit 1: –0.5 [–2.0 to 1.0], P = .08; median [IQR] change from visit 1 to visit 2: 0.0 [–2.0 to 1.0]; P = .86 vs delayed disclosure: median [IQR] change from baseline to visit 1: –1.0 [−3.0 to 1.0], P = .02; median [IQR] change from visit 1 to visit 2: 0.0 [–1.0 to 2.0]; P = .61). No between-arm differences were observed at any visit. Similarly, self-reported quality of life on the EQ-5D visual analog scale (0-100) also remained stable in both arms across visits. Exploratory analyses stratified by biomarker category did not show significant worsening in emotional outcomes after disclosure among participants receiving either low- or high-likelihood results for AD pathology or neurodegeneration.
Discussion
In this randomized clinical trial embedded within routine memory-clinic care, earlier disclosure of blood-based biomarkers increased etiologic diagnostic certainty and influenced clinical management compared with delayed disclosure. Earlier blood-based biomarker disclosure (1) increased the proportion of patients receiving a very high-confidence etiologic diagnosis at 3 months; (2) was associated with earlier therapeutic decisions, including more frequent initiation of symptomatic AD treatment, fewer planned follow-up neuropsychological reassessments, and more planned discharge to primary care; and (3) was not associated with worse patient-reported anxiety and depressive symptoms or perceived stress. Together, these results suggest that, beyond diagnostic accuracy, blood-based biomarkers can meaningfully inform and tailor clinical decision-making in routine care.
Although plasma p-tau217 shows high diagnostic accuracy for detecting AD pathology, evidence on the clinical impact of blood-based biomarkers in routine practice remains limited. Most prior studies have relied on observational designs without concurrent control groups, such as pre-post comparisons or retrospective clinician surveys. Consequently, it remains uncertain whether reported changes in diagnostic certainty or care decisions are directly attributable to blood-based biomarkers. This study addresses this gap using a randomized earlier- vs delayed-disclosure design, similar to approaches previously applied to amyloid PET (eg, AMYPAD-DPMS), enabling more robust causal inference regarding blood-based biomarker implementation.
Earlier disclosure resulted in substantially higher proportions of very high-confidence etiologic diagnoses at 3 months, with convergence between groups after biomarker disclosure in both arms. This pattern indicates that diagnostic certainty increases promptly following blood-based biomarker disclosure, supporting their use in the diagnostic workflow. The effect was observed across clinical syndromes, with 1 notable exception: among participants with MCI, higher diagnostic certainty persisted at 9 months in the earlier-disclosure arm, possibly reflecting the greater etiologic and prognostic uncertainty in MCI, where early biological information may have a sustained anchoring effect on clinical judgment. As expected, gains in diagnostic certainty were largest at plasma p-tau217 extremes (low or high likelihood of AD) and minimal for intermediate values, consistent with a dual-cutoff framework that preserves uncertainty when results are inconclusive.
When focusing specifically on AD or neurodegenerative etiologies, earlier blood-based biomarker access increased very high clinician-estimated probabilities (≥90%) primarily in MCI and mild dementia, whereas in SCD, blood-based biomarker disclosure tended to support rule-out rather than confirmatory attribution, underscoring the importance of pretest probability in interpretation.
Beyond increasing diagnostic certainty, earlier blood-based biomarker disclosure was associated with earlier therapeutic decisions and different follow-up plans. Clinicians initiated symptomatic AD treatment and referred patients to cognitive stimulation therapy sooner, whereas consideration for participation in clinical trials of DTT was more frequent but did not reach statistical significance. Furthermore, fewer follow-up neuropsychological reassessments and more discharge to primary care were planned. These patterns indicate that earlier biological information facilitates a more decisive transition from diagnostic evaluation to management, supporting both escalation and deescalation of care according to the estimated likelihood of AD or neurodegenerative pathology. The trial was not designed to determine whether earlier symptomatic treatment initiation improved cognition, function, quality of life, or disease course. To preserve standard clinical care while blood-based biomarkers remained investigational, ancillary investigations and follow-up planning were recorded as clinician-reported intended management rather than mandated clinical actions. Higher rates of planned discharge among participants with low-likelihood biomarker profiles suggest that biomarker-informed reassurance can reduce prolonged diagnostic follow-up in individuals unlikely to have AD pathology or neurodegeneration. Although emotional responses could plausibly differ according to the biomarker result received, exploratory analyses showed no significant worsening after disclosure of either low- or high-likelihood results; however, these analyses were underpowered and should be interpreted cautiously. Conversely, delayed disclosure was associated with more planned diagnostic reassessment, consistent with continued uncertainty in the absence of biomarker information. This study included participants with SCD, a group often excluded from biomarker studies. In this population with generally low pretest probability of AD or neurodegeneration, exploratory analyses suggest that blood-based biomarkers may support clinically guided reassurance and discharge in lower-risk individuals. In the absence of clear guidance for biomarker use in SCD, these findings support a pragmatic, context-dependent implementation strategy.
Unlike most prior studies, this trial prospectively assessed patient-reported emotional outcomes following biomarker disclosure. Earlier disclosure was not associated with increased anxiety or depressive symptoms, addressing concerns about psychological harm. Earlier disclosure was associated with more favorable perceived stress trajectories, whereas no between-arm differences in quality-of-life changes were observed; delayed disclosure was associated with a transient increase in perceived stress that resolved after blood-based biomarker disclosure. These findings suggest that timely, structured biomarker communication is emotionally safe and may reduce uncertainty-related distress. Whether awareness of allocation to the delayed-disclosure arm, waiting longer for biomarker results, contributed to this transient increase in perceived stress remains uncertain.
Strengths and Limitations
This study has several strengths. The randomized earlier- vs delayed-disclosure design and intention-to-treat analysis enabled rigorous assessment of the causal effect of blood-based biomarker disclosure within a routine clinical workflow. Inclusion of patients across SCD, MCI, and mild dementia enhances clinical relevance and allows evaluation of heterogeneity across clinical phenotypes. The structured and standardized disclosure procedure is consistent with emerging best practices for biomarker communication and likely supported safe and interpretable disclosure. Additionally, the joint assessment of clinician decision-making and patient-reported emotional outcomes addresses a key gap in prior research.
Several limitations should be considered. First, this was a single-center study, which may limit generalizability to other memory clinic populations, particularly given the relatively high proportion of participants with SCD, although consecutive recruitment and embedding in routine care enhanced representativeness. Additionally, the protocol excluded pregnant or lactating participants and those planning pregnancy. Although no participants were excluded on this basis, this criterion may limit the generalizability to some younger individuals presenting with cognitive symptoms. Second, not all participants underwent reference-standard diagnostic testing for AD (CSF or amyloid PET); this was intentional, as the study aimed to evaluate clinical impact rather than diagnostic accuracy, which is already well established. Third, attrition inherent to routine clinical practice reduced the available sample size for some analyses, particularly subgroup analyses, which should therefore be interpreted cautiously. Fourth, because plasma p-tau217 and NfL were disclosed together, their independent contributions cannot be disentangled, although stratified analyses provide insight into their relative informativeness. Also, kidney function and body mass index were not incorporated into blood-based biomarker disclosure, although kidney function was available to the treating neurologist as part of routine care and could be considered when interpreting blood-based biomarker results. Fifth, all participants underwent a standardized 3-month follow-up visit, whereas follow-up in routine clinical practice is individualized. Although some influence of this standardized follow-up schedule cannot be completely excluded, it was equal in both randomized groups and is therefore unlikely to explain the observed between-arm differences. Sixth, DTT for AD was not available in routine clinical practice in our country during the study. Although clinical trials with DTT were available at our site, referral for trial participation differs from routine treatment decisions, and the impact of blood-based biomarker disclosure on management may therefore differ in current clinical practice. Seventh, follow-up was limited to approximately 9 months, and longer-term clinical outcomes of blood-based biomarker disclosure remain unknown.
Conclusions
In conclusion, earlier disclosure of blood-based biomarkers increased etiologic diagnostic certainty and supported earlier clinical decision-making without evidence of psychological harm, supporting their integration into memory-clinic diagnostic pathways. These findings align with recent clinical guidance advocating careful adoption of blood-based biomarkers, with attention to context of use, test limitations, and standardized communication. Future studies should evaluate multicenter implementation, compare alternative diagnostic algorithms (eg, blood-based biomarker-first triage with confirmatory testing for intermediate or discordant cases), and assess downstream outcomes including costs, access to DTT, and equity.
Protocol and Statistical analysis plan
eTable 1. Inclusion and exclusion criteria
eTable 2. Recruitment, randomization, and analysis populations of participants in the PLASMAR trial
eTable 3. Baseline distribution of clinical diagnosis and biomarker category
eTable 4. Other demographic and clinical characteristics of PLASMAR participants at baseline
eTable 5. Very-high-confidence etiologic diagnosis (≥90%) in the per-protocol population by study arm, time point, and prespecified stratifications
eTable 6. Clinician-estimated probability of Alzheimer disease as the underlying cause (≥90%) by study arm and time point
eTable 7. Clinician-estimated probability of neurodegenerative disease as the underlying cause (≥90%) by study arm and time point
eTable 8. Very-high-confidence etiologic diagnosis and clinician-estimated probability of AD or neurodegenerative disease, stratified by median age
eTable 9.1. Changes in etiologic diagnostic certainty and clinician-estimated probability of AD and neurodegenerative disease as the underlying cause across study visits by study arm
eTable 9.2. Changes in etiologic diagnostic certainty and clinician-estimated probability of AD and neurodegenerative disease as the underlying cause across study visits by study arm, stratified by clinical syndrome
eTable 9.3. Changes in etiologic diagnostic certainty and clinician-estimated probability of AD and neurodegenerative disease as the underlying cause across study visits by study arm, stratified by plasma p-tau217 category
eTable 9.4. Changes in etiologic diagnostic certainty and clinician-estimated probability of AD and neurodegenerative disease as the underlying cause across study visits by study arm, stratified by plasma NfL category
eTable 10. Clinical management outcomes by study arm at the 3-month visit
eTable 11. Clinical management outcomes by study arm at the 9-month visit
eTable 12. Clinical management outcomes by study arm after disclosure in both arms
eTable 13.1. Clinical management outcomes by study arm at the 3-month visit, stratified by clinical syndrome
eTable 13.2. Clinical management outcomes by study arm at the 3-month visit (V1), stratified by plasma p-tau217 category
eTable 14. Baseline demographic and clinical characteristics of PLASMAR participants who completed emotional scales at baseline
eFigure 1. PLASMAR protocol-defined visits flowchart
eFigure 2. Alluvial diagram showing changes in etiologic diagnosis by study arm across visits
eFigure 3. Bar plot showing clinical management outcomes at the 3-month visit, according to study arm
eFigure 4. Emotional outcomes assessment flow diagram and analysis outline
eMethods
eAppendix 1. PLASMAR baseline questionnaire and PLASMAR follow-up questionnaire (visits1 and 2)
eAppendix 2. Hospital Anxiety and Depression Scale (HADS)
eAppendix 3. Perceived Stress Scale (PSS)
eAppendix 4. EuroQol (EQ-5D-5L)
eAppendix 5. PLASMAR infographic brochure
eReferences
Data sharing statement
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Protocol and Statistical analysis plan
eTable 1. Inclusion and exclusion criteria
eTable 2. Recruitment, randomization, and analysis populations of participants in the PLASMAR trial
eTable 3. Baseline distribution of clinical diagnosis and biomarker category
eTable 4. Other demographic and clinical characteristics of PLASMAR participants at baseline
eTable 5. Very-high-confidence etiologic diagnosis (≥90%) in the per-protocol population by study arm, time point, and prespecified stratifications
eTable 6. Clinician-estimated probability of Alzheimer disease as the underlying cause (≥90%) by study arm and time point
eTable 7. Clinician-estimated probability of neurodegenerative disease as the underlying cause (≥90%) by study arm and time point
eTable 8. Very-high-confidence etiologic diagnosis and clinician-estimated probability of AD or neurodegenerative disease, stratified by median age
eTable 9.1. Changes in etiologic diagnostic certainty and clinician-estimated probability of AD and neurodegenerative disease as the underlying cause across study visits by study arm
eTable 9.2. Changes in etiologic diagnostic certainty and clinician-estimated probability of AD and neurodegenerative disease as the underlying cause across study visits by study arm, stratified by clinical syndrome
eTable 9.3. Changes in etiologic diagnostic certainty and clinician-estimated probability of AD and neurodegenerative disease as the underlying cause across study visits by study arm, stratified by plasma p-tau217 category
eTable 9.4. Changes in etiologic diagnostic certainty and clinician-estimated probability of AD and neurodegenerative disease as the underlying cause across study visits by study arm, stratified by plasma NfL category
eTable 10. Clinical management outcomes by study arm at the 3-month visit
eTable 11. Clinical management outcomes by study arm at the 9-month visit
eTable 12. Clinical management outcomes by study arm after disclosure in both arms
eTable 13.1. Clinical management outcomes by study arm at the 3-month visit, stratified by clinical syndrome
eTable 13.2. Clinical management outcomes by study arm at the 3-month visit (V1), stratified by plasma p-tau217 category
eTable 14. Baseline demographic and clinical characteristics of PLASMAR participants who completed emotional scales at baseline
eFigure 1. PLASMAR protocol-defined visits flowchart
eFigure 2. Alluvial diagram showing changes in etiologic diagnosis by study arm across visits
eFigure 3. Bar plot showing clinical management outcomes at the 3-month visit, according to study arm
eFigure 4. Emotional outcomes assessment flow diagram and analysis outline
eMethods
eAppendix 1. PLASMAR baseline questionnaire and PLASMAR follow-up questionnaire (visits1 and 2)
eAppendix 2. Hospital Anxiety and Depression Scale (HADS)
eAppendix 3. Perceived Stress Scale (PSS)
eAppendix 4. EuroQol (EQ-5D-5L)
eAppendix 5. PLASMAR infographic brochure
eReferences
Data sharing statement
