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. 2023 Jul 31;80(9):969-979.
doi: 10.1001/jamaneurol.2023.2338. Online ahead of print.

Prevalence and Clinical Implications of a β-Amyloid-Negative, Tau-Positive Cerebrospinal Fluid Biomarker Profile in Alzheimer Disease

Pontus Erickson  1 , Joel Simrén  1   2 , Wagner S Brum  1   3 , Gilda E Ennis  4   5 , Gwendlyn Kollmorgen  6 , Ivonne Suridjan  6 , Rebecca Langhough  4   5 , Erin M Jonaitis  4   5 , Carol A Van Hulle  4   5 , Tobey J Betthauser  4   5 , Cynthia M Carlsson  4   5   7   8 , Sanjay Asthana  4   5   7   8 , Nicholas J Ashton  1   9   10   11 , Sterling C Johnson  4   5 , Leslie M Shaw  12 , Kaj Blennow  1   2 , Ulf Andreasson  1   2 , Barbara B Bendlin  4 , Henrik Zetterberg  1   2   4   13   14   15 ; ADNI Cohort
Collaborators, Affiliations

Prevalence and Clinical Implications of a β-Amyloid-Negative, Tau-Positive Cerebrospinal Fluid Biomarker Profile in Alzheimer Disease

Pontus Erickson et al. JAMA Neurol. .

Abstract

Importance: Knowledge is lacking on the prevalence and prognosis of individuals with a β-amyloid-negative, tau-positive (A-T+) cerebrospinal fluid (CSF) biomarker profile.

Objective: To estimate the prevalence of a CSF A-T+ biomarker profile and investigate its clinical implications.

Design, setting, and participants: This was a retrospective cohort study of the cross-sectional multicenter University of Gothenburg (UGOT) cohort (November 2019-January 2021), the longitudinal multicenter Alzheimer Disease Neuroimaging Initiative (ADNI) cohort (individuals with mild cognitive impairment [MCI] and no cognitive impairment; September 2005-May 2022), and 2 Wisconsin cohorts, Wisconsin Alzheimer Disease Research Center and Wisconsin Registry for Alzheimer Prevention (WISC; individuals without cognitive impairment; February 2007-November 2020). This was a multicenter study, with data collected from referral centers in clinical routine (UGOT) and research settings (ADNI and WISC). Eligible individuals had 1 lumbar puncture (all cohorts), 2 or more cognitive assessments (ADNI and WISC), and imaging (ADNI only) performed on 2 separate occasions. Data were analyzed on August 2022 to April 2023.

Exposures: Baseline CSF Aβ42/40 and phosphorylated tau (p-tau)181; cognitive tests (ADNI: modified preclinical Alzheimer cognitive composite [mPACC]; WISC: modified 3-test PACC [PACC-3]). Exposures in the ADNI cohort included [18F]-florbetapir amyloid positron emission tomography (PET), magnetic resonance imaging (MRI), [18F]-fluorodeoxyglucose PET (FDG-PET), and cross-sectional tau-PET (ADNI: [18F]-flortaucipir, WISC: [18F]-MK6240).

Main outcomes and measures: Primary outcomes were the prevalence of CSF AT biomarker profiles and continuous longitudinal global cognitive outcome and imaging biomarker trajectories in A-T+ vs A-T- groups. Secondary outcomes included cross-sectional tau-PET.

Results: A total of 7679 individuals (mean [SD] age, 71.0 [8.4] years; 4101 male [53%]) were included in the UGOT cohort, 970 individuals (mean [SD] age, 73 [7.0] years; 526 male [54%]) were included in the ADNI cohort, and 519 individuals (mean [SD] age, 60 [7.3] years; 346 female [67%]) were included in the WISC cohort. The prevalence of an A-T+ profile in the UGOT cohort was 4.1% (95% CI, 3.7%-4.6%), being less common than the other patterns. Longitudinally, no significant differences in rates of worsening were observed between A-T+ and A-T- profiles for cognition or imaging biomarkers. Cross-sectionally, A-T+ had similar tau-PET uptake to individuals with an A-T- biomarker profile.

Conclusion and relevance: Results suggest that the CSF A-T+ biomarker profile was found in approximately 5% of lumbar punctures and was not associated with a higher rate of cognitive decline or biomarker signs of disease progression compared with biomarker-negative individuals.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Ennis reported receiving grants from National Institute on Aging during the conduct of the study. Dr Kollmorgen reported being a full-time employee of Roche Diagnostics GmbH during the conduct of the study. Dr Langhough reported receiving grants from National Institutes of Health during the conduct of the study. Dr Jonaitis reported receiving grants from National Institutes of Health during the conduct of the study. Dr Betthauser reported receiving grants from the University of Wisconsin and National Institutes of Health and speaker honoraria from Intermountain Healthcare outside the submitted work. Dr Carlsson reported receiving grants from the National Institutes of Health, Eisai, Eli Lilly, Veterans Affairs; nonfinancial support from Amarin; data safety monitoring board/travel/advisory board honoraria from Alzheimer's Association, National Institutes of Health, and American Fed Aging Res Beeson Program outside the submitted work. Dr Asthana reported receiving grants from National Institute on Aging/National Institutes of Health, Genentech, Merck, Toyoma Chemical, and Lundbeck outside the submitted work. Dr Johnson reported receiving grants from the National Institutes of Health and Cerveau and consultant fees from Roche Diagnostics, Merck, and ALZpath outside the submitted work. Dr Shaw reported receiving grants from the National Institute on Aging and teaching honoraria from Biogen outside the submitted work. Dr Blennow reported serving as a consultant and at advisory boards for Acumen, ALZPath, BioArctic, Biogen, Eisai, Julius Clinical, Lilly, Novartis, Ono Pharma, Prothena, Roche Diagnostics, and Siemens Healthineers; serving at data monitoring committees for Julius Clinical and Novartis; giving lectures, producing educational materials, and participating in educational programs for Biogen, Eisai, and Roche Diagnostics; and being a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the work. Dr Bendlin reported receiving grants from the National Institutes of Health during the conduct of the study. Dr Zetterberg reported receiving personal/advisory board fees from AbbVie, Acumen, Alector, Alzinova, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave Scientific; receiving lecture fees from Cellectricon, Fujirebio, Alzecure, Biogen, and Roche outside the submitted work; and being a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Prevalence Estimates in a Clinical Laboratory Routine Setting Across Ages and Cerebrospinal Fluid (CSF) β-Amyloid 42 (Aβ42) and Aβ40 Concentrations Among Amyloid-Negative Individuals
A, The color dots represent the prevalence in percentage at each age (in years) of each biomarker category based on the cutoffs used in clinical routine. The solid lines represent corresponding locally estimated scatterplot smoothing (LOESS) regression lines, with shaded areas indicating 95% CIs. B, The graphs display group comparisons Aβ42 and Aβ40 for the Aβ-negative amyloid-tau (AT) biomarker profiles in both the University of Gothenburg (UGOT) and Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohorts. Group comparisons were performed with linear regression models adjusting for relevant available covariates (UGOT: age, sex; ADNI: age, sex, APOE ε4 status, years of education). In the UGOT cohort, mean levels of CSF Aβ42 were significantly increased in individuals with an A−T+ profile by a mean of 627 pg/mL (95% CI, 586-667 pg/mL; P <.001), and CSF levels of Aβ40 were significantly increased in the A−T+ group by a mean of 6504 pg/mL (95% CI, 6104-6904 pg/mL; P <.001). In ADNI, mean levels of CSF Aβ42 were significantly increased in individuals with an A−T+ profile by a mean of 673 pg/mL (95% CI, 554-793 pg/mL; P <.001), and CSF levels of Aβ40 were significantly increased in the A−T+ group by a mean of 3543 pg/mL (95% CI, 3054-4054 pg/mL; P <.001).
Figure 2.
Figure 2.. Associations Between Cerebrospinal Fluid (CSF) Amyloid-Tau (AT) Status and Longitudinal Cognitive Decline
Mean predicted trajectories of cognitive decline according to CSF AT status and baseline cognitive status are shown for individuals who were cognitively unimpaired (CU) (A) or had mild cognitive impairment (MCI) (B) at baseline in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and in 2 Wisconsin cohorts, Wisconsin Alzheimer Disease Research Center and Wisconsin Registry for Alzheimer Prevention (WISC) (C). The mean predicted trajectories for the modified Preclinical Alzheimer’s Cognitive Composite (mPACC; ADNI) and modified 3-test PACC (PACC-3; WISC) are displayed with solid lines and 95% CIs. Trajectories were estimated including terms for CSF AT status, covariates (age, years of education, APOE ε4 genotype, sex, and practice [and cohort in WISC]), as well as the age × CSF AT status interaction. A+/− indicates CSF Aβ42/40 binary status, and T+/− indicates CSF p-tau181 binary status.
Figure 3.
Figure 3.. Associations Between Cerebrospinal Fluid (CSF) Amyloid-Tau (AT) Status and Longitudinal Biomarker Signs of β-Amyloid (Aβ) Accumulation and Neurodegeneration
Mean predicted trajectories of Aβ [18F]-florbetapir and [18F]–fluorodeoxyglucose (FDG) positron emission tomography (PET), as well as magnetic resonance imaging (MRI)–derived hippocampal volume according to CSF AT status (only in Alzheimer’s Disease Neuroimaging Initiative [ADNI]) are shown for individuals who were cognitively unimpaired (CU; A) or had mild cognitive impairment (MCI; B) at baseline. The mean predicted trajectories for the Aβ-PET and FDG-PET, as well as hippocampal volume are displayed with solid lines and 95% CIs. Trajectories were estimated including terms for CSF AT status, covariates (age, years of education, APOE ε4 genotype, sex), and the age × CSF AT status interaction. A+/− indicates CSF Aβ42/40 binary status, and T+/− indicates CSF p-tau181 binary status.
Figure 4.
Figure 4.. Cross-Sectional Differences in Tau Positron Emission Tomography (PET) Deposition by Cerebrospinal Fluid (CSF) Amyloid-Tau (AT) Status
Cross-sectional analysis examining differences in tau-PET uptake across CSF AT groups using [18F]-flortaucipir in Alzheimer’s Disease Neuroimaging Initiative (ADNI) (A) and [18F]-MK6240 in 2 Wisconsin cohorts, Wisconsin Alzheimer Disease Research Center and Wisconsin Registry for Alzheimer Prevention (WISC) (B). Linear models, including age, sex, APOEε4 status, and years of education as covariates were used in both cohorts. A+/− indicates CSF Aβ42/40 binary status, and T+/− indicates CSF p-tau181 binary status.
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