Amyloid and tau PET-positive cognitively unimpaired individuals are at high risk for future cognitive decline

Nature Medicine, Journal Year: 2022, Volume and Issue: 28(11), P. 2381 - 2387

Published: Nov. 1, 2022

A major unanswered question in the dementia field is whether cognitively unimpaired individuals who harbor both Alzheimer's disease neuropathological hallmarks (that is, amyloid-β plaques and tau neurofibrillary tangles) can preserve their cognition over time or are destined to decline. In this large multicenter amyloid positron emission tomography (PET) study (n = 1,325), we examined risk for future progression mild cognitive impairment rate of decline among were PET-positive (A+) (T+) medial temporal lobe (A+TMTL+) and/or neocortex (A+TNEO-T+) compared them with A+T- A-T- groups. Cox proportional-hazards models showed a substantially increased A+TNEO-T+ (hazard ratio (HR) 19.2, 95% confidence interval (CI) 10.9-33.7), A+TMTL+ (HR 14.6, CI 8.1-26.4) 2.4, 1.4-4.3) groups versus (reference) group. Both 6.0, 3.4-10.6) 7.9, 4.7-13.5) also faster clinical than Linear mixed-effect indicated that (β -0.056 ± 0.005, T -11.55, P < 0.001), -0.024 -4.72, 0.001) -0.008 0.002, -3.46, significantly longitudinal global group (all 0.001). (P 0.002) progressed summary, evidence advanced pathological changes provided by combination abnormal PET examinations strongly associated short-term 3-5 years) therefore high relevance.

Language: Английский

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Differential roles of Aβ42/40, p-tau231 and p-tau217 for Alzheimer’s trial selection and disease monitoring

Nature Medicine, Journal Year: 2022, Volume and Issue: 28(12), P. 2555 - 2562

Published: Dec. 1, 2022

Abstract Blood biomarkers indicative of Alzheimer’s disease (AD) pathology are altered in both preclinical and symptomatic stages the disease. Distinctive may be optimal for identification AD or monitoring progression. that correlate with changes cognition atrophy during course could used clinical trials to identify successful interventions thereby accelerate development efficient therapies. When disease-modifying treatments become approved use, blood-based might also inform on treatment implementation management practice. In BioFINDER-1 cohort, plasma phosphorylated (p)-tau231 amyloid-β42/40 ratio were more changed at lower thresholds amyloid pathology. Longitudinally, however, only p-tau217 demonstrated marked amyloid-dependent over 4–6 years disease, no such observed p-tau231, p-tau181, amyloid-β42/40, glial acidic fibrillary protein neurofilament light. Only longitudinal increases associated deterioration brain AD. The selective increase its associations cognitive decline was confirmed an independent cohort (Wisconsin Registry Prevention). These findings support differential association strongly highlight as a surrogate marker progression prodromal AD, impact new treatments.

Language: Английский

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Blood biomarkers for Alzheimer’s disease in clinical practice and trials

Nature Aging, Journal Year: 2023, Volume and Issue: 3(5), P. 506 - 519

Published: May 18, 2023

Language: Английский

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Astrocyte reactivity influences amyloid-β effects on tau pathology in preclinical Alzheimer’s disease

Nature Medicine, Journal Year: 2023, Volume and Issue: 29(7), P. 1775 - 1781

Published: May 29, 2023

Abstract An unresolved question for the understanding of Alzheimer’s disease (AD) pathophysiology is why a significant percentage amyloid-β (Aβ)-positive cognitively unimpaired (CU) individuals do not develop detectable downstream tau pathology and, consequently, clinical deterioration. In vitro evidence suggests that reactive astrocytes unleash Aβ effects in pathological phosphorylation. Here, biomarker study across three cohorts ( n = 1,016), we tested whether astrocyte reactivity modulates association with phosphorylation CU individuals. We found was associated increased plasma phosphorylated only positive (Ast + ). Cross-sectional and longitudinal tau–positron emission tomography analyses revealed an AD-like pattern tangle accumulation as function Ast Our findings suggest important upstream event linking initial pathology, which may have implications biological definition preclinical AD selecting trials.

Language: Английский

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Highly accurate blood test for Alzheimer’s disease is similar or superior to clinical cerebrospinal fluid tests

Nature Medicine, Journal Year: 2024, Volume and Issue: 30(4), P. 1085 - 1095

Published: Feb. 21, 2024

With the emergence of Alzheimer's disease (AD) disease-modifying therapies, identifying patients who could benefit from these treatments becomes critical. In this study, we evaluated whether a precise blood test perform as well established cerebrospinal fluid (CSF) tests in detecting amyloid-β (Aβ) plaques and tau tangles. Plasma %p-tau217 (ratio phosporylated-tau217 to non-phosphorylated tau) was analyzed by mass spectrometry Swedish BioFINDER-2 cohort (n = 1,422) US Charles F. Joanne Knight Alzheimer Disease Research Center (Knight ADRC) 337). Matched CSF samples were with clinically used FDA-approved automated immunoassays for Aβ42/40 p-tau181/Aβ42. The primary secondary outcomes detection brain Aβ or pathology, respectively, using positron emission tomography (PET) imaging reference standard. Main analyses focused on individuals cognitive impairment (mild mild dementia), which is target population available treatments. equivalent classifying PET status, an area under curve (AUC) both between 0.95 0.97. generally superior classification tau-PET AUCs 0.95-0.98. cognitively impaired subcohorts (BioFINDER-2: n 720; ADRC: 50), plasma had accuracy, positive predictive value negative 89-90% 87-88% tests, further improving 95% two-cutoffs approach. Blood demonstrated performance that AD pathology. Use high-performance clinical practice can improve access accurate diagnosis AD-specific

Language: Английский

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Prediction of Longitudinal Cognitive Decline in Preclinical Alzheimer Disease Using Plasma Biomarkers

JAMA Neurology, Journal Year: 2023, Volume and Issue: 80(4), P. 360 - 360

Published: Feb. 6, 2023

Importance Alzheimer disease (AD) pathology starts with a prolonged phase of β-amyloid (Aβ) accumulation without symptoms. The duration this differs greatly among individuals. While has high relevance for clinical trial designs, it is currently unclear how to best predict the onset progression. Objective To evaluate combinations different plasma biomarkers predicting cognitive decline in Aβ-positive cognitively unimpaired (CU) Design, Setting, and Participants This prospective population-based prognostic study evaluated data from 2 longitudinal cohort studies (the Swedish BioFINDER-1 Wisconsin Registry Prevention [WRAP]), collected February 8, 2010, October 21, 2020, August 11, 2011, June 27, 2021, WRAP cohort. were CU individuals recruited memory clinics who had brain Aβ defined by cerebrospinal fluid (CSF) Aβ42/40 Pittsburgh Compound B (PiB) positron emission tomography (PET) study. A total 564 eligible Aβ-negative participants available relevant cohorts included study; those, 171 main analyses. Exposures Baseline P-tau181, P-tau217, P-tau231, glial fibrillary filament protein, neurofilament light measured plasma; CSF cohort, PiB PET uptake Main Outcomes Measures primary outcome was measures cognition (using Mini-Mental State Examination [MMSE] modified Preclinical Cognitive Composite [mPACC]) over median 6 years (range, 2-10 years). secondary conversion AD dementia. used linear regression models rates change (calculated separately). Models adjusted age, sex, education, apolipoprotein E ε4 allele status, baseline cognition. Multivariable compared based on model R coefficients corrected Akaike information criterion. Results Among analyses, 119 (mean [SD] 73.0 [5.4] years; 60.5% female) study, 52 64.4 [4.6] 65.4% In P-tau217 marker mPACC (model = 0.41) MMSE 0.34) superior covariates-only (mPACC: 0.23; MMSE: 0.04; P &amp;lt; .001 both comparisons). validated cohort; example, associated slopes ( 0.13 vs 0.01 model; .01) 0.29 0.24 .046). Sparse identified as predictor decline. Power calculations enrichment hypothetical trials revealed large relative reductions sample sizes when using enrich likely experience time. Conclusions Relevance predicted patients preclinical AD. These findings suggest that may be complement or participant selection novel disease-modifying treatments.

Language: Английский

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Plasma and CSF biomarkers in a memory clinic: Head‐to‐head comparison of phosphorylated tau immunoassays

Alzheimer s & Dementia, Journal Year: 2022, Volume and Issue: 19(5), P. 1913 - 1924

Published: Nov. 12, 2022

Abstract Introduction Direct comparisons of the main blood phosphorylated tau immunoassays in memory clinic populations are needed to understand possible differences. Methods In BIODEGMAR study, 197 participants presenting with cognitive complaints were classified into an Alzheimer's disease (AD) or a non‐AD cerebrospinal fluid (CSF) profile group, according their amyloid beta 42/ (Aβ42/p‐tau) ratio. We performed head‐to‐head comparison nine plasma and CSF determined accuracy discriminate abnormal Aβ42/p‐tau Results All studied biomarkers significantly higher AD group compared discriminated For p‐tau biomarkers, discrimination was shown by Janssen p‐tau217 ( r = 0.76; area under curve [AUC] 0.96), ADx p‐tau181 0.73; AUC 0.94), Lilly 0.94). Discussion Several can be used specialized as stand‐alone biomarker detect biologically‐defined AD. Highlights Patients (AD CSF) have (p‐tau) levels than group. patients from p‐tau217, p‐tau181, show highest biologically defined UGot p‐tau231 performances that comparable counterparts.

Language: Английский

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Anti-Amyloid Monoclonal Antibodies for the Treatment of Alzheimer’s Disease

BioDrugs, Journal Year: 2023, Volume and Issue: 38(1), P. 5 - 22

Published: Nov. 13, 2023

Two monoclonal antibodies (mAbs), aducanumab and lecanemab, have received accelerated approval from the US FDA for initiation of treatment in early Alzheimer's disease patients who proven β-amyloid pathology (Aβ). One these, has subsequently full other are poised positive review approval. Anti-amyloid mAbs share feature producing a marked reduction total brain Aβ revealed by amyloid positron emission tomography. Trials associated with slowing cognitive decline achieved measurable plaque range 15–25 centiloids; trials agents that did not reach this threshold were benefit. differences terms titration schedules, MRI monitoring schedules amyloid-related imaging abnormalities (ARIA), continuing versus interrupted therapy. The approximate 30% observed is clinically meaningful extended integrity delay onset more severe dementia phases disease. Approval these initiates new era therapeutics disease-modifying properties. Further advances needed, i.e. greater efficacy, improved safety, enhanced convenience, better understanding ill-understood observations such as volume loss.

Language: Английский

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Blood-based biomarkers for Alzheimer’s disease: Current state and future use in a transformed global healthcare landscape

Neuron, Journal Year: 2023, Volume and Issue: 111(18), P. 2781 - 2799

Published: June 8, 2023

Language: Английский

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CSF MTBR-tau243 is a specific biomarker of tau tangle pathology in Alzheimer’s disease

Nature Medicine, Journal Year: 2023, Volume and Issue: 29(8), P. 1954 - 1963

Published: July 13, 2023

Abstract Aggregated insoluble tau is one of two defining features Alzheimer’s disease. Because clinical symptoms are strongly correlated with aggregates, drug development and diagnosis need cost-effective accessible specific fluid biomarkers aggregates; however, recent studies suggest that the currently available cannot specifically track aggregates. We show microtubule-binding region (MTBR) containing residue 243 (MTBR-tau243) a new cerebrospinal (CSF) biomarker for aggregates compared it to multiple other phosphorylated measures (p-tau181, p-tau205, p-tau217 p-tau231) in independent cohorts (BioFINDER-2, n = 448; Knight Alzheimer Disease Research Center, 219). MTBR-tau243 was most associated tau-positron emission tomography (PET) cognition, whereas showing lowest association amyloid-PET. In combination explained total variance tau-PET burden (0.58 ≤ R 2 0.75) performance predicting cognitive (0.34 0.48) approached (0.44 0.52). levels longitudinally increased unlike CSF p-tau species. aggregate pathology, which may be utilized interventional trials patients. Based on these findings, we propose revise A/T/(N) criteria include as representing (‘T’).

Language: Английский

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