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Plasma biomarkers of amyloid, tau and neurodegeneration (ATN) need to be characterized in cognitively unimpaired (CU) elderly individuals. Here, the authors show plasma ATN biomarkers predict clinical deterioration and cognitive decline and show in a simulated clinical trial combining all three biomarkers reduced the required sample size.

A brief, self-administered digital cognitive test, in combination with a blood test, accurately detects clinical Alzheimer’s disease in primary care.

Asymmetrical distribution of tau pathology in Alzheimer’s disease is linked to asymmetrical amyloid-beta deposition, not reduced brain connectivity, suggesting regional vulnerability plays a key role in determining the distribution of tau pathology.

Montoliu-Gaya, Salvadó et al. develop a blood-based model using tau biomarkers measured in a single analysis enabling biological staging of Alzheimer’s disease to support the diagnosis, prognosis and identification of patients likely to benefit from targeted therapies.

This study shows that combinations of blood-based biomarkers can be used to predict cognitive decline and dementia due to Alzheimer’s disease in patients with mild cognitive impairment. Biomarkers for tau and neurodegeneration provided accurate prognosis of decline and conversion over four years.

The largest harmonized proteomic dataset of plasma, serum and cerebrospinal fluid samples across major neurodegenerative diseases reveals both disease-specific and transdiagnostic proteomic signatures, including a robust plasma profile associated with the APOEε4 genotype.

Ossenkoppele, Coomans and colleagues analyzed the tau PET data of 12,048 individuals from 42 cohorts worldwide. They found that age, amyloid-β status, presence of an APOE ε4 allele and female sex are key contributors to tau PET positivity, which should aid clinical decision-making and trial designs.

Longitudinal study of plasma biomarkers, in two independent cohorts, highlighted only p-tau217 as a surrogate marker of disease progression in early Alzheimer’s disease, supporting the development of new disease-modifying treatments.

Plasma eMTBR-tau243 is a specific biomarker of tau tangles in Alzheimer’s disease and enables the detecting and tracking of Alzheimer’s clinical impairment.

Among 1,767 patients in 5 centers, a fully automated blood test showed high accuracy for Alzheimer’s pathology in secondary and primary care using a predefined cutoff.

DOPA decarboxylase (DDC) in cerebrospinal fluid has great diagnostic potential for Lewy body disorders. Here, the authors report limited diagnostic potential of plasma DDC and a strong association with dopaminergic treatment.

Ossenkoppele, Salvado et al. show that plasma p-tau217 and tau-PET predict cognitive decline equally well among cognitively unimpaired individuals. Their combined use further boosts prognostic accuracy. A sequential approach can enhance precision and efficiency of preclinical Alzheimer trials.

Cognitively impaired subjects with both Alzheimer’s disease and Lewy body pathology determined using in vivo CSF biomarkers showed faster global cognitive decline and more posterior cortical hypometabolism compared to those with AD pathology only.

Using human cerebrospinal fluid proteomics, the authors found that proteins associated with Aβ pathology in Alzheimer disease were mainly expressed in glial cells, whereas those associated with tau tangle were linked to metabolism and mainly expressed in neurons.

A screening strategy with plasma p-tau217, evaluated in two independent cohorts from Sweden and Canada, showed that this biomarker may effectively streamline tau-PET referrals in memory clinic settings, optimizing the prognostic work-up of Alzheimer’s disease.

A longitudinal study of clinically unimpaired individuals reveals that Lewy body pathology measured in vivo is associated with worse smell and cognitive functions and predicted subsequent cognitive decline and progression to Parkinson’s disease or dementia with Lewy bodies.

Prospective and longitudinal analyses of patients with cognitive impairment reveal that in vivo detection of Lewy body pathology is independently associated with hallucinations, worse attention/executive, visuospatial and motor function and predicted future cognitive decline.

CSF biomarker concentrations may be influenced by non-disease related interindividual variability. Here, the authors show that reference proteins can capture this variability and enhance the accuracy of Alzheimer’s disease biomarkers.

The interplay between amyloid and tau pathology in Alzheimer’s disease is still not well understood. Here, the authors show that amyloid-related increased in soluble p-tau is related to subsequent accumulation of tau aggregates and cognitive decline in early stage of the disease.

The performance of plasma %p-tau217 is clinically equivalent in classification of Aβ PET status and superior in classification of tau PET status compared to clinically used and FDA-approved CSF tests in cognitively impaired participants.

Plasma P-tau, in combination with clinical measures, predicts future Alzheimer’s disease dementia in two independent cohorts with high accuracy and is superior to the clinical diagnostic predictions of specialists.

Here the authors identify genetic effectors of the level of inflammation-related plasma proteins and use Mendelian randomization to identify proteins that contribute to immune-mediated disease risk.

CSF MTBR-tau243 is more related to tau tangles and clinical cognitive impairment in Alzheimer’s disease than phospho-tau biomarkers, which are more related to amyloid plaques.

Andersson et al. identify that high Aβ₄₂/Aβ₄₀ ratios in brain protofibrils best predict lower Aβ₄₂/Aβ₄₀ ratios in the cerebrospinal fluid (CSF) and higher neurofilament light/total tau levels, indicating that CSF changes in Alzheimer’s disease reflect soluble protofibrils more accurately than amyloid plaques.

Therriault et al. provide a framework for the individual-level interpretation of plasma biomarkers by determining their positive and negative predictive values for amyloid positron emission tomography status in relation to patient age and clinical symptoms.

Individuals with young onset sporadic Alzheimer’s disease show faster pathological and clinical progression. Here the authors report that earlier symptom onset in Alzheimer’s disease is associated with higher tau pathology in globally connected brain hubs, accelerated connectivity-mediated tau spreading and faster cognitive decline.

Pereira, Kumar et al. identify cerebrospinal fluid DOPA decarboxylase as a promising biomarker for Parkinsonian disorders that may be used for early preclinical detection of Parkinsonian disorders as well as determining the risk of conversion to Lewy body disease.

The authors show that higher concentrations of disease-associated microglial activation stage 2 (DAM2) markers are associated with reduced tau accumulation and slower cognitive decline in nondemented individuals at risk for developing Alzheimer’s disease, suggesting that microglial activation delays disease progression.

Many fluid biomarker findings have had low reproducibility despite initially promising results. Here, the authors review possible sources for low reproducibility of studies on fluid biomarkers for neurodegenerative diseases and suggest guidelines for the biomarker community to agree on and implement.