Music engages brain regions involved in perceptual, socio-emotional and cognitive functions that may be relatively preserved in individuals with Alzheimer's disease but seem affected early in behavioural variant frontotemporal dementia. The effects of music in dementia are often assessed through observational studies, leaving the neurophysiological underpinnings of music processing in these dementia types unclear. Improved understanding of these mechanisms is relevant because the effectiveness of music therapy may depend on dementia types. In this study we investigated whether patients with behavioural variant frontotemporal dementia and Alzheimer's disease differ in music processing compared with healthy controls. We studied 60 participants (n = 35 female; aged 52-81), including 13 patients with behavioural variant frontotemporal dementia, 22 patients Alzheimer's disease, and 25 healthy controls. We designed a novel functional MRI paradigm based on passive listening to self-selected favourite music and experimenter-selected unfamiliar musical pieces using a sparse-sampling design. Activation patterns of favourite music listening (favourite > silence), unfamiliar music listening (unfamiliar > silence), and favourite music more than unfamiliar music (favourite > unfamiliar) were determined for each participant. Next, we compared activation patterns across groups for each contrast. Finally, associations between activation patterns and disease severity were investigated in behavioural variant frontotemporal dementia and Alzheimer's disease separately. The patient groups exhibited typical neuropsychological, socio-emotional and structural anatomical changes associated with Alzheimer's disease and behavioural variant frontotemporal dementia. Patients with behavioural variant frontotemporal dementia showed overall less activation during favourite music listening compared with Alzheimer's disease and healthy controls. When contrasting favourite and unfamiliar music, we found that patients with behavioural variant frontotemporal dementia showed reduced activation in the supplementary motor area, a region that has previously been implicated as an important region for semantic musical memory. Increased connectivity of the auditory cortices was observed in behavioural variant frontotemporal dementia compared with controls, potentially indicating network immaturity. Only patients with Alzheimer's disease exhibited activation in the caudate nucleus during unfamiliar music, a region associated with musical reward processing. Disease severity in Alzheimer's disease and behavioural variant frontotemporal dementia were associated with distinct patterns of functional activation. Our results confirm and expand the observation that music is processed differently in patients with behavioural variant frontotemporal dementia and Alzheimer's disease. The reduced activation in the supplementary motor area may explain altered music processing in behavioural variant frontotemporal dementia. These differences in music processing could have clinical implications in the selection of music therapy.
There is much excitement about the potential for dementia prevention by targeting modifiable risk factors, yet sociodemographic disparities in dementia-related knowledge, stigma, and risk factor awareness remain underexplored. This study examines these differences among minoritised ethnic communities in the UK. As part of a project by the NIHR Dementia and Neurodegeneration Policy Research Unit at Queen Mary (DeNPRU-QM), dementia knowledge, stigma, and risk factor awareness of 3500 participants were assessed in a secondary analysis of data from two national surveys conducted in 2023 by Alzheimer's Research UK. Linear regression models were used to examine associations between ethnicity and knowledge-related outcomes, while ordinal logistic regression was used for stigma, adjusting for age, sex, education, social grade, chronic conditions, and knowing someone with dementia. Compared to White participants, South Asian (Coef. = -0.45, 95% CI [-0.55, -0.34], p < 0.001) and Black participants (Coef. = -0.17, 95% CI [-0.27, -0.06], p < 0.005) had lower knowledge about dementia. Compared to White participants, Black participants had higher odds of reporting greater stigma (OR = 2.55, 95% CI [2.10, 3.09], p < 0.001), as did South Asian participants (OR = 1.62, 95% CI [1.34, 1.97], p < 0.001) and participants from Other ethnic groups (OR = 1.55, 95% CI [1.17, 2.07], p = 0.003). Black individuals also had lower knowledge of dementia risk factors compared to White participants (Coef. = -0.655, 95% CI [-1.110, -0.200], p = 0.005). Education level, chronic health conditions, gender, profession, and knowing someone with dementia were also associated with some outcomes, although associations varied by outcome. Ethnic disparities exist in dementia knowledge, stigma, and dementia risk factor awareness. Any future public information campaign around dementia risk reduction and timely diagnosis should ensure cultural competency and include strategies to reach minoritised ethnic communities. Policymakers should consider how prevention might be promoted in all health and social care encounters, since people with chronic conditions who may not be eligible for primary health checks had lower levels of knowledge about dementia.
Grey matter network topology is altered in Alzheimer's disease and these alterations are related to cognitive decline. Understanding the biological underpinnings of loss of brain connectivity may provide insights into mechanisms related to developing Alzheimer's dementia (i.e. dementia A+). We investigated which biological processes as measured in CSF proteomics were associated with loss of brain connections across the Alzheimer's disease continuum. We included 347 individuals with abnormal CSF amyloid [mean age ± standard deviation (SD) 66 ± 8; 98 cognitively unimpaired-A+, 88 mild cognitive impairment-A+, 161 dementia A+] and 146 cognitively unimpaired individuals with normal CSF amyloid (mean age ± SD 62 ± 8) and available T1w MRI-scans and CSF proteomic data (3097 proteins using tandem mass tag spectrometry) from the Amsterdam Dementia Cohort. We used an automated pipeline to construct grey matter networks from 3D-T1 sequences and for each network, calculated the small-worldness coefficient, which we previously found to be robustly related to cognitive decline. Linear models were applied to test associations between CSF protein levels and connectivity measures using an interaction term for clinical stage while controlling for connectivity density, age and sex. We validated our results in data from the Alzheimer's disease Neuroimaging Initiative (ADNI). Pathway enrichment analysis was performed for proteins associated with loss of brain connectivity (P < 0.05) using the Gene Ontology database. Individuals across the Alzheimer's disease continuum had lower small-worldness coefficients compared with controls (ANOVA P < 0.001). In amyloid positive individuals, higher levels of 222 proteins and lower levels of 482 proteins were associated with lower small-worldness coefficients and were enriched for innate immune system and neuroplasticity pathways, respectively. Stratified for disease stage, most protein associations with lower small-worldness coefficients were found in mild cognitive impairment A+ (n = 527 proteins) and dementia A+ (n = 799 proteins) with considerable overlap (n = 239 proteins). Proteins in these stages were enriched for complement activation and synaptic integrity. In cognitive unimpairment A+, we found proteins enriched for processes involved in apoptosis. We did not find any enriched biological processes in controls. Repeating analyses in ADNI indicated that similar biological processes were associated with altered grey matter network connectivity. Higher CSF levels of proteins involved in immune responses and lower levels of proteins related to neuroplasticity were associated with lower small-worldness coefficients across the Alzheimer's disease continuum. This suggests that preserving cognitive function in the presence of amyloid and prevention of dementia A+ may require therapies that strengthen synapses and targets the innate immune system in addition to amyloid and tau.
Individuals with Type 1 diabetes are at a higher risk of dementia compared to individuals without diabetes. Younger age at Type 1 diabetes onset has been linked to an increased risk of cardiovascular disease and higher mortality. This study aimed to determine whether younger age at Type 1 diabetes onset was also associated with all-cause dementia. This nationwide prospective cohort study used data from individuals with Type 1 diabetes from the Swedish National Diabetes Register. All-cause dementia, including Alzheimer's disease, vascular dementia and non-Alzheimer's-non-vascular dementia, was prospectively ascertained as ICD-10 codes. Age at onset was stratified into < 10 years, 10-17 years and 18-30 years. The 18-30 years group was used as the reference group for all analyses. Cox regression modelling with age as the time-axis, from age at diabetes onset, was deployed to investigate dementia risk. Of 43 440 included individuals (mean age 33.0 (SD 14.0) years; 44% female), Type 1 diabetes developed before age 10 in 11 776 individuals (27%), between age 10 and 17 in 15 846 (36%) and between 18 and 30 (reference group) in 15 818 (36%). During a median 29.3 [17.6-43.7] years follow-up, 530 (1.2%) developed all-cause dementia. Compared to the reference group, all-cause dementia risk was increased in individuals aged < 10 years at onset (HR 1.37 [95% CI 1.08-1.73]), but not in individuals aged 10-17 years at onset (HR 1.04 [95% CI 0.85-1.26]) (fully adjusted model). Type 1 diabetes onset before age 10 is associated with an increased risk of all-cause dementia compared to onset between ages 18 and 30.
BackgroundBlood-based biomarkers (BBM) are promising to help diagnose Alzheimer's disease (AD) and are on the verge of implementation in diagnostic dementia workups. However, evaluating BBM performance in peripheral memory clinics is essential to establish their real-world clinical utility.ObjectiveTo evaluate the diagnostic concordance of BBMs with clinically established diagnoses in an unselected peripheral memory clinic population using predefined, validated thresholds.MethodsIn a peripheral memory clinic, plasma levels of phosphorylated Tau217 (pTau217), amyloid-β 42/40 ratio (Aβ42/Aβ40), glial fibrillary acidic protein, and neurofilament light (NfL) were measured in patients (mean age 75.2 ± 8.8 years, 48.3% female) clinically diagnosed with subjective cognitive decline (SCD; n = 108), mild cognitive impairment (MCI; n = 55), AD dementia (n = 132), or non-AD dementia (non-AD; n = 28). BBM levels were compared across diagnostic groups and concordance between clinical diagnoses and BBM test results, based on thresholds developed in an academic memory clinic, were analyzed.ResultsThe levels of all four BBMs differed between SCD and AD dementia (p < 0.001). Between AD dementia and non-AD dementia, only PTau217 levels differed (p = 0.03). In SCD participants, 50% (pTau217) to 79% (NfL) showed abnormality in at least one BBM. In AD dementia patients, this ranged from 83% (pTau217) to 97% (NfL); all had at least one abnormal BBM, and 68% had abnormalities in all four BBMs.ConclusionsIn a peripheral real-world memory clinic setting the BBMs demonstrated high concordance with clinically diagnosed dementia due to AD. Our findings suggest utility of BBMs in peripheral memory clinic practice, in patients with suspected dementia.
IntroductionAlthough rehabilitation can improve the quality of life of individuals with Alzheimer's disease and Alzheimer's disease-related dementias (AD/ADRD), awareness and acceptance of its benefits vary across healthcare providers and care settings. The aim of this study was to explore the perspectives of healthcare providers on the adoption and utilization of rehabilitation among individuals with AD/ADRD.MethodsWe adopted an exploratory qualitative descriptive study design using semi-structured interviews. Using purposive sampling, ten healthcare providers that provide rehabilitation services for individuals with AD/ADRD were recruited from the Alzheimer's Disease Research Center (ADRC), University of Pittsburgh and the University of Pittsburgh Pepper Center.ResultsParticipants emphasized the substantial potential benefits of rehabilitation for this population. Interview data indicated that several participants viewed rehabilitation services as significantly enhancing the quality of life and wellbeing of individuals with AD/ADRD. Feedback underscored the important role of rehabilitation in optimizing care for individuals with AD/ADRD and highlighted key barriers to its broader implementation.ConclusionsOverall, the findings suggest that rehabilitation offers meaningful value in the management of AD/ADRD. Although participants identified several barriers, rehabilitation services were consistently viewed as beneficial for individuals with AD/ADRD. Addressing these gaps will be important for strengthening the effectiveness and reach of rehabilitation services.
Blood-based biomarkers are emerging as scalable tools for the diagnosis and monitoring of neurodegenerative diseases, but markers enabling differential diagnosis across major dementias remain limited. Here we show that large-scale plasma proteomics identifies disease-associated signatures across Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia. We analyzed 1,318 plasma samples from well-characterized international cohorts and identified more than 200 dysregulated proteins across disease groups. Glial fibrillary acidic protein showed the strongest increase along the Alzheimer's disease continuum, whereas integrin alpha-V and integrin alpha-M were consistently reduced in Lewy body disorders, including autopsy-confirmed cases. Elevated neurofilament light chain and lower glial fibrillary acidic protein were associated with frontotemporal dementia. We translated these findings into a 21-protein quantitative multiplex panel and validated it in an independent multicenter cohort (n = 805). These findings support plasma proteomics as an approach for biomarker-based differential diagnosis and disease staging across major neurodegenerative dementias.
Young-onset dementia (YOD), defined as dementia with symptom onset before the age of 65, is associated with distinct and often complex care needs that differ from those with late-onset dementia. Current national data on YOD incidence, prevalence, and demographic characteristics are limited, underscoring the importance of prospective studies to inform policy and tailored care services. We conducted two prospective one-year prevalence and incidence studies using active case-finding in two Dutch catchment areas, one urban and one more rural region, between 2020 and 2022. Individuals with YOD making use of care services were registered in an online database. Data on dementia subtype, living situation, and migration background were collected to explore regional variation. We identified 372 individuals with YOD in the urban Rotterdam area, and 209 in the more rural Eindhoven-De Kempen area. Age-standardized prevalence per 100,000 individuals, standardized to the Dutch population, was 77.3 in the Rotterdam region, and 66.1 in the Eindhoven-De Kempen region for ages 30-69 years, and 46.3 and 36,9, respectively, for ages 30-64 years. Corresponding age-standardized incidence rates were 24.2 and 23.5 for ages 30-69 years, and 13.9 in both regions for ages 30-64 years. Alzheimer's disease was the most common diagnosis in both areas. Compared with Eindhoven-De Kempen, the Rotterdam region had significantly more vascular dementia cases (p < 0.05 for incidence, and p < 0.001 for prevalence) and longer diagnostic delays (2.2 vs. 1.3 years between first GP consultation and diagnosis). Most individuals lived at home (76.4% and 85.4% resp. in Rotterdam and Eindhoven-De Kempen) and 30.8% in Rotterdam and 12.5% in Eindhoven-De Kempen had a migration background. Extrapolation of incidence figures suggests that between 14,655 and 20,340 individuals were living with YOD in the Netherlands in 2021. This study estimates the number of people living with YOD in the Netherlands. In addition, our findings show regional variation in dementia subtypes, a high proportion of people with YOD living at home, and a substantial proportion of people with YOD with a migration background. These insights underline the importance of region‑specific, person‑centered, culture sensitive YOD care at home.
Adverse social conditions across the life course influence brain aging and dementia, yet their compounded impact on clinical phenotypes remains underexplored, particularly in Latin America, where social inequality and dementia burden are high. We studied 3941 individuals from six Latin American countries, including cognitively unimpaired controls (CU), Alzheimer's disease (AD), and frontotemporal lobar degeneration (FTLD). A life-course questionnaire captured eight domains of social vulnerability, used to derive a social vulnerability index and latent vulnerability profiles. Brain health was characterized across 37 cognitive, functional, mental health, and dementia severity indicators. Higher vulnerability was mostly associated with executive and memory deficits in CU, cognitive and functional impairment in AD, and social cognition and neuropsychiatric symptoms in FTLD. Multidimensional brain health was affected across groups. Compounded social vulnerability is a key determinant of clinical expression in aging and dementia, underscoring the need for life-course-informed and equity-oriented dementia models.
Recent studies suggest that copy number variants (CNVs) may contribute to the missing heritability of complex diseases such as Alzheimer's disease (AD) and related dementias (ADRD). We performed a CNV analysis using genotyping data (Axiom 815 K Spanish biobank array) from the GR@ACE/DEGESCO dementia dataset (n = 20,067) of the Spanish population. Applying PennCNV and extensive quality control, 8275 controls and 7818 dementia cases were selected for gene-level case/control associations. We identified 43,833 CNVs with deletions (47%) and duplications (53%). No genome-wide significant associations were found, but nominal associations were observed in PKP3-SIGIRR and FBRSL1 loci. CNVs in 2970 genes were exclusive to dementia cases and enriched in vascular-related pathways. Notable findings included 14q11.2 duplication and VPS13B deletions in ADRD cases, the latter confirmed by optical genome mapping. Our findings suggest potential novel genes associated with ADRD in the Spanish population. However, the limited resolution of array-based technologies in detecting CNVs warrants further investigation.
Objective: Young-onset dementia (YOD; onset < 65 years) frequently presents with phenotypes that involve specific cognitive domains whilst relatively sparing episodic memory, such as behavioral variant frontotemporal dementia (bvFTD), posterior cortical atrophy (PCA), and primary progressive aphasias (PPA). We hypothesized that standard neuropsychological batteries may fail to identify these phenotypes and tested their ability to pick up cognitive deficits for YOD phenotypes based on their clinical criteria. Methods: In this observational study, we included 2,056 consecutive YOD patients from the Amsterdam Dementia Cohort, who were seen at Alzheimer Center Amsterdam, Amsterdam UMC between 2010 and 2023. Domain scores were created based on a neuropsychological battery comprising tests in memory, executive, visuospatial, and language. Using three qualitative strategies-normative domain-based classification, alignment with simulated clinical reasoning, and intra-individual profiling-we categorized patients in cognitive domain groups based on either count, kind, or severity of domain impairments. Results: Across approaches, typical (i.e., amnestic) Alzheimer's disease, PCA, and semantic variant PPA (svPPA) were relatively well recognized, yet bvFTD, logopenic variant PPA (lvPPA), and nonfluent variant PPA (nfvPPA) remained poorly detected. Intra-individual profiling added some nuance by confirming memory, visuospatial, and semantic deficits in typical AD, PCA, and svPPA, respectively, but unexpectedly highlighted executive impairments in nfvPPA and to a lesser extent in lvPPA. Conclusions: Our standard neuropsychological battery reliably identified key impairments in typical AD, PCA, and svPPA, but underperformed for bvFTD, lvPPA, and nfvPPA. Our findings underscore the need to augment test batteries with targeted social cognition and language measures to aid differential diagnosis in YOD.
Structural pathways of the brain facilitate functional communication, and their disruption in preclinical Alzheimer's disease may reflect network vulnerability and compensatory brain maintenance. However, it remains unclear how early amyloid-β affects structure-function alignment, whether effects are explained by functional network organisation, how they relate to cognition, and which biological processes contribute to their development. We included 460 older adults without dementia from AMYPAD-PNHS with functional MRI, diffusion MRI, and amyloid-β PET. Structure-function coupling was quantified using the structural-decoupling index (SDI) at global, sub-network, and regional scales. Linear models investigated the effect of amyloid-β burden on SDI. Mediation analyses evaluated whether functional graph topology explained amyloid-associated SDI effects and whether SDI mediated the relationship between amyloid-β burden and cognition. Regional gene expression data were integrated to assess transcriptomic determinants of amyloid-related structure-function coupling. Amyloid-positive individuals exhibit higher global SDI, driven by visual cortices. Mediation analyses demonstrate that amyloid-related SDI alterations are explained by reductions in local clustering, indicating less segregated processing. Despite higher SDI in amyloid-positive individuals, elevated SDI in visual regions mitigates the negative effect of amyloid-β burden on cognition. Amyloid-related SDI changes correlate with genes associated with amyloid-β metabolism, microglial activation, and synaptic remodelling. Early amyloid-β pathology is associated with decoupling of brain structure and function, primarily in visual cortices, mediated by network reconfiguration and shaped by regional molecular architecture. These findings suggest that lower structure-function coupling may represent a compensatory mechanism in preclinical Alzheimer's disease and highlight SDI as a biomarker for stratification and monitoring in prevention trials. Alzheimer’s disease (AD) affects how different parts of the brain communicate and results in changes in people’s behaviour and ability to remember and think. In its early stages, before symptoms appear, changes in brain connections may already be happening. In this study, we examined how a key protein known to be involved in AD called amyloid-β affects the relationship between brain structure and brain activity, known as structure–function coupling, in older adults without dementia. We analysed brain scans from 460 participants and used a measure called the structural-decoupling index to assess this relationship. We found that higher amyloid-β levels were linked to weaker alignment between brain structure and function, especially in brain regions involved in sight. Our findings suggest that early changes in structure–function coupling could be used to monitor disease progression and support future prevention strategies.
Since 2016, the Alzheimer's Association and the Fondation Alzheimer have hosted Global Alzheimer's Leadership Series (GoALS) global think tanks, with world-leading experts for innovative discussions to advance Alzheimer's disease (AD) research and care. The second GoALS think tank, held in June 2024 in Paris, focused on the relationship between biological changes and clinical manifestations of AD in the context of the evolving therapeutic landscape. Discussions spanned real-world experiences of providers, patients, and their families, theoretical considerations, and health system challenges. The lived experience perspective was central to these discussions. The importance of shared decision-making, clear and transparent communication, and the need for real-world data to holistically support patients during their experiences were highlighted. This manuscript shares key insights from both the think tank meeting in Paris and a featured research session at the 2024 Alzheimer's Association International Conference that expanded the discussion themes for broader dissemination with the community.
Plasma proteomics detect multi-pathway biological changes preceding dementia onset. The Dementia SomaSignal Test (dSST) is a validated 25-protein score predicting 5- and 20-year all-cause dementia risk. Preclinical and clinical data suggest glucagon-like peptide-1 receptor agonists may have neuroprotective effects. In a post hoc analysis of the Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity (SELECT) trial, adults ≥ 65 years with overweight/obesity and cardiovascular disease without diabetes (n = 2970) were randomized to semaglutide 2.4 mg or placebo. Non-fasted serum samples at baseline and week 104 were analyzed using the dSST. Semaglutide reduced increases in predicted dementia risk versus placebo: 2.5-fold less increase in 5-year risk (26.0% lower predicted event rate; odds ratio [OR] 0.74, 95% confidence interval [CI] 0.65-0.85) and 1.67-fold less increase in 20-year risk (8.8% lower; OR 0.91, 95% CI 0.88-0.94). It also reduced odds of higher dementia risk classification by 36% (β -0.44; P < 0.001). Semaglutide slowed progression of a validated proteomics-based dementia risk signature.
While timely support can benefit people with dementia and their informal caregivers, the period between recognizing first symptoms and receiving a formal diagnosis is often prolonged. Barriers like stigma, denial, and symptom misinterpretation hinder care acceptance, leaving many without adequate support. This study aimed to (i) explore the needs of community-dwelling people with dementia and informal caregivers; (ii) gain insight into facilitators and barriers for support; and (iii) identify strategies used by healthcare professionals to improve early-stage care acceptance, and whether geographical context influenced this. This qualitative study used a cross-sectional design. We recruited 35 dyads of persons with dementia (mean age 77.7 ± 7 years; 51% female) and informal caregivers (70.0 ± 14 years; 60% female) through daycare centers and memory clinics in the Netherlands. Healthcare professionals (N = 47; 87% female; 38% dementia case manager) were contacted via regional dementia networks. Open-ended questionnaires assessed dyads' experiences and needs, while healthcare professionals participated in semi-structured interviews. Audio-recorded interviews were transcribed. Thematic content analysis was used on all data by two independent coders. Retrospectively, dyads indicated a strong need for timely knowledge, practical resources, and peer support in the early stage. Dementia case managers were considered crucial for accessing support. Effective strategies for professionals to improve early-stage care acceptance included: community engagement, raising societal awareness through education, a personal approach based on patience and trust, and better collaboration with other organizations to maintain short lines of communication. Barriers included reluctance to seek help, stigma, limited awareness, misalignment of services and needs, bureaucratic complexity, and difficulty navigating the healthcare system. Professionals stressed the need for tailored outreach strategies to both individual needs and local context, given perceived differences between city and rural regions in the effectiveness of strategies and dyads' needs. Our findings suggest that trust-based, relational approaches, characterized by patience, personal contact, and low-threshold access, are central to facilitating early-stage care acceptance. Early-stage support should be made more visible in communities and tailored to individual needs and local context. Reducing stigma and bureaucratic complexity, while strengthening local facilitators, may improve access to timely and meaningful support.
This study investigates sex differences in institutionalization, mortality, and health care costs among individuals with dementia. Retrospective cohort study using nationwide Dutch health insurance claims data with 6 years of follow-up. 15,214 people diagnosed with dementia in 2018 from all Dutch hospitals. We used a multistate model to examine transitions between community, institutional care, and death. We estimated differences in annual health care and long-term care costs between men and women using bootstrapped multilevel analyses, adjusting for age, previous health care use, a diagnosing specialist, institutionalization, and time × sex interactions. The cohort included 6749 men (78.2 ± 7.5 years) and 8465 women (55.6%; 79.5 ± 7.5 years). Women had a higher risk of institutionalization than men (hazard ratio [HR], 1.21; 95% CI, 1.16-1.26) and lower mortality once institutionalized (HR, 0.61; 95% CI, 0.58-0.64), resulting in longer stays (median, 2.44 vs 1.47 years). Women also had lower overall mortality (HR, 0.72; 95% CI, 0.70-0.75). On average, women had lower yearly health care costs (-€1297; 95% CI, -€1597 to -€1086) but higher long-term care costs (€11,247; 95% CI, €10,462-€11,852) than men across care settings. While adjustment for age and institutionalization reduced the differences, they remained significant. In addition, women's long-term care costs increased more over time (€1129 per year; 95% CI, €899-€1308), whereas their health care costs decreased more (-€246 per year; 95% CI, -€394 to -€121). Women lived longer with dementia than men and used more formal long-term care, both at home and in institutional settings. These findings highlight the need for care systems to account for sex-specific differences in care trajectories when planning and financing long-term dementia care.
Patients with Alzheimer's disease (AD) with a low to intermediate tau-PET burden might benefit most from anti-amyloid treatment. Staging tau burden with plasma biomarkers would offer a scalable alternative to staging with tau-PET. This study investigated whether key plasma biomarkers P-tau217, P-tau181, Aβ42/40, GFAP and NfL can be used to accurately stage amyloid status (A-/A+) and tau-PET burden, and evaluated the relation of such a plasma-based staging system with cognitive outcomes over time. We included 105 participants with subjective cognitive decline (n = 27 A-, n = 18 A+), A+ mild cognitive impairment (n = 10) or A + AD-dementia (n = 50) from the Amsterdam Dementia Cohort who underwent [18F]flortaucipir PET-burden assessment (Tlow, Tintermediate or Thigh; based on MUBADA SUVr) and longitudinal cognitive assessment (average follow-up: 4.1 ± 3.5 years). AD-related plasma biomarkers were measured with Simoa. Discriminative performance (AUC) of each marker was compared using ROC analysis, and combined utility was assessed with logistic regression. Subsequently, cutoffs were established aiming for 90%-specificity, to regroup participants into a plasma-based staging scheme. Age-, sex- and education-adjusted linear mixed models (LMM) were performed to compare associations of plasma versus PET-based staging with longitudinal cognition. 27 participants were A-TPET_low, 22 A+TPET_low, 27 A+TPET_int and 29 A+TPET_high. To discriminate A-TPET_low participants from A+TPET_low/int participants, P-tau217 performed best among all measured markers P-tau217, P-tau181, Aβ42/40, GFAP and NfL (AUC = 0.92 [95% CI: 0.856-0.985]). To discriminate A+TPET_high participants from A+TPET_low/int participants, also P-tau217 performed best among all markers (AUC = 0.74 [95% CI: 0.618-0.862]). A combination of Wald's backward-selected plasma markers did not statistically improve discriminative performance (DeLong's p > 0.05; two-marker combinations selected). Applying two cutoffs for P-tau217 as well as for the two-marker combinations, at 90% specificity to discriminate subsequent groups, we derived two plasma-based staging schemes. While the tau-PET staging scheme significantly and consistently associated with cognitive performance and decline across cognitive domains in LMMs, the plasma staging schemes did not. Performance of plasma-based staging approaches developed in this study were high when discriminating individuals without amyloid pathology, while this was moderate when discriminating amyloid positive individuals with a high tau-PET burden. Our LMM findings visualize that tau staging in amyloid-positive individuals remains optimally performed with tau-PET scans.
Alzheimer's disease (AD) is not an inevitable outcome of pathology but a dynamic process shaped by how brain cells respond to amyloid-β (Aβ) and tau. To disentangle these responses, we combined spatial transcriptomics and single-nucleus RNA sequencing of the superior frontal cortex from octogenarians living with or without dementia and from cognitively intact centenarians with comparable Aβ accumulation. We identified six distinct tissue domains representing a spatial pathological continuum of AD, with a key inflection point marked by a shift from Aβ-associated inflammatory changes to tau-associated cellular programs. This transition was accompanied by a change in microglial states, from early inflammatory to late antigen-presenting phenotypes, termed early and late plaque-induced gene (PIG) programs. Resilient individuals showed distinct pathological patterns: octogenarians without dementia lacked late PIGs, whereas centenarians showed late PIG activation that was uncoupled from tau accumulation. Together, these findings highlight divergent resilience-associated mechanisms in human aging and position microglial state transitions at the Aβ-tau interface as candidate points of resilience with potential therapeutic relevance.
The cost and complexity of phase 2 randomized-controlled trials (RCTs) hinder further development of promising treatment candidates for Alzheimer disease (AD). The Simon Two-Stage futility trial design, originally developed for oncology, offers a streamlined approach to evaluate potential disease-modifying therapies by comparing single-arm outcomes with historical controls, but is predicated on identifying outcome measures that reliably worsen with the natural history of the disease, with minimal risk of improvement. We sought to determine the feasibility of such futility trials in AD-associated dementia and mild cognitive impairment (MCI) using a large prospective cohort. We analyzed longitudinal data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Cognitive decline was assessed using AD Assessment Scale-Cognitive Subscale (ADAS-Cog 11 and ADAS-Cog 13), Clinical Dementia Rating-Sum of Boxes (CDR-SB), and Mini-Mental State Examination (MMSE) at 6, 12, and 24 months using different thresholds for worsening vs improvement. Binary logistic regression models examined baseline factors associated with cognitive worsening using different thresholds of worsening for each outcome of interest to assess what additional selection criteria may be needed for futility trials in AD-associated dementia vs MCI. Sample size estimates were derived based on expected rates of decline. Among 2,665 participants (mean age 73.4 years [SD: 7.5], 1,260 [47.3%] female, 424 with AD-associated dementia), the CDR-SB exhibited the largest percentage of decline in AD-associated dementia and MCI, with 60.6% of patients with AD-associated dementia showing worsening when using a threshold of ≥1.0 points at 12 months vs 6.2% showing improvement. ADAS-Cog 11 and 13 showed similar decline patterns; for example, 41.7% with AD-associated dementia worsened by ≥ 5 points at 12 months on ADAS-Cog 13, whereas 5.8% improved. MMSE exhibited lower sensitivity; 25.8% with AD-associated dementia worsened by ≥ 5 points at 12 months, whereas 2.9% improved. Shorter trials (6-12 months) with 35-62 participants seemed feasible in AD-associated dementia, whereas MCI trials seemed to require 24 months and specific entry criteria based on age, apolipoprotein E ε4 status, and baseline CDR-SB performance. Futility trials seem feasible in AD-associated dementia, offering a faster, cost-effective alternative to traditional phase 2 RCTs. CDR-SB seems to be the optimal primary outcome. Further validation in clinical trial data sets is warranted.
Dementia with Lewy bodies (DLB) is the second most prevalent neurodegenerative dementia. It is clinically and biologically heterogeneous, yet longitudinal biomarker studies assessing different aspects of neuropathological processes in DLB are scarce. We systematically reviewed the literature to identify biomarkers suitable for tracking disease progression in DLB and to evaluate potential outcome measures for clinical trials by examining which biomarkers show longitudinal changes correlating with clinical progression. Following PRISMA guidelines, we searched CENTRAL, MEDLINE, Embase, Scopus, and Web of Science for longitudinal biomarker studies in DLB (sample size ≥10, follow-up duration ≥6 months). We conducted meta-analysis of three structural MRI-studies assessing whole-brain atrophy. Of 9162 titles screened, 17 studies met selection criteria including ±460 patients with MCI-LB/DLB. 15 studies included imaging biomarkers (MRI, SPECT, PET) and two studies included fluid biomarkers (plasma, CSF). Except for DAT-SPECT, most studies addressed non-DLB specific neurodegeneration or Alzheimer's disease (AD) pathology. Structural MRI-studies showed greater longitudinal atrophy in AD and mixed DLB + AD versus DLB and controls. Meta-analysis confirmed that DLB-patients were comparable to controls (p = 0.37), but showed lower atrophy rates than AD (p = 0.01). Amyloid-PET and biofluid studies suggested that amyloid accumulation follows typical progression, even in non-AD diagnoses. DAT-SPECT and FDG-PET demonstrated longitudinal changes correlating with clinical progression, showing promise as monitoring biomarkers. No single biomarker currently suffices to track disease progression in DLB. DAT-SPECT and FDG-PET showed promise, but further research is warranted on these and alternative, more disease-specific, accessible and feasible modalities to improve disease monitoring in future clinical trials.