Nationwide surveillance of Creutzfeldt-Jakob disease (CJD) and other human prion diseases is performed by the Australian National Creutzfeldt-Jakob Disease Registry (ANCJDR). National surveillance encompasses the period since 1 January 1970, with prospective surveillance occurring from 1 October 1993. Over this prospective surveillance period, considerable improvements have been developed in pre-mortem diagnostics in parallel with the delineation of new disease subtypes and heightened awareness of prion diseases in healthcare settings. Surveillance practices of the ANCJDR have evolved and adapted accordingly. This report summarises the activities of the ANCJDR during 2025. Since the ANCJDR began offering diagnostic cerebrospinal fluid (CSF) 14-3-3 protein testing in Australia in September 1997, the annual number of diagnostic test referrals has steadily increased. In 2025, there were 788 domestic CSF specimens referred for diagnostic testing; 92 persons with suspected human prion disease were formally added to the national register. As of 31 December 2025, more than half of the 84 initial case notifications for 2025 (44/84) remain classified as 'incomplete'; 35 cases have been confirmed as 'definite' or 'probable' prion disease; five cases were excluded. In 2025, most suspected human-prion-disease-related deaths in Australia (56%) underwent neuropathological examination. No cases of variant or iatrogenic CJD were identified in Australia during 2025.

INTRODUCTION: Alzheimer's disease (AD) progresses over decades, yet plasma biomarkers that resolve disease stage rather than simply detect disease remain scarce. This distinction is clinically consequential because effective AD intervention depends on identifying patients before disease biology has progressed beyond a therapeutically responsive stage. METHODS: We used small-molecule-modulated protein corona proteomics to profile plasma from 90 individuals in the Australian Imaging, Biomarker and Lifestyle cohort, stratified by Centiloid (CL) Aβ-amyloid burden (30 amyloid-negative, CL < 15; 30 moderate-to-high, CL 26 to 100; 30 very high, CL > 100). We quantified 3,176 proteins and applied differential abundance and actual causality analyses to identify stage-specific and candidate causal proteins. RESULTS: Differential protein abundance was exclusively captured during the moderate-to-high AD transition, revealing a discrete proteomic "switch." The switch was marked by accumulation of the autophagy receptor CALCOCO1, together with coordinated depletion of the S100A8/S100A9 calprotectin complex and core erythroid-cytoskeletal network structural markers (e.g., SPTA1, SPTB, ANK1). Adhesion G protein-coupled receptor G6 (ADGRG6) showed a significant moderate positive monotonic association with absolute CL burden, providing a proportional molecular anchor for cumulative disease burden. Actual causality analysis identified COL6A2, FOXRED2, P3H1, PRR4, and GOLGA5 as candidate upstream drivers linking matrix remodeling, Golgi trafficking, and collagen processing to AD progression. DISCUSSION: These findings suggest a candidate blood-accessible framework for staging AD by active disease biology, which, if replicated in independent cohorts, may have implications for therapeutic selection and mechanism-guided clinical trials.

BackgroundDecline in activities of daily living (ADL) is a defining feature of Alzheimer’s disease (AD), often emerging during mild cognitive impairment (MCI). Whether quantitative amyloid-beta (Aβ) burden relates to ADL performance across symptomatic stages remains unclear.MethodsWe analysed 134 cognitively impaired adults (≥ 60 years; MCI, n = 26; AD dementia, n = 108) from the Australian Imaging, Biomarkers and Lifestyle Study. ADL performance was examined in relation to PET-derived Aβ burden, expressed on the Centiloid scale, using multivariable regression with an interaction by clinical classification.ResultsBetter ADL performance was associated with lower Aβ burden (β = −0.08, P = .022). ADL x clinical classification interaction (p = .018) indicated stage-dependent effects, with lower Aβ in MCI (β = −0.07, P = .058), but not in AD dementia.ConclusionADL performance aligns more closely with amyloid burden in early symptomatic AD, supporting its relevance within biomarker-informed staging.

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.

Objective:To systematically evaluate pathway-informed polygenic risk score (PRS) strategies and determine which approaches most effectively leverage biological annotations for risk prediction, using brain amyloid-β (Aβ) positivity as a case study. Methods:We systematically benchmarked approaches for integrating pathway information into PRSs construction to predict brain Aβ positivity. Using two cohorts, the Alzheimer's Disease Neuroimaging Initiative (ADNI, n = 969) and Australian Imaging, Biomarkers and Lifestyle (AIBL, n = 251), we compared Apolipoprotein E ( APOE ) genetic risk score (GRS), clumping and thresholding (C+T) PRS, pathway-guided single nucleotide polymorphism (SNP) selection PRS, and pathway-specific PRSs ensembled via machine learning. Pathways were derived from manually curated literature or from pathway databases via Functional Mapping and Annotation (FUMA). Results:In cross-validation on the ADNI cohort, pathway-informed PRS using a narrow-set of pathways to guide SNP selection (PathPRS-SNP Lit without APOE locus) significantly outperformed the standard PRS model (median AUC = 0.742, p = 0.006) and the APOE locus model (median AUC = 0.736, p = 5.1 × 10 -5 ) based on the Mann-Whitney U test, achieving a median AUC of 0.763. This model showed enhanced ability to identify subgroups within the 10% lowest-and highest risk groups compared to the current standard of APOE locus alone (odds ratio = 0.67, 95% CI: 0.56-0.81; and OR = 13.23, 95% CI: 10.23-17.11), highlighting its clinical potential. Using a focused set l iterature-curated pathways outperformed using a broader set of database-derived pathways across configurations. When contrasting strategies for aggregating information across pathways, we observed that using pathways to guide selection of SNPs and then building a single PRS performed comparably to building PRS for each pathway and using machine learning (ML) to aggregate these, though the latter enabled pathway-level interpretability. S imilar trends were observed in the external AIBL validation dataset. Interpretation:Pathway-informed PRS can meaningfully improve genetic risk enrichment for Aβ positivity beyond APOE and standard C+T approaches, provided pathway definitions are carefully curated. The choice of pathway source has the strongest impact on predictive performance with aggregation strategies or ML model choice having far less impact. Our findings highlight the utility of literature-curated, pathway-informed PRSs for Aβ prediction and offer practical guidance for pathway-informed PRS construction in other polygenic traits.

Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) for ∼20 years prior to dementia onset. Phthalates, routinely added to plastics to increase flexibility, and bisphenol monomers, have been shown to interfere with neural activity/brain function. Phthalate and bisphenol exposure did not show association of individual urinary biomarkers with Aβ or clinical phenotype (mild cognitive impairment (MCI)/AD). Assessing biomarkers in quartiles, low mono(2-ethylhexyl) phthalate (MEHP), but not other biomarkers of di(2-ethylhexyl) phthalate (DEHP), was associated with Aβ+ and with having MCI/AD (q < 0.05), while high Bisphenol S (BPS) was associated with Aβ+ (q < 0.05). Mixture analysis shows significant association with MCI/AD but not Aβ.

Extracellular amyloid plaques, the pathognomonic hallmark of Alzheimer’s disease (AD), are also observed in cognitively unimpaired subjects in the preclinical stages. Progressive accumulation of fibrillar amyloid-β (Aβ) as plaques and perivascular deposits occur two decades before clinical onset, making Aβ a long-lived peptide. To characterize the amyloid plaques biochemically, both the Aβ-load as well the post-translational modifications (PTMs) could serve as markers for distinguishing the pre-clinical stage compared to later prodromal and clinical stages of AD. Recently, we described the presence of extensive isomerization of the Aβ N-terminus in AD post-mortem brains that is significantly increased compared to the age-matched non-AD control brains with Aβ aggregates. In this report, we performed Lys-N enzymatic digestion followed by mass spectrometry-based quantitative analysis of the most common PTMs associated with plaque Aβ. We focused on pyroglutamation (pGlu3), citrullination (cit5), N-terminal truncation (Aβ4-x), C-terminal isoforms (Aβx-42 and Aβx-40), and isomerization of aspartic acid residues (Asp-1 and Asp-7) in postmortem human brain tissue from pathologically negative (no Aβ plaques) controls (n = 23), controls with Aβ plaques (n = 35), Parkinson’s disease (PD) with (n = 28) and without Aβ accumulation/plaques (n = 30) and symptomatic AD (n = 60). The AD cases contained statistically significant amounts of Asp-1 and Asp-7 isomerized Aβ ( 90

In cognitively unimpaired (CU) individuals, the PACC is widely used as a cognitive outcome measure and endpoint in observational studies and clinical trials. However, it has drawn criticism for being heavily weighted towards memory. Increasing evidence indicates a decline spanning multiple cognitive domains in CU individuals. Therefore, using principal component analysis (PCA), we derived data-driven domain-specific cognitive composites. And subsequently, compared them against their summed z-score counterparts in predicting progression to mild cognitive impairment (MCI). Baseline cognitive, demographic, and genotype data of 2,853 CU older adults (aged 41.6 to 98.3) was obtained from the Alzheimer’s Dementia Onset and Progression in International Cohorts (ADOPIC) Consortium. Using varimax-rotated PCA, tests significantly loading (≥ 0.5) onto each principal component were extracted to derive domain-specific cognitive composites. The resulting domain scores were normalised to a mean of 0 and SD of 1, with a higher score indicating better cognition. Cox regression was used to assess the association between progression to MCI and baseline demographics, cognition, and APOE ε4 carriage. Akaike information criteria (AIC) was used to compare the fitness of PCA-derived composites against the zPACC and z-score domain-specific composites. Baseline cohort characteristics are described in Table 1. PCA explained 68% of the variance and resulted in four independent cognitive composites (Figure 1): memory; executive function; attention and processing speed; and global cognition. At 15 years from baseline, 309 participants progressed to MCI, while 2,544 remained CU. Cox regression showed that the four cognitive composites, age and APOE genotype significantly predicted progression to MCI (Concordance = 77%, p < 0.001, AIC = 4105, Table 1). Additionally, the PCA-derived composites performed comparably, if not better than the summed z-score counterparts, the PACC (Concordance = 74%, p < 0.001, AIC = 4163) and domain-specific composites (Concordance = 75%, p < 0.001, AIC = 4142). Baseline older age, APOE ε4 carriage in a dose-dependent manner (Figure 2) and poorer cognition for each PCA-composite were independently associated with progression to MCI. Together with APOE ε4 carriage, our PCA-derived domain-specific composites performed better than their summed z-score counterparts at predicting progression to MCI 15 years before symptom onset.

Recent advances in immunoassays have enabled sensitive detection of Aβ42/40 and pTau217 in plasma, components of Alzheimer’s disease (AD) neuropathological markers. Further characterization of increased diagnostic accuracy with PET Amyloid-β (Aβ) across the AD continuum is needed for clinical application. Participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of ageing (N=197) representing a cross-sectional population of four clinical and PET-Aβ subgroups: cognitive unimpaired (CU) Aβ- (n=75), CU Aβ+ (n=48), mild cognitive impairment (MCI) Aβ+ (n=26), and AD Aβ+ (n=48). EDTA plasma was analyzed with Aβ42/40 (Quanterix Simoa & Fujirebio Lumipulse) and pTau217 (ALZpath Simoa & Lumipulse). Data were investigated using Cohen’s D for effect size, Receiver Operating Characteristic (ROC) analyses to define AUC values for PET-Aβ positivity and Spearman’s Rho for correlation between biomarkers and Centiloid. Lower Lumipulse and Simoa plasma Aβ42/40 ratios were observed in Aβ+ vs Aβ- groups (p<0.0001; with effect size Cohen’s D indices = 1.39 and 1.07, respectively). Aβ42/40 ratios initially decreased with increasing amyloid PET Centiloid levels through the positivity threshold (25CL), levelling off with increasing Centiloid values across the disease continuum (Figure 1A). Highest effects sizes were seen for pTau217 when comparing Aβ+ vs Aβ- groups (p<0.0001; Cohen’s D: 1.54 [Simoa] and 1.49 [Lumipulse]), with stepwise increases per Centiloid group (Figure 1B). Biomarker AUC values to predict PET-Aβ were highest for pTau217 in the complete sample compared with the CU sample (Simoa AUC: 0.947/0.906, Lumipulse AUC: 0.941/0.906). For the Aβ42/40 ratio, AUC values were higher in the CU group as compared with the complete sample (Lumipulse AUC: 0.896/0.889, Simoa AUC: 0.885/0.849 (Figure 1C). Adding in age, gender, and APOE ε4 allele status improved prediction of PET-Aβ, with AUC values reaching 0.97 for pTau217 (Figure 1C). Correlations between biomarker and Centiloid were higher for pTau217 (Simoa: r=0.744 (Figure 1D), Lumipulse r=0.732) as compared with the Aβ42/40 ratio (Lumipulse r=-0.509, Simoa r=-0.462). Sensitive assays for the Aβ42/40 ratio may be more appropriate to detect Aβ burden in CU participants while p-Tau217 appears to be more accurate and has the highest effect size and AUC values to predict Aβ-PET across the AD continuum.

INTRODUCTION:This study was undertaken to evaluate the diagnostic performance of a novel plasma phosphorylated tau (p-tau) 217/amyloid beta (Aβ) 42 ratio test for Alzheimer's disease (AD). METHODS:The diagnostic performance of the Lumipulse G plasma p-tau217/Aβ42 ratio was evaluated using Aβ and tau positron emission tomography (PET) as reference standards in a clinic cohort (n = 391) and a community cohort (n = 121). RESULTS:Plasma p-tau217/Aβ42 exhibited high performance for abnormal statuses of Aβ PET (area under the curve [AUC]: 0.963 to 0.966) and tau PET (AUC: 0.947 to 0.974), which were clinically equivalent to those of cerebrospinal fluid (CSF) p-tau181/Aβ42 and Aβ42/Aβ40 and higher than those of blood p-tau217, Aβ42/Aβ40, p-tau181, and p-tau181/Aβ42 in both clinic and community cohorts. Applying a two-cutoff approach improved the specificity without reducing sensitivity. The p-tau217/Aβ42 ratio had a lower intermediate percentage than p-tau217 alone in both clinic (10.6% vs 13.0%) and community (16.5% vs 31.4%) cohorts. DISCUSSION:Plasma p-tau217/Aβ42 has high performance in detecting cerebral AD pathologies, thus offering a promising tool for clinical diagnosis and community screening of AD. HIGHLIGHTS:Lumipulse G plasma p-tau217 and the p-tau217/Aβ42 ratio accurately identified abnormal Aβ and tau PET statuses in both clinical and community cohorts. The performance of plasma p-tau217 and p-tau217/Aβ42 ratio were equivalent to CSF tests. Plasma p-tau217/Aβ42 ratio outperformed p-tau217 alone in identifying Aβ PET positivity, and this superiority is more obvious in the community cohort, suggesting an advantage in the early diagnosis of AD. Two cut points of p-tau217/Aβ42 were established in the Chinese population for clinical laboratory and community screening uses.

Nationwide surveillance of Creutzfeldt-Jakob disease (CJD) and other human prion diseases is performed by the Australian National Creutzfeldt-Jakob Disease Registry (ANCJDR). National surveillance encompasses the period since 1 January 1970, with prospective surveillance occurring from 1 October 1993. Over this prospective surveillance period, considerable improvements have been developed in pre-mortem diagnostics; in the delineation of new disease subtypes; and in heightened awareness of prion diseases in healthcare settings. Surveillance practices of the ANCJDR have evolved and adapted accordingly. This report summarises the activities of the ANCJDR during 2024. Since the ANCJDR began offering diagnostic cerebrospinal fluid (CSF) 14-3-3 protein testing in Australia in September 1997, the annual number of referrals has steadily increased. In 2024, a total of 760 domestic CSF specimens were referred for diagnostic testing and 88 persons with suspected human prion disease were formally added to the national register. As of 31 December 2024, approximately half (42) of the 83 initial case notifications for 2024 remain classified as 'incomplete'; 21 cases were classified as 'definite' and 17 as 'probable' prion disease; three cases were excluded through neuropathological examination. For 2024, seventy-two percent of all suspected human-prion-disease-related deaths in Australia underwent neuropathological examination. No cases of variant or iatrogenic CJD were identified in Australia during 2024.

Abstract Background Plasma phospho-tau biomarkers, such as p217+tau, excel at identifying Alzheimer’s disease (AD) neuropathology. However, their ability to substitute for tau PET to identify AD biological stage is unclear. Methods Participants included 248 cognitively unimpaired (CU) and 227 cognitively impaired (CI) individuals, with Janssen plasma p217+tau Simoa® assay, 18F-NAV4694 Aβ-PET (A) and 18F-MK6240 tau-PET (T) data. Biological PET stages were defined according to the Revised Criteria for Diagnosis and Staging of Alzheimer’s Disease (2024): Initial (A + T-), Early (A + TMTL + ), Intermediate (A + TMOD + ), and Advanced (A + THIGH + ). The threshold for A+ was 25 Centiloid and for THIGH + , the 75th percentile SUVRtemporo-parietal in A + CI. Sixty percent were A + , 36% Intermediate/Advanced, and 9% Advanced. The performance of p217+tau in discriminating AD stages was assessed using Receiver Operating Characteristic (ROC) analysis and logistic regression. Results Plasma p217+tau concentrations increase across the AD biological PET stages, except between Initial and Early stages. Screening for all AD stages (vs. A-T-), combined Intermediate/Advanced stages, or Advanced stage yields AUC of 0.92, 0.92, and 0.91, respectively (CI only: AUC 0.93, 0.89, 0.83). Plasma p217+tau Youden threshold provides sensitivity of 0.77 [0.73–0.90], specificity 0.91 [0.80–0.95], PPV 0.84 [0.71–0.89], and NPV 0.88 [0.85–0.93] for combined Intermediate/Advanced stages. For the Advanced stage alone, sensitivity is 0.89 [0.79–0.97], specificity 0.82 [0.75–0.9], NPV 0.99 [0.98–1.0], but PPV is only 0.33 [0.25–0.47]. Conclusions In addition to accurately screening for A+ individuals, plasma p217+tau is useful for identifying a combined Intermediate/Advanced stage AD cohort or pre-screening to reduce the tau-PET required to identify Advanced stage AD individuals.

INTRODUCTION:The current evidence supporting the complex, multifaceted etiology for Alzheimer's disease (AD) grows by the day, prompting increased research in non-"amyloid hypothesis"-related pathways. One of these pathways of interest pertains to an autoimmune component in this disease. METHODS:In this review, we briefly discuss current evidence of potential contributions of autoimmunity to AD pathobiology and describe the putative role of autoantibodies detected in patient fluids. We draw attention to the fact that the reported AD-related autoantibodies differ dramatically between published studies, raising doubts about the reliability and robustness of these findings. RESULTS:We hypothesize, and provide indirect evidence, that many of the reported autoantibodies in AD may represent false discoveries. We suggest follow-up validation and confirmatory studies with sufficient power, preferably by employing orthogonal testing techniques. DISCUSSION:Uncovering the putative autoimmune components of AD is important and could pave the way to new concepts for AD pathogenesis, diagnosis, and therapy. HIGHLIGHTS:Although Alzheimer's disease (AD) is not traditionally considered an autoimmune disease, growing evidence suggests immune system dysregulation and autoantibody generation, either in the form of naturally occurring or pathogenic autoantibodies. Numerous studies have discovered autoantibodies in AD, but only a few of them have been found independently and multiple times, including amyloid β (Aβ) and tau autoantibodies. Many of these findings represent false discoveries. Follow-up validation and confirmatory studies with sufficient power are imperative, preferably by employing orthogonal testing techniques. Understanding the immune and autoimmune landscape in AD will assist in future immunotherapy strategies.

INTRODUCTION:For a blood-based biomarker to be considered a confirmatory test for the detection of abnormal amyloid beta (Aβ) levels, the sensitivity and specificity must be equivalent to that of current cerebrospinal fluid tests. METHODS:In the current study we assessed the ability of phosphorylated tau (p-tau)217 and Aβ42/40 from the Lumipulse G p-tau217 and β-amyloid ratio (1-42/1-40) tests, individually and combined, to predict Aβ positron emission tomography status in two sub-cohorts from the Australian Imaging, Biomarkers, and Lifestyle Study of Ageing. RESULTS:Testing an Alzheimer's disease continuum cohort, the area under the curve (AUC), sensitivity, specificity, and accuracy for the p-tau217/Aβ42 ratio reached 0.961, 93%, 92%, and 93%, respectively. Validation in an intention-to-treat cohort demonstrated similar AUC (0.959), with increased sensitivity (99%), decreased specificity (87%), and increased accuracy (95%). Dual cut-offs generating balanced 95% sensitivity/specificity result in 93% accuracy. DISCUSSION:Combinations of plasma p-tau217 and Aβ42 demonstrate recommended performance, confirming the presence of Aβ positivity prior to selection for disease-modifying therapies. HIGHLIGHTS:The phosphorylated tau (p-tau)217/amyloid beta (Aβ)42 ratio had high performance to detect Aβ positron emission tomography (PET) status, with > 90% sensitivity, specificity, and accuracy. p-tau217/Aβ42 ratio dual cut-offs set at 95% sensitivity and specificity found 10% to 15% of participants in the intermediate zone. Cut-offs derived for the intention-to-treat cohort meet confirmatory assay criteria for a disease-modifying therapy and can be used in clinical settings.

Despite the health and societal burden that Alzheimer’s disease (AD) has on the elderly population, the underlying cause is not fully understood. Researchers are investigating possible mechanisms, and current studies have suggested that a number of comorbidities increase/decrease the likelihood of AD onset. The aim of the current study was to explore the associations between various comorbidities and AD in older Australians from an epidemiological perspective. This study used secondary participant data from the Australian Imaging, Biomarker & Lifestyle (AIBL) study (n = 2436) to perform a quantitative analysis. Univariable logistic regression was used to quantify the relationship between comorbidities and mild cognitive impairment (MCI)/AD, represented as odds ratios (ORs). The top 20 comorbidities were investigated as the exposure and based on the participants’ medical histories. MCI and AD were the outcomes of interest (with cognitive unimpairment as the reference) and were based on participants’ cognitive health diagnoses. Selected comorbidity associations with MCI/AD were also analysed via multivariable logistic regression, by stratifying and adjusting for sex, age, education, smoking, drinking and APOE ε4 allele carrier status. From the univariable logistic regression, the comorbidities with the strongest odds of developing AD in the AIBL cohort were anxiety, depression, neurological disorders, falls and stroke. Comorbidities with the most reduced odds of developing AD were kidney disease, liver disease and visual defects. These associations remained significant after multivariable logistic regression. When stratified for each covariate, several comorbidity associations observed effect modification from sex and APOE ε4 allele carrier status. When adjusted for all covariates, most of the selected comorbidity associations observed significant confounding. There were moderate similarities between the MCI and AD analyses. This study presents evidence that certain comorbidities appear to modify the clinical evolution of MCI/AD. Further research is needed to identify the mechanisms behind these associations and the potential modifying effect on MCI/AD.

Plasma phospho-tau biomarkers, such as p217+tau, excel at identifying Alzheimer’s Disease (AD) neuropathology. However, questions remain regarding their capacity to inform AD biological PET stages at group level and maintain the same precision at individual patient level. Participants included 248 cognitively unimpaired (CU) and 227 cognitively impaired (CI) individuals, with Janssen plasma p217+tau Simoa® assay, 18 F-NAV4694 Aβ PET (A) and 18 F-MK6240 tau PET (T) data. Biological PET stages were defined based on the draft NIA-AA Revised Criteria (July 2023): Initial (A+T-), Early (A+T MTL +), Intermediate (A+T MOD +), and Advanced (A+T HIGH +). We used thresholds for A+ of 25 Centiloid and for T HIGH of 80 Centaur (2.68 SUVR temporo-parietal ). Adding an A-T- stage for comparison, we assessed the performance of p217+tau in discriminating between these stages at the group level using Receiver Operating Characteristic (ROC) analysis and at the individual level using logistic regression. Plasma p217+tau concentrations increased across the stages, with significant differences between them, except for the Initial and Early stages. Screening for Advanced (vs. lower stages), combined Intermediate/Advanced (vs. lower stages), or all stages (vs. A-T-), p217+tau showed good group-level discriminations (AUC 0.91, 0.92 and 0.92; CI only: AUC 0.83, 0.89, 0.93, respectively). At the individual level, the likelihood of PET stage vs. p217+tau level showed good discrimination of A-T- vs any A+ stage and of combined Intermediate/Advanced disease stage vs lower stages in the CI. In addition to accurately screening for A+ individuals, plasma p217+tau shows promise for separating persons with either Intermediate or Advanced stage AD from those at a lower stage, providing prognostic information and informing better selection for trials and disease modifying therapies.

Associations between mental health, diet, and risk of Alzheimer's disease highlight the need to investigate whether dietary patterns moderate the relationship between symptoms of depression and anxiety, and neurodegeneration-related blood-based biomarkers. Cognitively unimpaired participants (n = 89) were included from the Australian Imaging, Biomarkers and Lifestyle study (mean age 75.37; 44 % male). Participants provided dietary, depressive and anxiety symptom data, and had measurement of blood-based biomarkers. Dietary pattern scores (Mediterranean diet (MeDi), Dietary Approaches to Stop Hypertension diet (DASH), and Western diet) were generated. Moderation and simple slope analyses were employed. In males with mean and below mean MeDi adherence, depressive symptoms were associated with higher neurofilament light (NfL) levels. In Apolipoprotein E epsilon 4 non-carriers with lower than mean and mean MeDi adherence, depressive symptoms were associated with higher NfL and A beta 40 levels. No associations were observed between DASH and Western diets and neurodegeneration-related biomarkers. MeDi adherence is potentially a moderator of the relationship between depressive symptoms and neurodegeneration-related blood-based biomarkers, with sex- and genotype-specific approaches important to consider within this relationship.

Sex differences in cognitive reserve might contribute to females being disproportionately affected by Alzheimer's disease (AD). We investigated sex differences in the protective effects of cognitive reserve, and whether brain beta-amyloid accounts for differences. Older adults (n = 997 from the Australian Imaging, Biomarkers and Lifestyle Study of Ageing) diagnosed as Cognitively Normal, Mild Cognitive Impairment, or AD at baseline were assessed every 18 months for up to a maximum of seven visits. Cognitive reserve was calculated from the variance in episodic memory not explained by demographic or brain measures. Executive functioning (EF) intercept and slope were regressed onto the main and interaction effects of cognitive reserve x brain integrity x sex, plus covariates (age, number of APOE ε4 alleles). A three-way interaction was observed between cognitive reserve, brain integrity, and sex on the EF slope. Females benefitted more than males from the protective effects of cognitive reserve at low levels of brain integrity. Sex differences in the protective effect of cognitive reserve were not moderated by brain beta-amyloid burden.

BACKGROUND:Cognition monitoring is crucial for care planning in people with mild cognitive impairment (MCI) and Alzheimer's dementia (AD). OBJECTIVE:To develop a machine learning model to assist cognition monitoring. DESIGN:Florey Fusion Model (FFM) was constructed and validated in two phases: (i) model development and cross-validation using data collected via the Australian Imaging, Biomarker, and Lifestyle of Ageing (AIBL) study, and (ii) simulation and missing data trials with 30 new participants. METHODS:This prognostic study recruited 238 participants in the AIBL study. Support vector machine, gradient boosting and random forest were trialled to develop the FFM. Cognitive decline was assessed via changes in Clinical Dementia Rating Sum of Boxes (CDR-SB) and Mini-Mental State Examination (MMSE) scores. Model performance was evaluated by cross validation and compared against baseline models. RESULTS:The FFM achieved a median area under receive character curve (AUC-ROC) of 0.91 (IQR 0.87-0.93) for MCI-to-AD progression prediction. A mean absolute error (MAE) of 1.32 (IQR 1.30-1.33) for CDR-SB and 1.51 (IQR 1.50-1.52) for MMSE was achieved for 3-year cognition forecast. Simulation and missing data trials yielded up to 94% accuracy for MCI-to-AD conversion and MAEs of 1.27-2.12 for CDR-SB score prediction. CONCLUSION:The FFM holds the potential to facilitate cognition monitoring in people with MCI/AD; however, a larger trial will be required to refine it as a clinical grade tool.