BACKGROUND
Emerging plasma biomarkers are improving the diagnostic approach to Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD). Plasma amyloid beta42/amyloid beta40 (Aβ42/Aβ40) and phosphorylated tau217 (p-tau217) have excellent performance in discriminating patients with neuropathology-confirmed AD from cognitively-healthy controls or other neurodegenerative diseases.1–3 Both biomarkers identify patients with positive amyloid or tau positron emission tomography (PET) in symptomatic, prodromal and even presymptomatic AD stages, and correlate with cognitive function and rates of clinical progression.4–6 Plasma Aβ42/Aβ40 and p-tau181 tend to normalize their concentrations in response to the therapeutic effects of anti-amyloid immunotherapies, and they are gaining a central role as screening tools and exploratory outcome measures in clinical trials of AD.7,8 Neurofilament light (NfL) chain is a nonspecific, but highly sensitive marker of neurodegeneration that discriminates patients with FTLD from other neurodegenerative conditions, and has been introduced to clinical practice for this purpose.9 NfL predicts clinical progression in both AD and FTLD, and is being used as an outcome measure in clinical trials of AD and FTLD.8,10–13 FTLD is the pathological substrate of frontotemporal dementia (FTD), a spectrum of aggressive clinical syndromes that feature impairments in behavior, motor function, and cognition.14
One emerging question is whether the clinical performance of plasma Aβ42/Aβ40, p-tau217, and NfL is affected in the setting of multi-proteinopathy. The importance of this question is that AD and FTLD often coexist, and overlap clinically, making it difficult to distinguish between the two pathologies. Up to 64% cases of autopsy-confirmed primary FTLD have some form of AD co-pathology,15 and about 17% of patients with behavioral variant FTD (bvFTD) and 23% of corticobasal syndrome (CBS), both classically considered within the FTD spectrum, have primary AD pathology.16–18 Previous studies have shown that FTD typically features high NfL and normal plasma amyloid and tau biomarkers. Yet, those same studies show large variability of the concentrations of plasma biomarkers in FTD, raising the possibility that these may be detecting the presence of AD co-pathology. Indeed, a subset of patients with FTLD have positive amyloid PET or plasma p-tau217 concentrations that correlate with Thal phase, Braak stage, and neuritic plaque CERAD scores.3 Nevertheless, a systematic comparison of the performance of Aβ42/Aβ40, p-tau217, and NfL in relation to their clinical associations with scales of disease severity, brain volumes, and neuropathological data in suspected FTLD has not been conducted. Identification of AD co-pathology in FTLD may open new avenues to further care and research for the two conditions. The goal of this study is to compare the clinical performance of plasma Aβ42/Aβ40, p-tau217, and NfL, measured with state-of-the-art ultrasensitive technologies, in a large cohort of sporadic FTD. We contrast their relationships with FTD disease severity; apolipoprotein E (APOE) genotype; cognitive, motor, and social function; brain volume; and in a subset of cases with available autopsy data, neuropathological features.
METHODS
Study design and participants
This cross-sectional study included 620 participants (46% female, median age 69 ± 4 years) with available data on any of the three plasma biomarkers of interest, and recruited through the multi-site ALLFTD observational project of FTD.19 In the entire cohort, 1.7% of cases had missing data for Aβ42/Aβ40, 13% for p-tau217, and 8.6% for NfL. Only sporadic cases meeting clinical diagnostic criteria for an FTD syndrome, and cognitively healthy controls were included. Participants were confirmed to be negative for a genetic cause of FTD through research genetic testing.20 Sporadic phenotypes included mild cognitive or behavioral impairment (MCI), bvFTD, CBS, FTD with amyotrophic lateral sclerosis (FTD/ALS), logopenic primary progressive aphasia (lvPPA), semantic primary progressive aphasia (svPPA), non-fluent variant primary progressive aphasia (nfvPPA), progressive supranuclear palsy-Richardson's syndrome (PSP), amnestic dementia (AmD) and asymptomatic controls in the same families from which patients with affected phenotypes were recruited (CN).21 MCI included participants with mild amnestic, non-amnestic or behavioral impairment.22 AmD included cases with an amnestic dementia syndrome, that may or not be due to AD. This was in consideration that some forms of sporadic FTLD, such as FTLD-tau Pick's disease23 or FTLD-TDP type A,24 occasionally have amnestic presentations. Pathology-confirmed cases were co-enrolled in the University of California, San Francisco (UCSF) Brain Bank Program. The study was conducted following the ethical standards of the Declaration of Helsinki, and all participants or surrogate decision-makers provided informed consent for participation. The study protocol was approved by a centralized Institutional Review Board.
Biomarker measurement
Plasma samples were collected during the baseline research visit and processed using a standardized protocol described previously.3 Plasma Aβ42 and Aβ40 concentrations were measured by immunoprecipitation followed by mass spectrometry.25 Plasma p-tau217 concentrations were determined by a high-sensitivity electrochemiluminescence immunoassay,3 and NfL was quantified with Simoa.26 All assays were performed in a batch-wise manner to minimize variability, and laboratory personnel were blinded to the clinical data.
Clinical assessments, APOE genotype, and neuroimaging
Clinical variables of interest included FTLD-specific disease severity measured with the Clinical Dementia Rating (CDR) dementia staging instrument plus behavior and language domains from the National Alzheimer's Disease Coordinating Center (NACC) Frontotemporal Lobar Degeneration module sum of boxes (CDR+NACC/FTLDsb).27 Global cognition was measured with the Montreal Cognitive Assessment (MoCA).28 Verbal memory was measured with the delayed recall score on the short form of the California Verbal Learning Test, second edition (CVLT-I).29 Motor function was measured with the Unified Parkinson's Disease Rating Scale, motor component (UPDRS III).30 Social cognition was measured with the Revised Self-Monitoring Scale (RSMS).31 Research genetic testing for APOE was conducted in a centralized laboratory as described previously.32 Brain volumetric measures (n = 137 cases) were obtained from 1.5T or 3T structural MRI scans (n = 137). Acquisition, processing, and analyses of images were done with a standardized protocol, per the Mayo Clinic's Aging and Dementia Imaging Research Laboratory, as described previously.33
Neuropathological assessment
Primary neuropathological diagnosis was determined at autopsy in a subset of cases enrolled through the UCSF Brain Bank Program (n = 38). The neuropathological assessments followed previously described protocols.17 FTLD cases were classified into tau, TDP-43, and FUS molecular classes and their subtypes. AD co-pathology stages were determined using Alzheimer's disease neuropathologic change (ADNC),34 Braak,35 and Thal36 staging systems. ADNC staging assesses Aβ plaques and tau tangles in specific brain regions. Braak staging maps tau pathology progression, detailing neurofibrillary tangle distribution. Thal staging focuses on Aβ plaque distribution, categorizing deposition severity.
Statistical analyses
Biomarker data were explored visually with box plots. The Aβ42/Aβ40 ratio was used to test clinical performance since it is a better marker of amyloidosis compared to individual values of its components.37 Plasma p-tau217 and NfL concentrations were log transformed for analyses. Comparative analysis of biomarker concentrations by sex was done with t-tests. Biomarker concentration differences across FTD phenotypes, disease severity, APOE genotype, and pathological diagnoses were performed with analysis of variance (ANOVA) or general linear models. Biomarker diagnostic performance was assessed with receiver operating characteristic (ROC) curves, and cutoff values were generated with Youden indices.38 We used a nonparametric approach to compare the areas under two or more ROC curves.39
RESEARCH IN CONTEXT
Systemic review: AD and FTLD overlap clinically and co-exist as neuropathological entities. Plasma Aβ42/Aβ40, p-tau217, and NfL are markers of neurodegeneration that discriminate between AD and FTLD. There are no systematic comparisons of the performance of these three biomarkers in relation to their associations with clinical disease severity, brain volumes assessed by neuroimaging, and neuropathological features in sporadic FTLD cohorts.
Interpretation: High plasma p-tau217, but not Aβ42/Aβ40 or NfL, was related to more severe Braak scores, APOEε4 carriership, amnestic and logopenic aphasia phenotypes, worse memory function, and lower hippocampal volumes, regardless of the primary FTLD diagnosis.
Future directions: Plasma p-tau217 has meaningful associations with clinical, neuroimaging, and neuropathological features of AD as co-pathology of primary FTLD, and it could be used as a tool to advance FTLD care and research, and for the study of the multi-proteinopathy characteristic of sporadic neurodegenerative diseases.
Baseline associations between biomarkers and clinical variables and brain volumes were determined with linear regressions corrected for age and sex. Regressions with brain volumes were additionally corrected for total intracranial volume. Brain MRI regions of interest were selected based on the Desikan–Killiany atlas to form regional composites of left, right, and combined frontal, temporal, parietal, and occipital regions, as described before.40 Additionally, regions vulnerable in AD were tested separately, including the hippocampus, posterior cingulate cortex, precuneus, angular gyrus, and supramarginal gyrus. Linear mixed-effects models (LMM) tested the relationship of baseline fluid biomarker concentrations with the longitudinal change in clinical scales. Models were corrected for age, sex, and APOE genotype and included random slopes and intercepts. We initially evaluated biomarkers as both continuous and categorical independent variables. However, according to the Bayesian information criterion (BIC), employing biomarkers as a categorical variable resulted in a lower BIC and better model fit, and we opted for the categorical biomarker variables. Categorical variables were generated using cutoff values obtained through ROC curves. The ROC curve cutoff values were 0.1 for Aβ42/Aβ40, 0.43 pg/mL for p-tau217, and 20 pg/mL for NfL. A two-tailed p-value < 0.05 was considered statistically significant. All statistical analyses were performed with R and GraphPad Prism version 10.
RESULTS
Plasma biomarker concentrations by sporadic FTD phenotype and APOE genotype
Phenotypes did not differ by plasma Aβ42/Aβ40 ratios. Plasma p-tau217 concentrations, however, were elevated in AmD (median 0.79 pg/mL ± interquartile range 0.7 pg/mL) and lvPPA (0.65 ± 0.5 pg/mL), compared to other phenotypes (0.2 ± 0.1 pg/mL) or controls (0.15 ± 0.1 pg/mL, p < 0.001 and p < 0.0001, respectively). In turn, plasma NfL was elevated in all phenotypes, compared to controls (Figure 1 and Table 1). In the whole cohort, APOEε4 carriers had lower Aβ42/Aβ40 and higher p-tau217 compared to non-carriers (Aβ42/Aβ40, 0.10 ± 0.01 vs. 0.18 ± 0.01, respectively, p < 0.0001; p-tau217, 0.3 ± 0.3 pg/mL vs. 0.19 ± 0.1 pg/mL, respectively, p < 0.0001, Figure S1). NfL concentrations did not differ by APOE genotype.
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TABLE 1 Baseline clinical features of sporadic FTD cohort.
| Clinical phenotype | CN | MCI | AmD | bvFTD | lvPPA | nfvPPA | svPPA | FTD/ALS | CBS | PSP | Others |
| Total number, n (%) | 47 (7.6) | 15 (2.5) | 10 (1.6) | 183 (29.5) | 11 (1.7) | 57 (9.2) | 82 (13.3) | 15 (2.4) | 65 (10.4) | 110 (17.7) | 25 (4.1) |
| Neuropathological data available, n (%) | 0 | 0 | 1 (10) | 11 (6) | 0 | 3 (5) | 9 (11) | 2 (13) | 3 (5) | 8 (7) | 1 (4) |
| Volumetric MRI data available, n (%) | 35 (74) | 3 (20) | 1 (10) | 41 (22) | 1 (9) | 5 (9) | 9 (11) | 1 (7) | 9 (14) | 28 (25) | 4 (16) |
| Sex (female, n, %) | 35 (75) | 8 (53) | 2 (20) | 69 (38) | 6 (55) | 31 (54) | 42 (51) | 4 (27) | 26 (40) | 52 (47) | 9 (36) |
| Age at visit, years, median (IQR) | 64 (9) | 70 (12.3) | 69 (8) | 63 (12) | 72 (7) | 71 (12) | 66 (10) | 59 (17) | 70 (14.3) | 70 (10) | 64 (11) |
| Education, years, median (IQR) | 16 (5) | 18 (6) | 17 (5) | 16 (4) | 18 (5) | 16 (4) | 16 (3) | 16 (5) | 17 (4) | 16 (4) | 16 (6) |
| Race (White, n, %) | 39 (83) | 11 (73) | 9 (90) | 170 (93) | 11 (100) | 48 (84) | 80 (98) | 13 (87) | 55 (85) | 90 (82) | 20 (80) |
| APOEε4 carrier, n (%) | 3 (6) | 4 (27) | 4 (40) | 37 (20) | 7 (64) | 10 (18) | 22 (27) | 4 (27) | 15 (23) | 21 (19) | 1 (4) |
| APOE ε2/ε2, n (%) | 0 | 1 (6.7) | 0 | 0 | 0 | 1 (2) | 0 | 0 | 0 | 0 | 0 |
| APOE ε2/ε3, n (%) | 1 (2) | 0 | 0 | 20 (11) | 0 | 7 (12) | 8 (10) | 3 (20) | 7 (11) | 15 (14) | 5 (20) |
| APOE ε2/ε4, n (%) | 1 (2) | 0 | 0 | 2 (1) | 0 | 1 (2) | 1 (1) | 0 | 2 (3) | 1 (1) | 1 (4) |
| APOE ε3/ε3, n (%) | 4 (9) | 9 (60) | 6 (60) | 114 (62) | 3 (27) | 33 (58) | 47 (57) | 7 (46) | 36 (55) | 65 (59) | 14 (56) |
| APOE ε3/ε4, n (%) | 3 (6) | 3 (20) | 4 (40) | 35 (19) | 7 (64) | 9 (16) | 22 (27) | 3 (20) | 14 (21) | 19 (17) | 1 (4) |
| APOE ε4/ε4, n (%) | 0 | 1 (6.7) | 0 | 2 (1) | 0 | 1 (2) | 0 | 1 (7) | 1 (1) | 2 (2) | 0 |
| Unknown APOE | 38 (81) | 1 (6.6) | 0 | 10 (6) | 1 (9) | 5 (8) | 4 (5) | 1 (7) | 5 (8) | 8 (7) | 4 (16) |
| FTLD CDR sum of boxes, median (IQR) | 0 (0) | 3 (1.4) | 6.5 (2) | 9 (3) | 3 (2) | 4 (2) | 7 (2) | N/A | 5 (3) | 7.5 (3) | 5 (3.5) |
| MoCA | 28 (1) | 25 (2) | 16 (12) | 20 (7) | 15 (5) | 23 (4) | 17 (5) | N/A | 24 (5) | 22 (4) | 23 (8) |
| UPDRS | 0 (0) | 1 (1) | 1 (1) | 0 (0) | 0 (0) | 5 (4) | 0 (0) | N/A | 23 (11) | 28 (9) | 5 (3) |
| RSMS | 49 (5) | 41 (3) | 30 (15) | 19 (7) | 46 (15) | 42 (15) | 23 (8) | N/A | 40 (14) | 32 (9.3) | 30 (9) |
| CVLT late recall | 8 (2) | 6 (2) | 0 (0) | 3 (3) | 4 (3) | 6 (2) | 0 (0) | N/A | 6 (2.3) | 5 (2) | 5 (5) |
| Plasma Aβ42/Aβ40, median (IQR) | 0.12 (0.01) | 0.12 (0.02) | 0.1 (0.02) | 0.12 (0.01) | 0.1 (0.01) | 0.12 (0.01) | 0.12 (0.02) | 0.1 (0.02) | 0.12 (0.02) | 0.12 (0.02) | 0.12 (0.01) |
| Plasma p-tau217, pg/mL, median (IQR) | 0.15 (0.1) | 0.18 (0.1) | 0.79 (0.7) | 0.2 (0.09) | 0.65 (0.5) | 0.2 (0.08) | 0.18 (0.1) | 0.23 (0.1) | 0.22 (0.1) | 0.2 (0.09) | 0.17 (0.08) |
| Plasma NfL, pg/mL, median (IQR) | 9.2 (4.7) | 17.8 (17) | 23.1 (29) | 24.1 (26) | 21.2 (12) | 29 (17) | 29.6 (20) | 36.3 (41) | 28.9 (27) | 24.3 (15) | 24 (19) |
Clinical diagnostic performance
Only plasma NfL showed excellent discrimination between controls and any symptomatic FTD (AUC 0.92, 95% confidence interval [CI] 0.89–0.95, p < 0.0001, 67% sensitivity, 96% specificity, Figure 1B). In contrast, Aβ42/Aβ40 (AUC 0.56, 95% CI 0.47–0.64, p = 0.24), and p-tau217 (AUC 0.65, 95% CI 0.45–0.84, p = 0.14) did not discriminate between controls and any symptomatic FTD. Since p-tau217 concentrations were distinctively elevated in AmD and lvPPA, two phenotypes that often have primary AD as the underlying cause, we tested the comparative ability of p-tau217 to discriminate them from controls or the rest of the FTD phenotypes. When used to discriminate between AmD plus lvPPA and controls, both p-tau-217 (AUC 0.91, 95% CI 0.8–1, p = 0.0004, 70% sensitivity, 100% specificity) and NfL (AUC of 0.92, 95% CI 0.86–0.98, p < 0.0001, 58% sensitivity, 96% specificity) showed excellent discrimination (Figure S2). In contrast, Aβ42/Aβ40 showed only fair discrimination between AmD plus lvPPA and controls (AUC 0.74, 95% CI 0.6–0.89, p = 0.0017, 90.2% sensitivity, 29% specificity). The diagnostic performance of plasma p-tau217 to discriminate between AmD plus lvPPA vs. controls was superior when directly compared to Aβ42/Aβ40 (AUC 0.997, standard error = 0.004, p < 0.0001). When used to discriminate between AmD plus lvPPA and other symptomatic FTD phenotypes, p-tau217 showed good performance (AUC 0.86, (95% CI 0.75–0.96, p < 0.0001, 70% sensitivity, 92% specificity), whereas that of Aβ42/Aβ40 and NfL was only fair (Aβ42/Aβ40: AUC 0.73, 95% CI 0.61–0.85, p = 0.0003, 94% sensitivity, 29% specificity; NfL: AUC 0.6, 95% CI 0.5 to 0.72, p = 0.13, 68% sensitivity, 40% specificity).
Baseline associations with clinical scales
In the whole cohort, at baseline, Aβ42/Aβ40 did not correlate with any clinical scale (Figure 2, Table S1). High p-tau217 was associated with worse disease severity (CDR+NACC/FTLDsb β = 0.48, 95% CI 0.06–2.9, p = 0.05), global cognition (MoCA β = −5.6, 95% CI −8 to −4, p < 0.0001), and verbal memory (CVLT recall β = −1.52, 95% CI −2.5 to −0.5, p = 0.01), but not with motor function or social cognition scores. High NfL was strongly associated with worse disease severity (β = 2.29, 95% CI 1.5–3, p < 0.0001), global cognition (β = −3.71, 95% CI −5 to −2.6, p < 0.0001), verbal memory (β = −0.82, 95% CI −1.4 to −0.3, p = 0.01), and social cognition (RSMS β = −7.33, 95% CI −9.8 to −5, p = 0.01), but not with motor function. When analyzed by phenotype, none of the biomarkers related to disease severity, with the exceptions of positive relationships with p-tau217 in bvFTD and CBS and with NfL in bvFTD and svPPA (Table S2).
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Prediction of longitudinal change in clinical scales
In a longitudinal analysis, in the whole cohort, baseline Aβ42/Aβ40 did not relate to changes in any clinical scale. High baseline p-tau217, however, was associated with more severe decline in global cognition (β = −5.63, 95% CI −7.7 to −3.5, p < 0.0001) and verbal memory (β = −1.52, 95% CI −2.5 to −0.5, p = 0.003), compared to low baseline p-tau217 (Figure 3, Table S3). High baseline NfL was associated with faster decline in disease severity (β = 1.2, 95% CI 0.42–2, p = 0.004), global cognition (β = −2.6, 95% CI −3.6 to −1.5, p < 0.0001), social cognition (β = −4.7, 95% CI −6.9 to −2.5, p < 0.0001), and verbal memory (β = −0.75, 95% CI −1.3 to −0.24, p = 0.004), compared to low baseline NfL.
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Associations with brain volumes
A total of 137 cases had brain volumes assessed by MRI. There were no associations between Aβ42/Aβ40 and brain volumes. High p-tau217 correlated with low right supramarginal gyrus (β = −140.7, 95% CI −264 to −17, p = 0.03), right hippocampus (β = −93.9, 95% CI −174 to −14, p = 0.02), and left hippocampus (β = −91.2, 95% CI −165 to −18, p = 0.02) volumes. High NfL strongly correlated with low volumes of all analyzed composites and individual regions (Figure 4 and Tables S4 and S5).
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Associations with FTLD neuropathological diagnosis and AD co-pathology
Thirty-eight cases (median age 61 ± 9 years) had autopsy data with confirmed neuropathological diagnoses. The most common primary diagnosis was FTLD-tau (53%), followed by FTLD-TDP (26%). The rest (11.5%) included FET, ubiquitin proteasome system (UPS), or unclassifiable FTLD. Two cases actually had primary AD pathology, and one case had Lewy body disease (Table S6). There were no differences in plasma Aβ42/Aβ40, p-tau217, or NfL concentrations by primary neuropathology diagnosis (Figures S3 and S4). Also, regardless of the primary neuropathological diagnosis, there were no significant changes in Aβ42/Aβ40, p-tau217, or NfL with increasing AD co-pathology scores (Figure S5). After correction for sex, age, and the interval between plasma sample collection and death, only p-tau217 was associated with more severe Braak stages (β = 2.11, 95% CI 0.1–4.1, p = 0.05) (Table 2).
TABLE 2 Relationship between plasma biomarkers and AD co-pathology scores.
| Clinical scale | Biomarker + time between biomarker collection and death | Unstandardized beta | 95% CI | p-value |
| ADNC | Aβ42/Aβ40 + time between biomarker collection and death | −0.16 | −1.3, 1 | 0.79 |
| Braak | Aβ42/Aβ40 + time between biomarker collection and death | −0.66 | −2.8, 1.5 | 0.56 |
| Thal | Aβ42/Aβ40 + time between biomarker collection and death | 0.09 | −1.8, 2.02 | 0.93 |
| ADNC | p-tau217+ time between biomarker collection and death | 1.00 | −0.07, 2.1 | 0.08 |
| Braak | p-tau217+ time between biomarker collection and death | 2.11 | 0.1, 4.1 | 0.05 |
| Thal | p-tau217+ time between biomarker collection and death | 1.10 | −0.7, 2.9 | 0.25 |
| ADNC | NfL+ time between biomarker collection and death | 0.53 | −0.3, 1.3 | 0.21 |
| Braak | NfL+ time between biomarker collection and death | 0.11 | −1.4, 1.7 | 0.89 |
| Thal | NfL+ time between biomarker collection and death | 0.74 | −0.6, 2.08 | 0.29 |
DISCUSSION
This study investigated the clinical value of plasma biomarkers of amyloid (Aβ42/Aβ40), tau (p-tau217), and neurodegeneration (NfL) in a cohort of clinically-diagnosed sporadic FTD cases, including a sub-cohort of neuropathologically-confirmed FTLD cases. The analysis revealed significant differences in the clinical performance of the three biomarkers. Notably, Aβ42/Aβ40 was lower in APOEε4 carriers but did not differentiate between FTD phenotypes and was not associated with baseline or longitudinal clinical measures of disease severity, brain volumes, or AD co-pathology scores. In contrast, high p-tau217 was not only observed in APOEε4 carriers but also in participants with AmD and lvPPA, two phenotypes in the FTD spectrum, but also strongly associated with AD pathology, and not in other FTD phenotypes. The p-tau217 correlated with global cognition and verbal memory at baseline and predicted worsening of these cognitive measures at 3 years. Remarkably, p-tau217 did not correlate with FTD-specific disease severity, motor function, or social cognition. High p-tau217 correlated with low volumes in the hippocampus and supramarginal gyrus, two regions vulnerable in AD, but not with composites of frontal, temporal, parietal, or occipital volumes. There were no differences in Aβ42/Aβ40, p-tau217, or NfL by primary FTLD diagnosis. After adjusting for sex, age, and the interval between plasma sample collection and death, only p-tau217 showed an association with more severe Braak stages, reflective of high tau burden. Finally, NfL was not influenced by the APOE genotype, but it was elevated across all symptomatic FTD phenotypes compared to controls, and strongly correlated, at baseline and longitudinally, with all clinical measures of disease severity, except for motor function. NfL also correlated with volumes of all analyzed brain regions. Taken together, the findings suggest that, when sporadic FTD is suspected, plasma p-tau217, but not Aβ42/Aβ40 or NfL, has meaningful associations with clinical, neuroimaging, and neuropathological features of AD, when present as a co-pathology, independent of the primary FTLD pathology.
Plasma p-tau217 has previously shown robust clinical associations in the AD clinical spectrum. It correlates with APOEε4 carriership,2 clinical disease severity and progression,41 cognitive function,6 brain atrophy in AD-vulnerable regions,3 amyloid and tau42,43 PET burden, and severity of AD neuropathology.44 Plasma p-tau217 also offers excellent discrimination between neuropathology-confirmed AD and FTLD,2 identifies amyloid PET-positive individuals among people with different types of dementia,3 and has value for estimating the primary pathology of phenotypes that could be caused by AD or FTLD, such as CBS.45 The current study contributes evidence that plasma p-tau217 has potential value for the identification of AD co-pathology in the setting of primary FTLD. The presence of AD co-pathology, as assessed by plasma p-tau217, seems to have clinical and neuroimaging correlates. Contrary to p-tau217, our study did not detect the same degree of clinicopathological associations for Aβ42/Aβ40 within the FTD cohort, which is consistent with other comparative studies between amyloid and tau biomarkers.46,47 Of note, Aβ42/Aβ40 was lower in APOEε4 carriers and showed numerical trends to be lower in participants with AmD and lvPPA phenotypes, the two clinical groups in which p-tau217 was significantly elevated. The reason for the better reflection of AD clinicopathological features by p-tau217 is not clear, but it may be related to a tighter relationship between tau burden and neurodegeneration, the types of analytes measured, the sensitivity of the platforms used for their quantification, or FTLD-specific factors that accentuate or mitigate disease expression and the clinicopathological associations of the biomarkers. For example, AD co-pathology has been shown to modulate the clinical presentation of four-repeat tauopathies, with less severe motor impairment and more severe functional dissociations in the default-mode network.48 We observed no added value of NfL to track AD co-pathology, but our data are certainly in line with previous studies that have established its value for the identification of symptomatic disease and its robust clinical and imaging associations in FTD.10,40,49
Our findings may have diagnostic and management implications. Coexistence of AD with other neurodegenerative disorders is common. With the introduction of plasma AD biomarkers into clinical practice, increasing numbers of positive AD biomarkers will be seen in the setting of phenotypes that are suspected to be due to FTLD. Detection of plasma p-tau217 may help clinicians redefine their diagnostic impressions, just as it has been demonstrated with the introduction of amyloid PET.50 Physicians may also increase their index of clinical suspicion around the presence of AD co-pathology, especially in phenotypes in which the prediction of FLTD primary pathology can be done with more confidence, such as PSP-RS or FTD/ALS. Although the distinction between primary AD pathology and AD as a co-pathology in primary FTLD may still not be possible, new avenues of inquiry may aim to better characterize clinical trajectories and investigate the biomarker evidence of AD as a management target, potentially allowing for personalized treatment strategies in FTD. It is possible that plasma p-tau217 could assist in selecting cases for FTD clinical trials, allowing for trial designs that account for the potential presence of AD co-pathology.
This study has a number of limitations. Longitudinal, neuroimaging, and neuropathological data were limited, which may restrict the ability to uncover other important clinical associations. Further validation of the results in a larger neuropathology-confirmed cohort is required. The demographic homogeneity of the studied population, mainly White and well-educated participants without major comorbidities, may limit the generalizability of the results to a broader and more diverse population. Generalizability is also limited by the lack of a replication cohort. Although state-of-the-art analytical platforms were used to quantify the biomarkers, even more precision may be required to determine clinically meaningful associations. Exploring other phosphorylated tau forms could offer further insights into the pathophysiology and progression of AD in the setting of FTLD. There is still a need for specific FTLD biomarkers, and more biomarker discovery efforts should be conducted.
In conclusion, this study supports the utility of plasma p-tau217 in identifying cases with neuropathologically confirmed AD co-pathology in the setting of primary FTLD and may be of value as a clinical biomarker when FTD is suspected. Continuing this line of investigation is crucial for advancing personalized treatment strategies and ultimately enhancing patient care and outcomes.
AUTHOR CONTRIBUTIONS
Julio C. Rojas, Adam L. Boxer, and Binita Rajbanshi co-conceived the study. Binita Rajbanshi conducted statistical analyses and drafted the manuscript. Randall J. Bateman's team performed the mass spectrometry for Aβ42 and Aβ40. All authors contributed a critical review of the manuscript.
ACKNOWLEDGMENTS
Patients and study companions enrolled in this study.
CONFLICT OF INTEREST STATEMENT
Binita Rajbanshi, Igor Prufer Q C Araujo, Lawren VandeVrede, Peter A. Ljubenkov, Hilary W. Heuer, Argentina Lario Lago, Leonard Petrucelli, Tania Gendron, William W. Seeley, Lea T. Grinberg, Salvatore Spina, Randall J. Bateman, Howard J. Rosen, Bradley F. Boeve, and Adam L. Boxer have no conflict of interest to disclose. Adam M. Staffaroni has received research support from the NIA/NIH, Bluefield Project to Cure FTD, the Alzheimer's Association, the Larry L. Hillblom Foundation, and the Rainwater Charitable Foundation, and has provided consultation to Alector, Lilly/Prevail, Passage Bio, and Takeda. Eliana Marisa Ramos receives research support from the NIH. Jeffrey L. Dage is an inventor on patents or patent applications of Eli Lilly and Company relating to the assays, methods, reagents and/or compositions of matter for p-tau assays and Aβ targeting therapeutics. He has served as a consultant or on advisory boards for Eisai, Abbvie, Genotix Biotechnologies Inc, Gates Ventures, Karuna Therapeutics, AlzPath Inc., Cognito Therapeutics, Inc., and received research support from ADx Neurosciences, Fujirebio, AlzPath Inc., Roche Diagnostics and Eli Lilly and Company in the past 2 years. He has received speaker fees from Eli Lilly and Company and is a founder and advisor for Monument Biosciences. Dr. Dage has stock or stock options in Eli Lilly and Company, Genotix Biotechnologies, AlzPath Inc. and Monument Biosciences. Julio C. Rojas is a site PI for clinical trials sponsored by Eli-Lilly, Eisai and Amylyx. He receives consulting fees from Roon Health, Inc and Ferrer International, S.A. This work was supported by K23AG059888, AlzOut and the John Douglas French Alzheimer's Foundation for J.C.R. Samples from the National Centralized Repository for Alzheimer Disease and Related Dementias (NCRAD), which receives government support under a cooperative agreement grant (U24 AG021886) awarded by the National Institute on Aging (NIA), were used in this study. The ALLFTD consortium is funded by the NIA and the National Institute of Neurological Diseases and Stroke (NINDS) (U19: AG063911). The former ARTFL and LEFFTDS consortia received funding from the NIA, NINDS and National Center for Advancing Translational Science (U54 NS092089, U01 AG045390). Author disclosures are present in supporting information.
CONSENT STATEMENT
All human subjects provided informed consent to participate in this study.
DATA AVAILABILITY STATEMENT
The datasets from this study are available upon reasonable request.
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Abstract
INTRODUCTION
Plasma amyloid beta42/amyloid beta40 (Aβ42/Aβ40) and phosphorylated tau217 (p‐tau217) identify individuals with primary Alzheimer's disease (AD). They may detect AD co‐pathology in the setting of other primary neurodegenerative diseases, but this has not been systematically studied.
METHODS
We compared the clinical, neuroimaging, and neuropathological associations of plasma Aβ42/Aβ40 (mass spectrometry), p‐tau217 (electrochemiluminescence), and neurofilament light ([NfL], single molecule array [Simoa]), as markers of AD co‐pathology, in a sporadic frontotemporal dementia (FTD) cohort (n = 620).
RESULTS
Aβ42/Aβ40 showed no clinicopathological associations. High p‐tau217 was present in amnestic dementia (AmD) presumed to be due to FTD, logopenic primary progressive aphasia (lvPPA), and APOEε4 carriers, and correlated with worse baseline and longitudinal clinical scores, lower hippocampal volumes, and more severe AD co‐pathology (Braak Stage). NfL was elevated in all FTD phenotypes, and correlated with clinical scores and frontotemporal brain volumes.
DISCUSSION
Plasma p‐tau217 has clinical, neuroimaging, and neuropathological correlates in sporadic FTD and may identify FTD cases with AD co‐pathology.
Highlights
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Details
1 Weill Institute for Neurosciences, Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, California, USA
2 Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, California, USA
3 Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA
4 Department of Neurology, Indiana University School of Medicine, Indianapolis, Indiana, USA
5 Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA
6 Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA