In response to a Cochrane review (published in April 2026) on the clinical trials of monoclonal antibodies targeting beta amyloid, this perspective outlines a number of critiques. The scientists, methodologists, subject-matter experts, and clinicians on this perspective strongly recommend that the Cochrane editorial board consider a call for editorial response, correction of press materials, or commissioned reply to this review for four overarching reasons: (1) decision to pool antibodies that do and do not clear beta amyloid, (2) decision to include studies from a time when biomarkers of Alzheimer's disease were not available, (3) analytical and methodological limitations of the approach used, (4) conflating the distinct roles and methodological processes of systematic review and guideline methodologies, (5) contextualizing the present critique within the existing evidence-synthesis literature, and (6) mechanistic inference beyond the scope of the presented analyses. Conclusions that may not accurately reflect treatment-specific effects could cause significant downstream clinical and psychosocial harm to those currently undergoing treatment and their family members as well as individuals considering participation in Alzheimer's clinical trials.

Identifying new interventions to slow and prevent cognitive decline associated with dementia is critical. Nonpharmacological interventions targeting modifiable risk factors are promising, relatively low-cost, accessible, and safe approaches. To compare the effects of two 2-year lifestyle interventions on cognitive trajectory in older adults at risk of cognitive decline and dementia. Single-blind, multicenter randomized clinical trial enrolling 2111 participants from May 2019 to March 2023 (final follow-up, May 14, 2025) at 5 clinical sites in the US. Participant inclusion criteria enriched risk of cognitive decline and included age 60 to 79 years, sedentary lifestyle, and suboptimal diet plus at least 2 additional criteria related to family history of memory impairment, cardiometabolic risk, race and ethnicity, older age, and sex. Participants were randomly assigned with equal probability to structured (n = 1056) or self-guided (n = 1055) interventions. Both interventions encouraged increased physical and cognitive activity, healthy diet, social engagement, and cardiovascular health monitoring, but differed in structure, intensity, and accountability. The primary comparison was difference between intervention groups in annual rate of change in global cognitive function, assessed by a composite measure of executive function, episodic memory, and processing speed, over 2 years. Among the 2111 individuals enrolled (mean age, 68.2 [SD, 5.2] years; 1455 [68.9%] female), 89% completed the year 2 assessment. The mean global cognitive composite z score increased from baseline over time in both groups, with a mean rate of increase per year of 0.243 SD (95% CI, 0.227-0.258) for the structured intervention and 0.213 SD (95% CI, 0.198-0.229) for the self-guided intervention. The mean rate of increase per year was statistically significantly greater for the structured group than the self-guided group by 0.029 SD (95% CI, 0.008-0.050; P = .008). Based on prespecified secondary subgroup comparisons, the structured intervention benefit was consistent for APOE ε4 carriers and noncarriers (P = .95 for interaction) but appeared greater for adults with lower vs higher baseline cognition (P = .02 for interaction). Fewer ascertained adverse events were reported in the structured group (serious: 151; nonserious: 1091) vs the self-guided group (serious: 190; nonserious: 1225), with a positive COVID-19 test result being the most common adverse event overall and more frequent in the structured group. Among older adults at risk of cognitive decline and dementia, a structured, higher-intensity intervention had a statistically significant greater benefit on global cognition compared with an unstructured, self-guided intervention. Further investigation of functional outcomes, biomarkers, and ongoing extended follow-up will help address clinical relevance and sustainability of the observed cognitive benefits. ClinicalTrials.gov Identifier: NCT03688126

Several neural mechanisms underlying resilience to Alzheimer's disease (AD) have been proposed, including redundant neural connections between the posterior hippocampi and all other brain regions, and global functional connectivity of the left frontal cortex (LFC). Here, we investigated if functional redundancy of the hippocampus (HC) and LFC underscores neural resilience in the presence of early AD pathologies. From the ADNI database, cognitively normal older adults (CN) (N = 220; 36 % Aβ+) and patients with Mild Cognitive Impairment (MCI) (N = 143; 51 % Aβ+) were utilized. Functional redundancy was calculated from resting state fMRI data using a graph theoretical approach by summing the direct and indirect paths (path lengths = 1-4) between each region of interest and its 263 functional connections. Posterior HC, but not anterior HC or LFC, redundancy was significantly lower in Aβ+ than Aβ-groups, regardless of diagnosis. Posterior HC redundancy related to higher education and better episodic memory, but it did not moderate the Aβ-cognition relationships across the diagnostic groups. Together, these findings suggest that posterior HC redundancy captures network disruption that parallels selective vulnerability to Aβ deposition. Further, our findings indicate that functional redundancy may underscore a network metric different from global functional connectivity of the LFC.

INTRODUCTION:TRAILBLAZER-ALZ 6 (NCT05738486) is a multicenter, double-blind, ongoing phase 3b study in early symptomatic Alzheimer's disease. METHODS:Participants (n = 843) were randomized 1:1:1:1 (standard + three alternative donanemab dosing arms). Primary outcome was relative risk reduction (RRR) of amyloid-related imaging abnormalities with edema/effusions (ARIA-E) at 24 weeks assessed with Bayesian logistic regression. Amyloid plaque levels by positron emission tomography and serum donanemab pharmacokinetics were measured. RESULTS:ARIA-E frequencies for standard, modified titration, dose skipping, and Cmax arms were 23.7%, 13.7%, 18.6%, and 18.3%, respectively, at 24 weeks and similar at 52 weeks: 24.2%, 15.6%, 18.6%, and 18.8%, respectively. Modified titration met the 24-week primary outcome with 94% probability of achieving ≥ 20% RRR versus the standard arm. Modified titration also had significantly lower ARIA-E severity, but similar cumulative exposure and mean amyloid reduction compared to the standard arm. DISCUSSION:Gradual up-titration of dose significantly reduced ARIA-E risk while demonstrating comparable pharmacokinetics/pharmacodynamics compared to standard dosing. HIGHLIGHTS:In TRAILBLAZER-ALZ 6, the amyloid-related imaging abnormalities-edema/effusions (ARIA-E) frequency was 13.7% in the modified titration arm compared to 23.7% in the standard arm at week 24. The modified titration arm met the primary endpoint of ARIA-E relative risk reduction at 24 weeks versus the standard arm. The modified titration versus standard arm at week 24 had comparable non-ARIA-E related safety profile, amyloid reduction, plasma phosphorylated tau217 reduction, cumulative exposure, and pharmacokinetics. Data at week 52 were consistent with week 24 results.

Importance Data from 2 phase 3 studies of gantenerumab, GRADUATE I/II, and their open-label extensions represent a resource to further characterize amyloid-related imaging abnormalities (ARIA), including long-term sequelae. Objectives To describe the characteristics of ARIA and risk factors and clinical consequences of ARIA-edema (ARIA-E). Design, Setting, and Participants Secondary data collection from the GRADUATE I/II phase 3 randomized, double-blind, placebo-controlled, 116-week parallel-group studies and their open-label extensions, including PostGraduate, with up to 210 (mean, 125) weeks of total gantenerumab treatment were conducted between 2018 and 2023. The study included multicenter trials at 288 sites across 30 countries. GRADUATE I/II enrolled 985 and 980 participants, respectively, with early symptomatic Alzheimer disease (AD) and amyloid-beta (A beta) pathology who were aged 50 to 90 years. PostGraduate enrolled 1382 participants (671 previously randomized to gantenerumab). Data were analyzed from November 2, 2022, to October 10, 2023. Interventions GRADUATE I/II participants were randomized 1:1 to gantenerumab or placebo. Nine-month uptitration was used to mitigate ARIA risk. Main outcomes and measures Postbaseline safety monitoring, including brain magnetic resonance imaging (MRI) findings, and adverse events and cognitive assessments. Results The safety-evaluable MRI population of GRADUATE I/II comprised 1939 participants (mean age, 71.7 years; 1105 female [57.0%]). Severity of AD-related A beta neuropathology (lower cerebrospinal fluid [CSF] A beta 42, hazard ratio [HR] for CSF A beta 42: 0.4; 95% CI, 0.2-0.7) and comorbid cerebrovascular pathology (Fazekas score: HR, 1.6; 95% CI, 1.3-2.0; total superficial siderosis count: HR, 1.9; 95% CI, 1.3-2.6; total microhemorrhage count: HR, 1.3; 95% CI, 1.0-1.5) may be important baseline risk factors for ARIA-E, in addition to apolipoprotein E (APOE) epsilon 4 status (APOE epsilon 4 heterozygous carrier: HR, 2.0; 95% CI, 1.4-2.8 and APOE epsilon 4 homozygous carrier: HR, 4.7; 95% CI, 3.2-6.7). At the group level, ARIA-E did not impact long-term cognitive and functional performance (relative difference in adjusted means for Clinical Dementia Rating-Sum of Boxes was -9% in pooled GRADUATE analysis at week 116 and when censored at first ARIA-E). While taking gantenerumab, ARIA-E and ARIA-hemosiderin occurred in 24.9% (247 of 993) and 22.9% (227 of 993) participants, respectively; first ARIA-E occurred by week 64 in 86.2% (213 of 247) of participants with ARIA-E. Narratives are provided for all serious symptomatic ARIA-E cases. Conclusions and Relevance These results show that in addition to APOE epsilon 4 allele count, severity of A beta neuropathology and comorbid cerebrovascular pathology may be relevant for clinicians prescribing anti-A beta monoclonal antibodies for early AD and developing individualized safety monitoring plans. Evaluation of these risk factors in other anti-A beta monoclonal antibodies is recommended. Trial registrations ClinicalTrials.gov Identifiers: NCT03444870, NCT03443973, NCT04374253.

In autosomal dominant Alzheimer disease (ADAD), the position of a pathogenic genetic variant within the presenilin-1 ( PSEN1 ) coding sequence influences how amyloid-beta accumulates and how dementia progresses (Joseph-Mathurin et al, 2024). In the first trial of anti-amyloid monoclonal antibodies in individuals at risk for ADAD (Dominantly Inherited Alzheimer Network Trials Unit study 1 [DIAN-TU-001]), gantenerumab demonstrated target engagement but did not meet its primary clinical endpoint (Salloway et al, 2021). Whether the distribution of pathogenic genetic variants within the cohort may have influenced the trial results remains unclear. Here, we investigated the primary outcomes from DIAN-TU-001 as a function of mutation position. We evaluated 72 participants with a PSEN1 mutation who completed the DIAN-TU-001 study under the placebo (n = 29) and the gantenerumab (n = 43) arms. Both arms were grouped by the PSEN1 mutation position relative to codon 200 as precodon-200 and postcodon-200 (Table 1). Mixed models for repeated measures were adjusted for sex, baseline Clinical Dementia Rating ® (CDR ® ) scores, and baseline EYO and estimated the effect of PSEN1 mutation position on the mean change from baseline PiB-PET composite and baseline cognitive composite, as imaging and clinical outcomes, respectively. Significance of differences in least squares (ls) means on year 4 between pre-codon 200 and post-codon 200 mutation groups were calculated. Within each codon group, compared to placebo, the treated group had significant changes in PiB-PET but not in cognitive composite (Figure 1). Placebo precodon-200 group showed significantly faster amyloid accumulation rates (PiB PET composite SUVR) through year 4 than the placebo postcodon-200 group (ls means diff. P -value = 0.0065). However, no difference was observed between precodon-200 and postcodon-200 gantenerumab groups (ls means diff. P -value = 0.45) through year 4. Difference in cognitive composite precodon-200 vs. postcodon-200 placebo groups was not significant (ls means diff. P -value = 0.98). Differences in cognitive composite groups between treated groups trended toward significance (ls means diff. P -value = 0.05). These preliminary results show the potential influence of PSEN1 mutation position on the outcome of a monoclonal antibody targeting amyloid plaque removal. Further investigation into the potential effects of specific mutation type on trial results is warranted.

Amyloid-β-directed monoclonal antibody therapies may lead to amyloid-related imaging abnormalities (ARIA). Clinical trials that formed the basis for the ARIA radiographic severity grading scale adopted by the approved drugs' labels utilized T2* gradient recalled echo (T2*-GRE) images for ARIA-hemorrhagic (ARIA-H) assessment. Little is known about the application of susceptibility-weighted imaging (SWI) to ARIA-H assessment. We exploited comparative studies on the usage of SWI instead of 2D T2*-GRE and simulated the impact of SWI's higher sensitivity on the derived ARIA-H severity distribution for three approved drugs. The simulations indicated that the two sequences are not equivalent when grading ARIA-H severity and that the rate of therapy discontinuation would increase by more than 50% compared to the rates reported in the drugs' prescribing information. This should be taken into consideration whenever SWI is applied for ARIA safety monitoring. Appropriate imaging guidelines are needed to enhance management of amyloid-β-directed antibody therapies.

CADASIL, linked to NOTCH3 variants, is a primary monogenic cause of vascular dementia, leading to vascular cognitive impairment and dementia (VCID) observable in early stages. The NIH-funded USA CADASIL Consortium aims to explore CADASIL's onset and progression in the USA, crucial due to varying phenotype-genotype associations globally. The consortium will identify biological and clinical markers across the disease spectrum, contributing to clinical trial preparations. It will focus on clinical outcome assessments, biofluids and neuroimaging for biomarker identification, and disease modeling for subtypes, informing future clinical trial designs. The study will also examine genetic, health, and lifestyle factors impacting CADASIL outcomes. The methodology involves establishing a longitudinal cohort of 400 NOTCH3 carriers and 100 non-carrier family members across 12 USA sites ( www.cadasil-consortium.org ). Participants undergo annual clinical, cognitive assessments, advanced neuroimaging, and blood-based phenotyping, targeting optimal biomarkers to determine minimal sample sizes for clinical trials. Despite COVID-19 challenges, over 200 participants are enrolled, many already in longitudinal assessments. The Symptomatic (SYM) group, individuals with mild to moderate disability (Rankin Scale scores 1-3), displays different cognitive and functional patterns from the Non-Symptomatic (NSYM) group. The SYM group, mostly females (63) and Caucasians (101), has lower MOCA scores (average 25.2 vs. NSYM's 26.8) and SDMT averages (43.7 vs. NSYM's 51.4), indicating reduced cognitive function and processing speed. Functionally, SYM's average WHODAS score is 9.1, higher than NSYM's 3.1. The SYM group, averaging 53 years, is older than NSYM's 47.7 years, highlighting age's role in symptom severity. The upcoming AAIC presentation will provide a comprehensive overview of the US CADASIL cohort, contrasting it with international data. Efforts are ongoing to establish a worldwide CADASIL Study Group to advance knowledge and treatment for vascular cognitive impairment and dementias.

The clinical presentations of early-onset Alzheimer’s disease (EOAD) and late-onset Alzheimer’s disease are distinct, with EOAD having a more aggressive disease course with greater heterogeneity. Recent publications from the Longitudinal Early-Onset Alzheimer’s Disease Study (LEADS) described EOAD as predominantly amnestic, though this phenotypic description was based solely on clinical judgment. To better understand the phenotypic range of EOAD presentation, we applied a neuropsychological data-driven method to subtype the LEADS cohort. Neuropsychological test performance from 169 amyloid-positive EOAD participants were analyzed. Education-corrected normative comparisons were made using a sample of 98 cognitively normal participants. Comparing the relative levels of impairment between each cognitive domain, we applied a cut-off of 1 SD below all other domain scores to indicate a phenotype of “predominant” impairment in a given cognitive domain. Individuals were otherwise considered to have multidomain impairment. Whole-cortex general linear modeling of cortical atrophy was applied as an MRI-based validation of these distinct clinical phenotypes. We identified 6 phenotypic subtypes of EOAD: Dysexecutive Predominant (22

The Alzheimer's Association and the Society of Nuclear Medicine and Molecular Imaging convened a multidisciplinary workgroup to update appropriate use criteria (AUC) for amyloid positron emission tomography (PET) and to develop AUC for tau PET. Methods: The workgroup identified key research questions that guided a systematic literature review on clinical amyloid/tau PET. Building on this review, the workgroup developed 17 clinical scenarios in which amyloid or tau PET may be considered. A modified Delphi approach was used to rate each scenario by consensus as "rarely appropriate," "uncertain," or "appropriate." Ratings were performed separately for amyloid and tau PET as stand-alone modalities. Results: For amyloid PET, 7 scenarios were rated as appropriate, 2 as uncertain, and 8 as rarely appropriate. For tau PET, 5 scenarios were rated as appropriate, 6 as uncertain, and 6 as rarely appropriate. Conclusion: AUC for amyloid and tau PET provide expert recommendations for clinical use of these technologies in the evolving landscape of diagnostics and therapeutics for Alzheimer's disease.

INTRODUCTION:Deep brain stimulation of the fornix (fx-DBS) is being investigated for treatment of Alzheimer's disease (AD). The therapy aims at alleviating memory and cognitive circuit dysfunction. In preclinical models of AD, electrical stimulation of the memory circuit has demonstrated a possible disease-modifying potential. Here we examined changes resulting from fx-DBS in hippocampal atrophy and amyloid accumulation in AD patients with fx-DBS. METHODS:Repeated magnetic resonance imaging and positron emission tomography (PET) images acquired over the course of 12 months were used to assess changes in hippocampal volume in 36 ADvance trial patients compared to 40 matched untreated AD patients from the Alzheimer's Disease Neuroimaging Initiative, and in 10 separate patients with repeated flutemetamol PET and cerebrospinal fluid (CSF) markers. RESULTS:We observed a reduction of hippocampal atrophy and amyloid beta (Aβ) PET binding, and an increase in the CSF Aβ/total-tau ratio in DBS patients. DISCUSSION:These findings highlight the potential of fornix deep brain stimulation to modify AD biomarkers and possibly progression in some patients. HIGHLIGHTS:Fornix deep brain stimulation (fx-DBS) is being investigated to treat Alzheimer's disease (AD). Results show that fx-DBS modifies imaging and cerebrospinal fluid (CSF) markers. It reduces hippocampal atrophy and increases the amyloid beta/total-tau CSF ratio. These findings highlight the potential of fx-DBS to modify AD.

The TRAILBLAZER-ALZ 6 study (NCT05738486) evaluated the effect of different donanemab dosing regimens on amyloid-related imaging abnormalities with edema/sulcal effusions (ARIA-E). The modified titration arm met the primary outcome and significantly reduced ARIA-E frequency compared with the standard dosing while maintaining a similar pharmacodynamic effect on amyloid reduction at 24 weeks. Primary outcome and 52-week data were previously published. Completed study results at 76 weeks are reported here. ARIA-E frequencies were 15.6 % and 24.2 % in the modified titration and standard arms, respectively. ARIA-E radiographic severity was significantly lower (p = 0.015) with modified titration than with standard dosing. Additionally, symptomatic ARIA-E frequency was lower with modified titration versus standard dosing (2.8 % vs 4.8 %). The frequency of serious adverse events was comparable between the modified titration and standard dosing arms. A more gradual titration of donanemab dosing significantly reduced ARIA-E risk versus standard dosing. CLINICALTRIALS.GOV: NCT05738486.

INTRODUCTION:The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) is a 2-year randomized controlled trial of two lifestyle interventions in 2111 older adults at increased risk for cognitive decline. METHODS:Sociodemographic and clinical characteristics and rates of ancillary study participation were described with means and frequencies. RESULTS:U.S. POINTER successfully enrolled a cohort, ages 60-79 years, which was ethno-racially inclusive (>30% individuals from groups often under-represented in clinical trials with cognitive outcomes) and 18% residing in neighborhoods with moderate or high levels of socioeconomic deprivation. Enrollees were cognitively intact but at increased risk for cognitive decline. Participation in ancillary studies (overall 73%) was uniformly high across sociodemographic groups. DISCUSSION:The trial cohort meets study goals and provides a basis for assessing multidomain lifestyle intervention effects on cognitive function and other health outcomes that will generalize to large portions of the at-risk US populations. CLINICALTRIALS: GOV IDENTIFIER:NCT00017953. HIGHLIGHTS:The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) enrolled individuals at enhanced risk for cognitive decline. Efforts to engage socio-demographically representative individuals were successful. Four ancillary studies with high rate of recruitment extend scientific impact.

Alzheimer disease (AD) related cognitive decline occurs at relatively young ages in individuals with Down syndrome (DS, early-mid 50s) and in those with autosomal dominant mutations (ADAD, 40-50s). Both groups show similar patterns of amyloid accumulation. We examined if brain volumes are similarly affected by AD pathology in individuals with DS and ADAD. Data for cognitively stable and declining participants was obtained from the Alzheimer Biomarker Consortium-Down Syndrome (ABC-DS) and the Dominantly Inherited Alzheimer Network (DIAN). Stability/decline was identified based on cognitive testing and interview of individuals and caregivers by trained assessors. Cognitively stable family members without DS/ADAD mutations were recruited as controls from both studies. Participants underwent MRI and amyloid positron emission tomography (PET) scans from which brain volumes and amyloid (centiloids) were derived, respectively. Participants from DIAN had Pittsburgh Compound-B (PIB) scans, ABC-DS had PIB or florbetapir. Nonlinear cross-sectional associations between regional brain volumes and estimated years to onset of cognitive decline (EYO, negative values before onset, positive after) and centiloid were evaluated using generalized additive models while controlling for sex and random effects of family. EYO was set to 52 for all participants with DS and based on parental decline/mutation type for participants with ADAD. EYO for controls was based on the EYO of their family member. Data from 239 participants with DS (47 declining), and 340 participants with ADAD (122 declining), and 263 familial controls were included. Higher EYO and centiloid values were associated with lower brain volumes in almost all regions. At earlier EYOs, individuals with DS typically had smaller regional volumes than ADAD or sibling controls, with volume declining linearly across the EYO range. By contrast, ADAD mutation carriers had similar volumes to non-carriers at early EYOs, with volumes diverging as early as 10 years before decline. Brain volumes and centiloid values were inversely related in ADAD and DSAD. Volume in key cortical regions were similar by the expected year of onset in both groups. ADAD and DSAD demonstrated different temporal patterns of regional neurodegeneration prior to cognitive change despite being similarly affected by early onset amyloid.

BACKGROUND:Soluble species of multimeric amyloid-beta including globular amyloid-beta oligomers (AβOs) and linear amyloid-beta protofibrils are toxic to neurons. Sabirnetug (ACU193) is a humanized monoclonal antibody, raised against globular species of soluble AβO, that has over 650-fold greater binding affinity for AβOs over monomers and appears to have relatively little binding to amyloid plaque. OBJECTIVES:To assess safety, pharmacokinetics, and exploratory measures including target engagement, biomarker effects, and clinical efficacy of sabirnetug in participants with early symptomatic Alzheimer's disease (AD; defined as mild cognitive impairment and mild dementia due to AD). DESIGN:Randomized, double-blind, placebo-controlled, ascending dose first-in-human phase 1 study. SETTING:Fifteen study centers in the United States. PARTICIPANTS:Sixty-five participants with early symptomatic AD. INTERVENTION:Participants received one infusion of sabirnetug 2 mg/kg, 10 mg/kg, 25 mg/kg, 60 mg/kg, or placebo (Part A) or three infusions of sabirnetug 10 mg/kg, 25 mg/kg, 60 mg/kg, or placebo (Part B). MEASUREMENTS:Safety, tolerability, serum pharmacokinetics, and central target engagement of single and multiple doses of sabirnetug, cerebrospinal fluid (CSF) concentrations of sabirnetug, and amyloid plaque load, as determined by positron emission tomography. RESULTS:Sabirnetug was generally well tolerated. A larger percentage of participants receiving sabirnetug (56.3%) versus placebo (42.9%) had at least one treatment emergent adverse event, with approximately 29% in each group considered related to study drug. Most events were mild-to-moderate in severity. Of 48 participants given sabirnetug, five developed amyloid related imaging abnormalities - edema/effusion, including one instance that was mildly symptomatic in a participant who had received one dose sabirnetug 60 mg/kg. Notably, none of the six apolipoprotein E Ɛ4 homozygotes who received sabirnetug developed amyloid related imaging abnormalities - edema/effusion or - hemorrhage/hemosiderin deposition. Infusion reactions, such as rash, pain, or erythema, were not frequent (6.3% for sabirnetug versus 0.0% for placebo). Sabirnetug exposure was dose proportional in both serum and CSF. Target engagement, defined as drug bound to AβOs in CSF, was shown to be dose and exposure dependent. Over three months, approximately 25% and 20% reduction in amyloid plaques, respectively, were observed in participants receiving three infusions of sabirnetug 60 mg/kg every four weeks and 25 mg/kg every two weeks. CONCLUSIONS:The Phase 1 INTERCEPT-AD study provided safety, tolerability, dosing, and target engagement data that supported the design of the ongoing ALTITUDE-AD study (NCT06335173).

OBJECTIVE:Early-onset Alzheimer's disease (EOAD) and late-onset Alzheimer's disease (LOAD) differ in many respects. Here, we address the issue of possible differences in fibrillar amyloid pathology as measured by positron emission tomography (PET), which remains unresolved due to the lack of large-scale comparative studies. METHODS:Three hundred ninety-nine cognitively impaired participants younger than 65 years of age from the multicenter Longitudinal Early-onset Alzheimer's Disease Study (LEADS) and 450 cognitively impaired participants older than 65 years from the Alzheimer's Disease Neuroimaging Initiative (ADNI) underwent clinical assessment, brain magnetic resonance imaging (MRI), and amyloid PET and were included in this study. We compared amyloid PET outcomes (positivity rate based on visual read and quantified tracer uptake expressed as Centiloids [CLs]) between the 2 cohorts and studied their association with age, sex, APOE genotype, and cognition. RESULTS:The amyloid positivity rate was higher in LEADS (78%, 95% confidence interval [CI] = 74-82) than in ADNI (71%, 95% CI = 67-75, p = 0.02). Lower Mini-Mental State Examination (MMSE) and APOE4 genotype increased the odds of amyloid positivity in both cohorts. Visually positive scans had higher CLs in LEADS (EOAD, mean = 95.3 ± 26.1) than in ADNI (LOAD, mean = 80.9 ± 36.8, p < 0.0001), predominantly in parietal cortex/precuneus, superior temporal, and frontal cortices. In amyloid-positive patients, (1) CLs were higher in female patients in both cohorts; (2) APOE4 carriership was associated with lower CLs in EOAD, which was not observed in LOAD; and (3) correlations between CLs and MMSE scores were significantly stronger in EOAD than in LOAD. INTERPRETATION:Differences in the burden of amyloid pathology may contribute to differences in clinical and anatomic patterns in sporadic EOAD and LOAD, and have implications for optimizing therapeutic strategies in each group. ANN NEUROL 2025;98:236-248.

Brain network dynamics have been extensively explored in patients with subjective cognitive decline (SCD). However, these studies are susceptible to individual differences, scanning parameters, and other confounding factors. Therefore, how to reveal subtle SCD-related subtle changes remains unclear. Cross-sectional and longitudinal resting-state functional magnetic resonance imaging data from both Chinese and Western populations were analyzed. We proposed a framework of dynamic proportional loss of functional connectivity (DPLFC). After its stability was validated, the optimal parameters were applied for the clinical diagnosis of SCD. DPLFC yielded a relatively high intraclass correlation coefficient. In particular, the DPLFC of the left superior frontal gyrus (SFG) progressively decreased along the Alzheimer’s disease (AD) continuum. Compared with the traditional index, the DPLFC had better classification performance between cognitively normal controls and patients with SCD. Furthermore, DPLFC was related to Aβ deposition and scale scores. Patients with lower DPLFC values had a greater risk of cognitive decline. Decreased DPLFC in the left SFG may be a potential AD-related neuroimaging biomarker at an early stage.

New immunotherapies for Alzheimer’s Disease (AD) have shown promise in slowing disease progression and are most effective in the early stages of the disease. New, low-cost methodologies are needed to detect early AD pathological change. Digital cognitive tools may represent a cost effective, efficient, and sensitive method to detect early AD-related pathological change. The present analysis utilizes data from the BioFINDER-Brown study to investigate whether individuals with and without elevated plasma phosphorylated tau- 217 (p-tau 217 ) demonstrate differential performance on digital cognitive assessments of spatial working memory (SWM) and paired associates learning (PAL). 90 cognitively normal (CN; M MMSE = 29.00) older adults ( M age = 63.36, 72.2% female, 95.6% white, 5.6% Latinx) completed a blood draw to evaluate plasma p-tau 217 and two brief tablet-based digital cognitive assessments: SWM and PAL. as part of screening for the BioFINDER-Brown study. Approximately 42% of the sample (n = 38) had elevated plasma p-tau 217 . Independent samples t-tests were used to determine whether performance on these measures differed between individuals with and without elevated p-tau 217 . Lower scores on both measures are indicative of better performance. The total number of errors on the SWM was not found to differ between individuals with and without elevated plasma p-tau 217 ( t (89) = -1.33, p = 0.093). However, differences in strategy use were found on the SWM task ( t (89) = -2.11, p = 0.019); Individuals with elevated p-tau 217 had a less efficient strategy and required more trials to complete the task (M = 8.79 trials) than non-elevated individuals (M = 7.65 trials). Group differences between those with and without elevated p-tau 217 on the PAL task approached significance ( t (89) = 1.08, p = .075), with worse performance in those with elevated p-tau 217 . The preliminary findings suggest that group differences may exist for process scores (i.e., strategy use) but not overall performance on digital cognitive assessments between individuals with and without elevated plasma p-tau 217 . Future research should evaluate 1) which digital assessments are most sensitive to AD-related pathological change and 2) whether digital cognitive assessments can be used in conjunction with novel, affordable plasma biomarkers to improve early detection of AD.