Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder characterized by the deposition of amyloid-β (Aβ) in the walls of leptomeningeal and cortical blood vessels that increases risk of intracerebral hemorrhages and progressive cognitive decline. More than 90
Blood biomarkers have emerged as accurate tools for detecting Alzheimer's disease (AD) pathology, offering a minimally invasive alternative to traditional diagnostic methods such as imaging and cerebrospinal fluid (CSF) analysis. Yet, the logistics surrounding venipuncture for blood collection, although considerably simpler than the acquisition of imaging and CSF, require precise processing and storage specific to AD biomarkers that are still guided by medical personnel. Consequently, limitations in their widescale use in research and broader clinical implementation exist. The DROP-AD project investigates the potential of dried plasma spot (DPS) and dried blood spot (DBS) analysis, derived from capillary blood, for detecting AD biomarkers, including phosphorylated tau at amino acid 217 (p-tau217), glial fibrillary acidic protein and neurofilament light. Here, 337 participants from 7 centers were included, with 304 participants providing paired capillary DPS or DBS and venous plasma samples. We observed strong correlations between DPS p-tau217 and venous plasma p-tau217 (r(S) = 0.74, P < 0.001). DPS p-tau217 progressively increased with increasing disease severity, and showed good accuracy in predicting CSF biomarker positivity (area under the curve = 0.864). Similarly, we demonstrated the successful detection of glial fibrillary acidic protein and neurofilament light with strong correlations between DBS and DPS, respectively, using paired venous plasma samples. Notably, the method was also effective in individuals with Down syndrome, a population at high genetic risk for AD but in whom standard blood sampling by venipuncture may be more complicated, revealing elevated biomarkers in those with dementia compared with asymptomatic individuals. The study also explored unsupervised blood collection, finding high concordance between supervised and self-collected samples. These findings underscore the potential of dried blood collection and capillary blood as a minimally invasive, scalable approach for AD biomarker testing in research settings. Yet, further refinement of collection and analytical protocols is needed to fully translate this approach to be viable and useful as a clinical tool.
BACKGROUND:Evidence, including animal, clinical, and real-world studies in individuals with type 2 diabetes and/or obesity, suggests reduced risk of dementia and Alzheimer's disease after GLP-1 receptor agonist exposure. The evoke and evoke+ trials aimed to investigate the efficacy and safety of oral semaglutide in individuals with early Alzheimer's disease. METHODS:evoke and evoke+ were multicentre, randomised, double-blind, placebo-controlled phase 3 trials conducted across 566 sites in 40 countries. The trials assessed the efficacy and safety of oral semaglutide up to 14 mg once daily in participants with amyloid-confirmed Alzheimer's disease, aged 55-85 years, with mild cognitive impairment or mild dementia due to Alzheimer's disease. In evoke+, participants with significant small vessel pathology were included. Participants were randomly assigned (1:1) to once-daily semaglutide 14 mg (flexible dose) or placebo for up to 156 weeks. The primary endpoint was change in Clinical Dementia Rating-Sum of Boxes (CDR-SB) score from baseline to week 104, assessed in all randomised participants. Safety was assessed in all randomised participants and reported for those receiving at least one dose of study drug. These trials were registered at ClinicalTrials.gov (NCT04777396 and NCT04777409); both trials have been discontinued due to negative clinical outcome. FINDINGS:Between May 18, 2021, and Sept 8, 2023, 9981 participants were screened, of whom 3808 were randomly assigned; 1855 in evoke (semaglutide, n=928; placebo, n=927) and 1953 in evoke+ (semaglutide, n=976; placebo, n=977). Mean age was 72·2 years (SD 7·1), and mean CDR-SB score was 3·7 (SD 1·6) at baseline. In evoke+, 54 (2·8%) participants had small vessel pathology. In evoke and evoke+, mean changes in CDR-SB score from baseline to week 104 were 2·3 (SE 0·1) and 2·2 (0·1) with semaglutide, compared with 2·3 (0·1) and 2·1 (0·1) with placebo (estimated difference -0·08 [95% CI -0·35 to 0·20], p=0·57 in evoke and 0·10 [-0·17 to 0·38], p=0·46 in evoke+). Treatment-emergent adverse events were reported in 1729 (91·2%) of 1896 participants receiving semaglutide versus 1613 (84·8%) of 1902 receiving placebo. There were five fatalities considered treatment-related by the investigators (one in the semaglutide group and four in the placebo group). INTERPRETATION:Oral semaglutide was not efficacious in slowing clinical progression in participants with early Alzheimer's disease. Safety and tolerability of semaglutide in early Alzheimer's disease is consistent with studies in other indications. FUNDING:Novo Nordisk.
INTRODUCTION:The glucagon-like peptide-1 receptor agonist semaglutide may impact neuroinflammation and reduce neurodegeneration. We present baseline characteristics of participants enrolled in the evoke (NCT04777396) and evoke+ (NCT04777409) trials, referred to as "evoke (+)" hereafter. METHODS:Evoke (+) are two ongoing global, multicenter, randomized, double-blind, parallel-group, placebo-controlled phase 3 trials investigating semaglutide in participants with early-stage symptomatic Alzheimer's disease (AD) with confirmed amyloid positivity (by positron emission tomography or cerebrospinal fluid testing). Inclusion criteria are the same for both trials, except that by design, evoke+ also includes participants with significant small vessel pathology. Both trials include a 12-week screening phase before randomization (1:1) to receive oral semaglutide titrated to 14 mg or placebo for 156 weeks. Baseline data were summarized and analyzed descriptively. Additionally, data were pooled and assessed by five main geographical regions. RESULTS:Evoke (+) recruited 9996 participants from 566 sites in 40 countries. The mean (standard deviation) age of participants was 71.8 (7.1) and 72.6 (7.1) years in evoke and evoke+, respectively; more participants were female than male (female: 53.0% and 51.9%, respectively) and most had a Clinical Dementia Rating (CDR) global score of 0.5 (72.8% and 71.4%; CDR global score of 1: 26.5% and 27.6%). Both trial populations had similar demographics, and clinical and cognitive baseline characteristics, except that 2.8% of participants in evoke+ had magnetic resonance imaging-documented significant small vessel pathology as per protocol inclusion criteria. Regional-level data demonstrated some differences in AD treatment characteristics, including cholinesterase inhibitor use of 41.7% in North America versus 61.6% in Asia. DISCUSSION:Evoke (+) are the only large-scale, phase 3 trials investigating the longer-term efficacy and safety of semaglutide in early AD as a potential disease-modifying treatment. The baseline characteristics from evoke (+) reflect a varied, global population with early-stage symptomatic AD. Primary readouts are expected in the second half of 2025. Highlights:evoke and evoke+ are the only large-scale randomized controlled trials (RCTs) investigating the longer-term efficacy and safety of semaglutide in early AD.Baseline characteristics reflect a varied, global population.The trials' primary readouts are expected in the second half of 2025.
Importance:Blood-based biomarkers (BBMs) demonstrate high accuracy in detecting Alzheimer disease (AD) pathological changes in symptomatic individuals. In autosomal dominant AD and in individuals with Down syndrome, both populations with near-universal development of AD pathology, elevations in BBMs are detectable years before clinical onset, supporting their utility for identifying preclinical disease in these cases. Among BBMs, plasma phosphorylated tau 217 (p-tau217) exhibits strong concordance with established in vivo markers of AD pathology. However, its ability to identify older adults without cognitive impairment who are amyloid-positive remains variable across studies and settings. Objective:To assess the standardized effect size of mean differences and classification accuracy of p-tau217 for published studies that compared amyloid-positive and amyloid-negative older adults without cognitive impairment. Data Sources:PubMed, Embase, and EBSCOhost databases from inception to September 1, 2025. Study Selection:Observational studies or randomized clinical trials with baseline data on individuals without cognitive impairment who were classified as either amyloid positive or amyloid negative and reported numeric data for p-tau217 levels. Data Extraction and Synthesis:The Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) reporting guideline was used for this study. Two authors independently carried out literature searches to identify studies with older adults without cognitive impairment who were classified as either amyloid positive or amyloid negative where p-tau217 was quantified. Main Outcome and Measure:The standardized mean difference (Hedges g) was used to characterize differences in mean p-tau217 levels. A pooled area under the curve (AUC) value was used to summarize the diagnostic accuracy of p-tau217 in identifying amyloid-positive individuals. Between-study heterogeneity was investigated using subgroup and sensitivity analyses. Publication bias was assessed using Egger tests. Results:Data for 7834 participants (2533 amyloid positive, 5301 amyloid negative) from 18 publications were analyzed. A large effect size was observed for p-tau217 (Hedges g = 1.50; 95% CI, 1.33-1.68). Values for p-tau217 also demonstrated high accuracy for identifying amyloid-positive individuals without cognitive impairment (AUC = 0.87; 95% CI, 0.85-0.90). Conclusion and Relevance:These findings demonstrate that plasma p-tau217 can reliably detect AD pathology in the preclinical stage. These findings support the clinical utility of plasma p-tau217 as a scalable, minimally invasive tool for early identification of AD, particularly in settings where timely intervention with disease-modifying therapies may offer the greatest benefit in slowing or preventing disease progression.
