Alzheimer's Research & Therapy最新文献

Tau pathology is a defining feature of Alzheimer's disease (AD), with hyperphosphorylated Tau (p‑Tau) emerging as a central biomarker for early diagnosis and disease monitoring. Various p‑Tau epitopes have demonstrated superior diagnostic precision and now form the molecular basis of updated AD diagnostic frameworks. Classical immunoassays such as enzyme-linked immunosorbent assay (ELISA), chemiluminescent enzyme immunoassay (CLEIA), and single molecule array (SIMOA) remain central to fluid based detection, offering high sensitivity and clinical validation. Recent advances in tau biology, especially in post-translational modifications, have driven the development of next generation biosensors. Electrochemical, optical, and nanostructured platforms now enable real-time, label-free, and attomolar level detection of p‑Tau in biofluids and live cell models. These systems are increasingly portable and suitable for point of care or in vivo applications. This review highlights the evolution of p‑Tau detection technologies, from benchmark immunoassays to cutting edge biosensors. Special attention is given to advanced affinity reagents, including aptamers, synthetic peptides, and antibody mimetics, which enhance biosensor specificity, stability, and translational potential. Together, these innovations are redefining AD diagnostics, enabling early intervention and more effective disease monitoring.

Background: As understanding of biomarkers for genetic frontotemporal dementia (FTD) advances, there is a need to develop onset-predictive biomarker tests (OPBTs) to detect changes before the onset of symptoms. OPBTs can be used to recruit carriers or individuals at 50% risk of carriership into clinical trials of investigational therapies targeting the preclinical and prodromal phases of FTD. OPBT results should be disclosed as part of the informed consent process, with positive results indicating that symptom onset is likely in the next few years. This information can be psychologically burdensome, especially in individuals at 50% risk, for whom a positive OPBT result would reveal their genetic status. There is a need for ethical guidance for disclosure processes to help researchers implement disclosure of OPBT results responsibly at their study sites.

Methods: Existing literature on disclosure of genetic and biomarker results in neurodegenerative conditions informed the design of this disclosure process for OPBT in FTD. Drafts were discussed with the multidisciplinary research team, scientific and clinical FTD experts across European countries, and other stakeholders and revised accordingly.

Results: The suggested disclosure process provides guidance for first-time or repeated disclosure of OPBT results to carriers or individuals at 50% risk of genetic FTD in research settings.

Conclusions: Researchers involved in clinical trials using OPBTs can adopt this disclosure process as a framework for responsible communication of OPBT results at their study site. The process was designed for international applicability and facilitates the alignment of disclosure processes for clinical trial recruitment across European countries.

Background: Multidomain lifestyle interventions have shown effectiveness in preventing dementia, but identifying high-risk groups most likely to benefit remains unclear.

Methods: We re-evaluated the SUPERBRAIN-MEET multidomain intervention study in mild cognitive impairment (MCI) patients, incorporating polygenic risk scores (PRS) for Alzheimer's disease and APOE ε4 status using Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) total index as the primary outcome.

Results: Both intervention and control groups showed cognitive improvement over 24 weeks, with greater gains in the intervention arm. Relative intervention efficacy (RIE) increased with higher genetic risk, being most pronounced among APOE ε4 carriers and individuals with high PRS. When both factors were considered jointly, APOE ε4 carriers with high PRS exhibited the largest RIE (β = 7.54, SE = 2.59, p = 0.005), driven by markedly greater improvement in the intervention group. The secondary outcomes did not show as consistent results as RBANS total index.

Discussion: These findings suggest that MCI individuals who are APOE ε4 carriers with high PRS may benefit most from multidomain interventions. These results support the complementary use of PRS and APOE status for identifying high-risk subgroups most likely to benefit from multidomain interventions.

Trial registration: ClinicalTrials.gov identifier: NCT05023057. Registered on 26 August 2021.

Background: Early identification of cognitive impairment and brain pathology associated with Alzheimer's disease (AD) is essential to maximize benefits from lifestyle interventions and emerging pharmacologic disease-modifying treatments (DMT). Digital cognitive assessments (DCAs) can quickly capture an array of metrics that can be used to train machine-learning (ML) models to concurrently evaluate different outcomes. DCAs have the potential to optimize clinical workflows and enable efficient assessment of cognitive function and the likelihood of a given underlying pathology.

Methods: We assessed the ability of a multimodal ML-enabled DCA, the Digital Clock and Recall (DCR), to concurrently estimate brain amyloid-beta (Aβ) status and detect cognitive impairment, as compared with traditional cognitive assessments, including the MMSE, RAVLT, a DCA, Cognivue^®, and blood-based biomarkers in 930 participants from the Bio-Hermes-001 clinical study.

Results: Aβ42/40, p-tau181, APS, and p-tau217 poorly classified cognitive impairment (AUCs: 0.61; 0.63; 0.63; 0.70, respectively), but accurately classified Aβ status (AUCs: 0.81; 0.78; 0.85, 0.89, respectively). MMSE, RAVLT, and Cognivue poorly classified Aβ status (AUCs: 0.70, 0.73, 0.70, respectively). However, separate multimodal, DCR-based ML classification models, run in parallel, accurately classified both cognitive impairment (AUC = 0.83) and Aβ-PET status (AUC = 0.81).

Conclusions: DCAs that leverage digital technologies to generate advanced metrics, such as the DCR, enable accurate and efficient detection of cognitive impairment associated with AD pathology. They have the potential to empower health systems and primary care providers to help their patients make timely treatment decisions.

Background: Although past screening cohorts have suggested a decline in the risk of dementia, it is important to monitor the population-level incidence and survival of diagnosed dementia, to inform care utilization and public health policies. This study provides nationwide analyses on time trends in the incidence of dementia diagnosis in Sweden between 2007 and 2022, as well as 5-year survival after a dementia diagnosis.

Methods: Data from the total Swedish population aged ≥ 61 years during the period 2007-2022 were used. Incident dementia diagnoses were identified from specialist care and dispensed anti-dementia drugs. The annual incidence rate of dementia diagnosis was calculated for the period 2007-2022. The proportion of individuals that survived 5 years after dementia diagnosis was compared across years of diagnosis. Health status at dementia diagnosis was assessed by calculating Charlson Comorbidity Index and Hospital Frailty Risk Score.

Results: Annual incidence rate of dementia diagnosis decreased from early 2010s and onwards, particularly among older age groups of 80-89 and ≥ 90 years. Mean age at dementia diagnosis remained constant, i.e., 82.2 years during 2007-2009 and 82.2 years during 2019-2022. The proportion of individuals with frailty at diagnosis increased from 74.3% in 2007-2009 to 80.6% in 2019-2022 (odds ratio (OR) = 1.42, 95% confidence interval (CI): 1.39-1.46); the proportion of individuals with comorbidities also increased over the same period. The proportion that survived 5 years since dementia diagnosis remained constant at 33% during 2007-2017 but improved over time when accounting for comorbidity and frailty level at diagnosis.

Conclusions: While the incidence of dementia diagnosis has declined from early 2010s and onwards, patients diagnosed today are on average frailer and more comorbid than those diagnosed 15 years ago, which partly explains the lack of improvement in dementia survival over time. Enhancing healthcare planning for people with dementia diagnosis and improving their survival is still highly relevant.