Revised criteria for diagnosis and staging of Alzheimer's disease: Alzheimer's Association Workgroup

Alzheimer s & Dementia, Journal Year: 2024, Volume and Issue: 20(8), P. 5143 - 5169

Published: June 27, 2024

Abstract The National Institute on Aging and the Alzheimer's Association convened three separate work groups in 2011 single 2012 2018 to create recommendations for diagnosis characterization of disease (AD). present document updates research framework response several recent developments. Defining diseases biologically, rather than based syndromic presentation, has long been standard many areas medicine (e.g., oncology), is becoming a unifying concept common all neurodegenerative diseases, not just AD. consistent with this principle. Our intent objective criteria staging AD, incorporating advances biomarkers, serve as bridge between clinical care. These are intended provide step‐by‐step practice guidelines workflow or specific treatment protocols, but general principles inform AD that reflect current science. Highlights We define (AD) be biological process begins appearance neuropathologic change (ADNPC) while people asymptomatic. Progression burden leads later progression symptoms. Early‐changing Core 1 biomarkers (amyloid positron emission tomography [PET], approved cerebrospinal fluid accurate plasma [especially phosphorylated tau 217]) map onto either amyloid beta tauopathy pathway; however, these presence ADNPC more generally (i.e., both neuritic plaques tangles). An abnormal biomarker result sufficient establish decision making throughout continuum. Later‐changing 2 (biofluid PET) can prognostic information, when abnormal, will increase confidence contributing integrated scheme described accommodates fact copathologies, cognitive reserve, resistance may modify relationships stages.

Language: Английский

---

Association of Phosphorylated Tau Biomarkers With Amyloid Positron Emission Tomography vs Tau Positron Emission Tomography

JAMA Neurology, Journal Year: 2022, Volume and Issue: 80(2), P. 188 - 188

Published: Dec. 12, 2022

Importance The recent proliferation of phosphorylated tau (p-tau) biomarkers has raised questions about their preferential association with the hallmark pathologies Alzheimer disease (AD): amyloid-β plaques and neurofibrillary tangles. Objective To determine whether cerebrospinal fluid (CSF) plasma p-tau preferentially reflect cerebral β-amyloidosis or tangle aggregation measured positron emission tomography (PET). Design, Setting, Participants This was a cross-sectional study 2 observational cohorts: Translational Biomarkers in Aging Dementia (TRIAD) study, data collected between October 2017 August 2021, Alzheimer’s Disease Neuroimaging Initiative (ADNI), September 2015 November 2019. TRIAD single-center ADNI multicenter study. Two independent subsamples were derived from TRIAD. first subsample comprised individuals assessed CSF (p-tau 181 , 217 231 235 ), [ 18 F]AZD4694 amyloid PET, F]MK6240 PET. second included An cohort F]florbetapir F]flortaucipir based on availability PET biomarker assessments within 9 months each other. Exclusion criteria history head trauma magnetic resonance imaging/PET safety contraindications. No participants who met eligibility excluded. Exposures Amyloid single molecule array (Simoa) assay enzyme-linked immunosorbent assay. Main Outcomes Measures Associations Results A total 609 (mean [SD] age, 66.9 [13.6] years; 347 female [57%]; 262 male [43%]) For all 4 phosphorylation sites CSF, significantly more closely associated amyloid-PET values than tau-PET difference, 13%; 95% CI, 3%-22%; P = .006; 11%; 3%-20%; .003; 15%; 5%-22%; < .001; 9%; 1%-19%; .02) . These results replicated (difference, 1%-22%; .02), 3%-24%; .009), 1%-21%; cohorts. Conclusions Relevance this cohorts suggest that abnormality as an early event AD pathogenesis accumulation highlights need for careful interpretation context amyloid/tau/neurodegeneration, A/T/(N), framework.

Language: Английский

---

Astrocyte biomarker signatures of amyloid-β and tau pathologies in Alzheimer’s disease

Molecular Psychiatry, Journal Year: 2022, Volume and Issue: 27(11), P. 4781 - 4789

Published: Aug. 10, 2022

Astrocytes can adopt multiple molecular phenotypes in the brain of Alzheimer's disease (AD) patients. Here, we studied associations cerebrospinal fluid (CSF) glial fibrillary acidic protein (GFAP) and chitinase-3-like 1 (YKL-40) levels with amyloid-β (Aβ) tau pathologies. We assessed 121 individuals across aging AD clinical spectrum positron emission tomography (PET) imaging for Aβ ([

Language: Английский

---

Equivalence of plasma p‐tau217 with cerebrospinal fluid in the diagnosis of Alzheimer's disease

Alzheimer s & Dementia, Journal Year: 2023, Volume and Issue: 19(11), P. 4967 - 4977

Published: April 20, 2023

Abstract INTRODUCTION Plasma biomarkers are promising tools for Alzheimer's disease (AD) diagnosis, but comparisons with more established needed. METHODS We assessed the diagnostic performance of p‐tau 181 , 217 and 231 in plasma CSF 174 individuals evaluated by dementia specialists amyloid‐PET tau‐PET. Receiver operating characteristic (ROC) analyses to identify tau‐PET positivity. RESULTS had lower dynamic ranges effect sizes compared p‐tau. (AUC = 76%) 82%) assessments performed inferior 87%) 95%) However, 91%) indistinguishable from 94%) DISCUSSION equivalent biomarker‐defined AD. Our results suggest that may help reduce need invasive lumbar punctures without compromising accuracy identification Highlights diagnosis AD, suggesting increased accessibility is not offset accuracy. mean fold‐changes between negative positive groups than CSF. greater when differentiating groups. worse AD diagnosis.

Language: Английский

---

Accelerating Alzheimer’s therapeutic development: The past and future of clinical trials

Cell, Journal Year: 2023, Volume and Issue: 186(22), P. 4757 - 4772

Published: Oct. 1, 2023

Alzheimer's disease (AD) research has entered a new era with the recent positive phase 3 clinical trials of anti-Aβ antibodies lecanemab and donanemab. Why did it take 30 years to achieve these successes? Developing potent therapies for reducing fibrillar amyloid was key, as selection patients at relatively early stages disease. Biomarkers target pathologies, including tau PET, insights from past were also critical successes. Moving forward, challenge will be develop more efficacious greater efficiency. Novel trial designs, combination umbrella basket protocols, accelerate development. Better diversity inclusivity participants are needed, blood-based biomarkers may help improve access medically underserved groups. Incentivizing innovation in both academia industry through public-private partnerships, collaborative mechanisms, creation career paths build momentum exciting times.

Language: Английский

---

Predicting amyloid PET and tau PET stages with plasma biomarkers

Brain, Journal Year: 2023, Volume and Issue: 146(5), P. 2029 - 2044

Published: Feb. 15, 2023

Abstract Staging the severity of Alzheimer’s disease pathology using biomarkers is useful for therapeutic trials and clinical prognosis. Disease staging with amyloid tau PET has face validity; however, this would be more practical plasma biomarkers. Our objectives were, first, to examine approaches and, second, prediction stages Participants (n = 1136) were enrolled in either Mayo Clinic Study Aging or Research Center; had a concurrent PET, blood draw; met criteria cognitively unimpaired 864), mild cognitive impairment 148) syndrome dementia 124). The latter two groups combined into impaired group 272). We used multinomial regression models estimate discrimination [concordance (C) statistics] among three (low, intermediate, high), four (Braak 0, 1–2, 3–4, 5–6) stage (none/low versus intermediate/high severity) as predictors separately within individuals. Plasma analytes, p-tau181, Aβ1–42 Aβ1–40 (analysed Aβ42/Aβ40 ratio), glial fibrillary acidic protein neurofilament light chain measured on HD-X Simoa Quanterix platform. p-tau217 was also subset 355) participants Lilly Meso Scale Discovery assay. Models all analytes along risk factors (age, sex APOE) most often provided best (C 0.78–0.82). p-tau181 similar 0.72–0.85 C 0.73–0.86). Discriminating proxy from none/low neuropathological change excellent but not better than only 0.88 0.87 0.91 0.90 impaired). outperformed assay discriminating high intermediate 0.85 0.74) did improve over model 0.83). can discriminate between surrogate accuracy acceptable range. Combinations are single many predictions exception that alone usually performed equivalently combinations discrimination.

Language: Английский

---

Biomarker-based staging of Alzheimer disease: rationale and clinical applications

Nature Reviews Neurology, Journal Year: 2024, Volume and Issue: 20(4), P. 232 - 244

Published: March 1, 2024

Language: Английский

---

Disease staging of Alzheimer’s disease using a CSF-based biomarker model

Nature Aging, Journal Year: 2024, Volume and Issue: 4(5), P. 694 - 708

Published: March 21, 2024

Abstract Biological staging of individuals with Alzheimer’s disease (AD) may improve diagnostic and prognostic workup dementia in clinical practice the design trials. In this study, we used Subtype Stage Inference (SuStaIn) algorithm to establish a robust biological model for AD using cerebrospinal fluid (CSF) biomarkers. Our analysis involved 426 participants from BioFINDER-2 was validated 222 Knight Alzheimer Disease Research Center cohort. SuStaIn identified singular biomarker sequence revealed that five CSF biomarkers effectively constituted reliable (ordered: Aβ42/40, pT217/T217, pT205/T205, MTBR-tau243 non-phosphorylated mid-region tau). The stages (0–5) demonstrated correlation increased abnormalities other AD-related biomarkers, such as Aβ-PET tau-PET, aligned longitudinal changes reflective progression. Higher at baseline were associated an elevated hazard ratio decline. This study highlights common molecular pathway underlying pathophysiology across all patients, suggesting single collection can accurately indicate presence pathologies characterize stage proposed has implications enhancing assessments both

Language: Английский

---

Comparison of two plasma p-tau217 assays to detect and monitor Alzheimer’s pathology

EBioMedicine, Journal Year: 2024, Volume and Issue: 102, P. 105046 - 105046

Published: March 11, 2024

Language: Английский

---

Serum GFAP levels correlate with astrocyte reactivity, post-mortem brain atrophy and neurofibrillary tangles

Brain, Journal Year: 2024, Volume and Issue: 147(5), P. 1667 - 1679

Published: Feb. 1, 2024

Glial fibrillary acidic protein (GFAP), a proxy of astrocyte reactivity, has been proposed as biomarker Alzheimer's disease. However, there is limited information about the correlation between blood biomarkers and post-mortem neuropathology. In single-centre prospective clinicopathological cohort 139 dementia patients, for which time-frame GFAP level determination neuropathological assessment was exceptionally short (on average days), we analysed this biomarker, measured at three time points, in relation to proxies disease progression such cognitive decline brain weight. Most importantly, investigated use detect hallmarks disease, while accounting potential influences most frequent co-pathologies. The main findings demonstrated an association serum tau pathology (β = 12.85; P < 0.001) that independent amyloid deposits 13.23; 0.02). A mediation analysis provided additional support role astrocytic activation link Furthermore, negative observed pre-mortem weight (r -0.35; 0.001). This finding, together with evidence assessments -0.27; 0.005), supports monitoring, even late phases Moreover, diagnostic performance advanced patients explored, its discriminative power (area under receiver operator characteristic curve baseline 0.91) differentiating neuropathologically-confirmed dementias from non-Alzheimer's determined, despite challenging scenario age co-pathologies these patients. Independently levels were shown be associated two other pathologies targeting temporal lobes-hippocampal sclerosis 3.64; 0.03) argyrophilic grain -6.11; Finally, revealed correlated using GFAP-immunostained area (ρ 0.21; Our results contribute increasing suggesting offer mechanistic insights into relationship neuropathology, highlighting ties burden. data lesions provide clinicians consider when interpreting test results. longitudinal design reinforce robustness our findings. studies correlating are still scant, further research needed replicate validate diverse populations.

Language: Английский

---