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

Neuron, Год журнала: 2023, Номер 111(18), С. 2781 - 2799

Опубликована: Июнь 8, 2023

Язык: Английский

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Plasma phospho-tau in Alzheimer’s disease: towards diagnostic and therapeutic trial applications

Molecular Neurodegeneration, Год журнала: 2023, Номер 18(1)

Опубликована: Март 16, 2023

As the leading cause of dementia, Alzheimer's disease (AD) is a major burden on affected individuals, their families and caregivers, healthcare systems. Although AD can be identified diagnosed by cerebrospinal fluid or neuroimaging biomarkers that concord with neuropathological evidence clinical symptoms, challenges regarding practicality accessibility hinder widespread availability implementation. Consequently, many people suspected cognitive impairment due to do not receive biomarker-supported diagnosis. Blood have capacity help expand access diagnostics worldwide. One such promising biomarker plasma phosphorylated tau (p-tau), which has demonstrated specificity versus non-AD neurodegenerative diseases, will extremely important inform diagnosis eligibility for therapies recently been approved. This review provides an update diagnostic prognostic performances p-tau181, p-tau217 p-tau231, associations in vivo autopsy-verified pathological hallmarks. Additionally, we discuss potential applications unanswered questions p-tau therapeutic trials, given recent addition toolbox participant screening, recruitment during-trial monitoring. Outstanding include assay standardization, threshold generation verification diverse cohorts reflective wider community attending memory clinics included trials.

Язык: Английский

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A novel ultrasensitive assay for plasma p‐tau217: Performance in individuals with subjective cognitive decline and early Alzheimer's disease

Alzheimer s & Dementia, Год журнала: 2023, Номер 20(2), С. 1239 - 1249

Опубликована: Ноя. 17, 2023

Abstract INTRODUCTION Detection of Alzheimer's disease (AD) pathophysiology among individuals with mild cognitive changes and those experiencing subjective decline (SCD) remains challenging. Plasma phosphorylated tau 217 (p‐tau217) is one the most promising emerging biomarkers for AD. However, accessible methods are limited. METHODS We employed a novel p‐tau217 immunoassay (University Gothenburg [UGOT] p‐tau217) in four independent cohorts ( n = 308) including cerebrospinal fluid (CSF) biomarker‐classified cohort (Discovery), two consisting mostly cognitively unimpaired (CU) impaired (MCI) participants (MYHAT Pittsburgh), population‐based SCD (Barcelonaβeta Brain Research Center's At‐Risk Cohort [β‐AARC]). RESULTS UGOT showed high accuracy (area under curve [AUC] 0.80–0.91) identifying amyloid beta (Aβ) pathology, determined either by Aβ positron emission tomography or CSF Aβ42/40 ratio. In SCD, positive ratio (AUC 0.91). DISCUSSION can be an easily efficient way to screen monitor patients suspected AD pathophysiology, even early stages continuum.

Язык: Английский

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Blood-based biomarkers in Alzheimer’s disease – moving towards a new era of diagnostics

Clinical Chemistry and Laboratory Medicine (CCLM), Год журнала: 2024, Номер 62(6), С. 1063 - 1069

Опубликована: Янв. 22, 2024

Abstract Alzheimer’s disease (AD), a primary cause of dementia globally, is traditionally diagnosed via cerebrospinal fluid (CSF) measures and positron emission tomography (PET). The invasiveness, cost, limited accessibility these methods have led to exploring blood-based biomarkers as promising alternative for AD diagnosis monitoring. Recent advancements in sensitive immunoassays identified potential biomarkers, such Aβ42/Aβ40 ratios phosphorylated tau (p-tau) species. This paper briefly evaluates the clinical utility reliability across various stages, highlighting challenges like refining plasma assays enhancing precision p-tau, particularly p-tau181, p-tau217, p-tau231. discussion also covers other neurofilament light (NfL), glial fibrillary acidic protein (GFAP), synaptic assessing their significance diagnostics. need ongoing research development robust match performance CSF PET underscored. In summary, are increasingly crucial diagnosis, follow-up, prognostication, treatment response evaluation, population screening, care settings. These developments set revolutionize diagnostics, offering earlier more accessible detection management options.

Язык: Английский

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Alzheimer's disease pathophysiology in the Retina

Progress in Retinal and Eye Research, Год журнала: 2024, Номер 101, С. 101273 - 101273

Опубликована: Май 15, 2024

The retina is an emerging CNS target for potential noninvasive diagnosis and tracking of Alzheimer's disease (AD). Studies have identified the pathological hallmarks AD, including amyloid β-protein (Aβ) deposits abnormal tau protein isoforms, in retinas AD patients animal models. Moreover, structural functional vascular abnormalities such as reduced blood flow, Aβ deposition, blood-retinal barrier damage, along with inflammation neurodegeneration, been described mild cognitive impairment dementia. Histological, biochemical, clinical studies demonstrated that nature severity pathologies brain correspond. Proteomics analysis revealed a similar pattern dysregulated proteins biological pathways patients, enhanced inflammatory neurodegenerative processes, impaired oxidative-phosphorylation, mitochondrial dysfunction. Notably, investigational imaging technologies can now detect AD-specific deposits, well vasculopathy neurodegeneration living suggesting alterations at different stages links to pathology. Current exploratory ophthalmic modalities, optical coherence tomography (OCT), OCT-angiography, confocal scanning laser ophthalmoscopy, hyperspectral imaging, may offer promise assessment AD. However, further research needed deepen our understanding AD's impact on its progression. To advance this field, future require replication larger diverse cohorts confirmed biomarkers standardized retinal techniques. This will validate aiding early screening monitoring.

Язык: Английский

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Plasma brain-derived tau is an amyloid-associated neurodegeneration biomarker in Alzheimer’s disease

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Апрель 4, 2024

Abstract Staging amyloid-beta (Aβ) pathophysiology according to the intensity of neurodegeneration could identify individuals at risk for cognitive decline in Alzheimer’s disease (AD). In blood, phosphorylated tau (p-tau) associates with Aβ but an AD-type biomarker has been lacking. this multicenter study ( n = 1076), we show that brain-derived (BD-tau) blood increases concomitant (“A”) and (“N”) abnormalities (determined using cerebrospinal fluid biomarkers); We used blood-based A/N biomarkers profile participants study; p-tau+/BD-tau+ profiles had fastest atrophy rates, irrespective baseline status. Furthermore, BD-tau showed no or much weaker correlations age, renal function, other comorbidities/risk factors self-identified race/ethnicity, compared biomarkers. Here is a identifying Aβ-positive short-term atrophy, implications clinical trials implementation anti-Aβ therapies.

Язык: Английский

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Alzheimer’s disease: insights into pathology, molecular mechanisms, and therapy

Protein & Cell, Год журнала: 2024, Номер unknown

Опубликована: Май 11, 2024

Abstract Alzheimer’s disease (AD), the leading cause of dementia, is characterized by accumulation amyloid plaques and neurofibrillary tangles in brain. This condition casts a significant shadow on global health due to its complex multifactorial nature. In addition genetic predispositions, development AD influenced myriad risk factors, including aging, systemic inflammation, chronic conditions, lifestyle, environmental exposures. Recent advancements understanding pathophysiology are paving way for enhanced diagnostic techniques, improved assessment, potentially effective prevention strategies. These discoveries crucial quest unravel complexities AD, offering beacon hope management treatment options millions affected this debilitating disease.

Язык: Английский

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Alzheimer blood biomarkers: practical guidelines for study design, sample collection, processing, biobanking, measurement and result reporting

Molecular Neurodegeneration, Год журнала: 2024, Номер 19(1)

Опубликована: Май 15, 2024

Abstract Alzheimer’s disease (AD), the most common form of dementia, remains challenging to understand and treat despite decades research clinical investigation. This might be partly due a lack widely available cost-effective modalities for diagnosis prognosis. Recently, blood-based AD biomarker field has seen significant progress driven by technological advances, mainly improved analytical sensitivity precision assays measurement platforms. Several biomarkers have shown high potential accurately detecting pathophysiology. As result, there been considerable interest in applying these prognosis, as surrogate metrics investigate impact various covariates on pathophysiology accelerate therapeutic trials monitor treatment effects. However, standardization how blood samples collected, processed, stored analyzed reported can affect reproducibility measurements, potentially hindering toward their widespread use settings. To help address issues, we provide fundamental guidelines developed according recent findings sample handling measurements. These cover important considerations including study design, collection, processing, biobanking, measurement, result reporting. Furthermore, proposed include best practices appropriate procedures genetic ribonucleic acid analyses. While focus key AT(N) criteria (e.g., amyloid-beta [Aβ]40, Aβ42, Aβ42/40 ratio, total-tau, phosphorylated-tau, neurofilament light chain, brain-derived tau glial fibrillary acidic protein), anticipate that will generally applicable other types biomarkers. We also assist investigators planning executing research, enabling harmonization improve comparability across studies.

Язык: Английский

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Phospho-tau serine-262 and serine-356 as biomarkers of pre-tangle soluble tau assemblies in Alzheimer’s disease

Nature Medicine, Год журнала: 2025, Номер unknown

Опубликована: Фев. 10, 2025

Patients with Alzheimer's disease (AD) little or no quantifiable insoluble brain tau neurofibrillary tangle (NFT) pathology demonstrate stronger clinical benefits of therapies than those advanced NFTs. The formation NFTs can be prevented by targeting the intermediate soluble assemblies (STAs). However, biochemical understanding and biomarkers STAs are lacking. We show that Tris-buffered saline-soluble aggregates from autopsy-verified AD tissues include core sequence ~tau258-368. In neuropathological assessments, antibodies against phosphorylation sites serine-262 serine-356 within STA almost exclusively stained granular (that is, prefibrillar) in pre-NFTs while at serine-202 threonine-205 threonine-231, outside core, entire spectrum mature NFTs, dystrophic neurites neuropil threads hippocampus. Functionally, a recombinantly produced peptide robustly altered neuronal excitability synaptic transmission mouse hippocampal slices. Furthermore, we developed cerebrospinal fluid assay differentiated non-AD tauopathies, correlated severity NFT burden cognitive decline independently amyloid beta deposition, positron emission tomography uptake across Braak stages. Together, our findings inform about status early-stage aggregation, reveal aggregation-relevant epitopes offer diagnostic biomarker targeted therapeutic opportunities for AD.

Язык: Английский

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Plasma p-tau181 and p-tau217 in discriminating PART, AD and other key neuropathologies in older adults

Acta Neuropathologica, Год журнала: 2023, Номер 146(1), С. 1 - 11

Опубликована: Апрель 9, 2023

We examined whether plasma p-tau181 and p-tau217 are specific biomarkers of pathologically confirmed Alzheimer's disease (AD). In particular, we investigated the utility p-tau for differentiating AD from primary age-related tauopathy (PART), as well with mixed pathologies. Data came 269 older adults who participated in Religious Orders Study or Rush Memory Aging Project. Blood samples were collected during annual clinical evaluations. Participants died underwent brain autopsy. P-tau181 quantified proximate to death (average interval before death: 1.4 years) using Lilly-developed MSD immunoassays. Uniform neuropathologic evaluations assessed AD, PART, other common degenerative cerebrovascular conditions. Plasma was more strongly correlated β-amyloid paired helical filament tau (PHFtau) tangles than p-tau181. Both markers associated greater odds but had higher accuracy (area under ROC curve (AUC): 0.83) (AUC: 0.76). almost exclusively pathologic indices exception cerebral amyloid angiopathy. Compared p-tau181, showed a AUC (0.82 versus 0.74) PART. For either p-tau, did not observe level difference between individuals alone those summary, p-tau181and specifically pathological changes. Further, our data provide initial evidence that may be able differentiate PART comparable burdens tangle pathology. These results demonstrate specificity supporting its use identify patients suitable anti-AD therapies including immunotherapies.

Язык: Английский

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