Clinical application of plasma P-tau217 to assess eligibility for amyloid-lowering immunotherapy in memory clinic patients with early Alzheimer’s disease
(2024) In Alzheimer's Research and Therapy 16(1).- Abstract
Background: With the approval of disease-modifying treatments (DMTs) for early Alzheimer’s disease (AD), there is an increased need for efficient and non-invasive detection methods for cerebral amyloid-β (Aβ) pathology. Current methods, including positron emission tomography (PET) and cerebrospinal fluid (CSF) analysis, are costly and invasive methods that may limit access to new treatments. Plasma tau phosphorylated at threonine-217 (P-tau217) presents a promising alternative, yet optimal cutoffs for treatment eligibility with DMTs like aducanumab require further investigation. This study evaluates the efficacy of one- and two-cutoff strategies for determining DMT eligibility at the Butler Hospital Memory & Aging Program (MAP).... (More)
Background: With the approval of disease-modifying treatments (DMTs) for early Alzheimer’s disease (AD), there is an increased need for efficient and non-invasive detection methods for cerebral amyloid-β (Aβ) pathology. Current methods, including positron emission tomography (PET) and cerebrospinal fluid (CSF) analysis, are costly and invasive methods that may limit access to new treatments. Plasma tau phosphorylated at threonine-217 (P-tau217) presents a promising alternative, yet optimal cutoffs for treatment eligibility with DMTs like aducanumab require further investigation. This study evaluates the efficacy of one- and two-cutoff strategies for determining DMT eligibility at the Butler Hospital Memory & Aging Program (MAP). Methods: In this retrospective, cross-sectional diagnostic cohort study, we first developed P-tau217 cutoffs using site-specific and BioFINDER-2 training data, which were then tested in potential DMT candidates from Butler MAP (total n = 150). ROC analysis was used to calculate the area under the curve (AUC) and accuracy of P-tau217 interpretation strategies, using Aβ-PET/CSF testing as the standard of truth. Results: Potential DMT candidates at Butler MAP (n = 50), primarily diagnosed with mild cognitive impairment (n = 29 [58%]) or mild dementia (21 [42%]), were predominantly Aβ-positive (38 [76%]), and half (25 [50%]) were subsequently treated with aducanumab. Elevated P-tau217 predicted cerebral Aβ positivity in potential DMT candidates (AUC = 0.97 [0.92–1]), with diagnostic accuracy ranging from 0.88 (0.76–0.95, p = 0.028) to 0.96 (0.86–1, p <.001). When using site-specific cutoffs, a subset of DMT candidates (10%) exhibited borderline P-tau217 (between 0.273 and 0.399 pg/mL) that would have potentially required confirmatory testing. Conclusions: This study, which included participants treated with aducanumab, confirms the utility of one- and two-cutoff strategies for interpreting plasma P-tau217 in assessing DMT eligibility. Using P-tau217 could potentially replace more invasive diagnostic methods, and all aducanumab-treated participants would have been deemed eligible based on P-tau217. However, false positives remain a concern, particularly when applying externally derived cutoffs that exhibited lower specificity which could have led to inappropriate treatment of Aβ-negative participants. Future research should focus on prospective validation of P-tau217 cutoffs to enhance their generalizability and inform standardized treatment decision-making across diverse populations.
(Less)
- author
- Howe, Matthew D.
; Britton, Karysa J.
; Joyce, Hannah E.
; Menard, William
; Emrani, Sheina
; Kunicki, Zachary J.
; Faust, Melanie A.
; Dawson, Brittany C.
; Riddle, Meghan C.
; Huey, Edward D.
; Janelidze, Shorena
LU
; Hansson, Oskar
LU
and Salloway, Stephen P.
(Less) - organization
- publishing date
- 2024-12
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Alzheimer’s disease, Blood biomarkers, Clinical research, Dementia, Immunotherapy
- in
- Alzheimer's Research and Therapy
- volume
- 16
- issue
- 1
- article number
- 154
- publisher
- BioMed Central (BMC)
- external identifiers
-
- scopus:85197806826
- pmid:38971815
- ISSN
- 1758-9193
- DOI
- 10.1186/s13195-024-01521-9
- language
- English
- LU publication?
- yes
- id
- a06a2516-1540-4e69-8944-37e6e6656c1d
- date added to LUP
- 2024-08-30 14:13:20
- date last changed
- 2024-10-11 20:24:27
@article{a06a2516-1540-4e69-8944-37e6e6656c1d,
abstract = {{<p>Background: With the approval of disease-modifying treatments (DMTs) for early Alzheimer’s disease (AD), there is an increased need for efficient and non-invasive detection methods for cerebral amyloid-β (Aβ) pathology. Current methods, including positron emission tomography (PET) and cerebrospinal fluid (CSF) analysis, are costly and invasive methods that may limit access to new treatments. Plasma tau phosphorylated at threonine-217 (P-tau217) presents a promising alternative, yet optimal cutoffs for treatment eligibility with DMTs like aducanumab require further investigation. This study evaluates the efficacy of one- and two-cutoff strategies for determining DMT eligibility at the Butler Hospital Memory & Aging Program (MAP). Methods: In this retrospective, cross-sectional diagnostic cohort study, we first developed P-tau217 cutoffs using site-specific and BioFINDER-2 training data, which were then tested in potential DMT candidates from Butler MAP (total n = 150). ROC analysis was used to calculate the area under the curve (AUC) and accuracy of P-tau217 interpretation strategies, using Aβ-PET/CSF testing as the standard of truth. Results: Potential DMT candidates at Butler MAP (n = 50), primarily diagnosed with mild cognitive impairment (n = 29 [58%]) or mild dementia (21 [42%]), were predominantly Aβ-positive (38 [76%]), and half (25 [50%]) were subsequently treated with aducanumab. Elevated P-tau217 predicted cerebral Aβ positivity in potential DMT candidates (AUC = 0.97 [0.92–1]), with diagnostic accuracy ranging from 0.88 (0.76–0.95, p = 0.028) to 0.96 (0.86–1, p <.001). When using site-specific cutoffs, a subset of DMT candidates (10%) exhibited borderline P-tau217 (between 0.273 and 0.399 pg/mL) that would have potentially required confirmatory testing. Conclusions: This study, which included participants treated with aducanumab, confirms the utility of one- and two-cutoff strategies for interpreting plasma P-tau217 in assessing DMT eligibility. Using P-tau217 could potentially replace more invasive diagnostic methods, and all aducanumab-treated participants would have been deemed eligible based on P-tau217. However, false positives remain a concern, particularly when applying externally derived cutoffs that exhibited lower specificity which could have led to inappropriate treatment of Aβ-negative participants. Future research should focus on prospective validation of P-tau217 cutoffs to enhance their generalizability and inform standardized treatment decision-making across diverse populations.</p>}},
author = {{Howe, Matthew D. and Britton, Karysa J. and Joyce, Hannah E. and Menard, William and Emrani, Sheina and Kunicki, Zachary J. and Faust, Melanie A. and Dawson, Brittany C. and Riddle, Meghan C. and Huey, Edward D. and Janelidze, Shorena and Hansson, Oskar and Salloway, Stephen P.}},
issn = {{1758-9193}},
keywords = {{Alzheimer’s disease; Blood biomarkers; Clinical research; Dementia; Immunotherapy}},
language = {{eng}},
number = {{1}},
publisher = {{BioMed Central (BMC)}},
series = {{Alzheimer's Research and Therapy}},
title = {{Clinical application of plasma P-tau217 to assess eligibility for amyloid-lowering immunotherapy in memory clinic patients with early Alzheimer’s disease}},
url = {{http://dx.doi.org/10.1186/s13195-024-01521-9}},
doi = {{10.1186/s13195-024-01521-9}},
volume = {{16}},
year = {{2024}},
}