Stephanie Rainey-Smith

Short-chain fatty acids (SCFAs) produced by gut microbial fermentation influence host metabolism and neuroinflammatory processes implicated in Alzheimer’s disease (AD). However, the relationship between fecal SCFAs, microbial taxa, and cerebral amyloid-β (Aβ) burden in cognitively unimpaired individuals remains unclear. Fecal SCFAs were quantified using GC-MS, and microbial species were profiled by shotgun metagenomics in 87 participants. Associations between SCFAs, demographics, APOE ε4 status, and Aβ burden were tested using nonparametric statistics and multivariable regression. Microbial–SCFA links were evaluated using Spearman correlations and multivariate ordinations, with mediation analysis exploring potential indirect pathways. Acetate was the predominant SCFA and demonstrated the most robust microbial associations. Higher acetate concentrations were positively associated with Bacteroides ovatus and Faecalibacterium prausnitzii, whereas lower acetate levels were linked to species such as Bifidobacterium animalis and Lachnoclostridium scindens. Stratified analyses indicated that individuals with elevated Aβ burden exhibited more pronounced species–SCFA relationships, including a notable association between Bacteroides thetaiotaomicron and butyrate. Multivariate ordination further identified a significant overall coupling between SCFA profiles and microbial community structure. Mediation analysis suggested that an Oscillospiraceae species may represent a potential intermediary linking valerate concentrations with Aβ status. SCFA concentrations were not strongly influenced by demographic or genetic factors, but specific species demonstrated robust associations with acetate levels. Distinct SCFA–microbial interaction patterns in Aβ High individuals suggest subtle early gut microbial alterations linked to amyloid burden. These findings highlight the potential role of SCFA-related microbial pathways in preclinical AD.

Background
Alzheimer's disease (AD) is a complex and multifactorial disease, defined by accumulation of Amyloid-Beta (Aβ) and tau, and ultimately cognitive decline leading to dementia. Plasma biomarkers offer an efficient and non-invasive method to detect either Aβ or tau pathology but have demonstrated substantially different accuracy. Assessment of how these plasma biomarkers change along the disease continuum (Aβ and tau) are needed.

Method
In the current study, we investigated 15 high performing plasma biomarkers (pTau217: Lumipulse, ALZpath, Elecsys@ NeuroToolKit [Roche Diagnostics International Ltd, Rotkreuz, Switzerland], Janssen; pTau181: Simoa, Elecsys, UGOT; pTau231: UGOT; Aβ42/40: Lumipulse, Elecsys@; GFAP: Simoa, Elecsys@, NFL: Simoa, Elecsys, BD-Tau: Simoa, Elecsys) against PET-Aβ Centiloid (CL) and meta-temporal CenTauR (CTR) across the AD continuum. Samples from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of ageing were selected if they had both plasma and PET imaging for Aβ and tau (N = 272). Generalised additive models from biomarker Z-scores vs CL and CTR were computed, and receiver operating characteristic (ROC) analyses were performed to calculate area under the curve along with sensitivity, specificity, positive predictive value, negative predictive value and accuracy for both PET-Aβ and PET-tau positivity (CL>20 & CTR>24).

Result
Against both Centiloid and CenTauR, pTau217 had the largest increases over the disease continuum, with the Z-scores rising above the other biomarkers by 50CL for Aβ, and by 20 CTR for tau. From the point at which Aβ became positive to when tau became positive, pTau217 rose between 12% and 21%, whilst for all other markers rises of between 1% and 8% were seen. Highest correlations between biomarkers with CL and CTR were seen for pTau217 and optimal AUC values for CL and CTR reached approximate 0.95 and 0.91.

Conclusion
The findings from this research confirm that pTau217 is the strongest biomarker to predict either Aβ or tau across all the four assays analyzed. Unlike other plasma biomarkers which rise with increasing Amyloid burden and stay elevated, plasma pTau217 rises with increasing Amyloid, and then again with increasing Tau burden, indicating a dual response to different AD pathologies.

Background
With the increasing number of countries approving disease-modifying therapies (DMTs) for patients with either Mild Cognitive Impairment (MCI) or mild Alzheimer's disease (AD), it is vitally important to streamline treatment assessment processes. Blood-based biomarkers (BBMs) have been suggested as rivals to cerebrospinal fluid (CSF) biomarkers in their accuracy to detect neocortical Amyloid-Beta (Aβ). However, there is little consensus on potential thresholds and resulting confirmatory test performance for international use in target populations.

Method
Two separate sub-cohorts—the AD continuum cohort (ADCC) [cognitively impaired + unimpaired; N = 197] and the intention to treat cohort (ITTC) [cognitively impaired; N = 200]—from the Australian Imaging Biomarkers and Lifestyle (AIBL) study of aging, were designed to test the accuracy and potential cut-offs of leading BBM Lumipulse assays from Fujirebio (pTau217 and Aβ42/40) to detect PET-Aβ (centiloid ≥25; amyloid prevalence ∼63%).

Result
Using the pTau217/Aβ42 ratio significantly improved the area under the curve (AUC) over pTau217 alone to detect PET-Aβ positivity in both the ADCC and ITTC (Figure 1A, ADCC p = 0.01; Figure 1B: ITTC p = 0.009). The Youden's Index cut-off for pTau217 was higher in the ITTC compared to the ADCC (0.25 pg/mL vs. 0.179 pg/mL). The highest accuracy observed for either single BBMs, the ratio of BBMs, or the linear combination of BBMs that included age, gender, and APOE ε4 was 93-95% in the ADCC (linear combination of pTau217, Aβ42/40, age, gender, and APOE ε4; pTau217/Aβ42 ratio) and 95-97% in the ITTC ( linear combination; pTau217/Aβ42 ratio). The lowest number of participants in the intermediate zone using dual cut-offs at 95% sensitivity and specificity was 9% and 14% for the pTau217/Aβ42 ratio in the ADCC and ITTC (92-93% accuracy), and 0% for the linear combination (pTau217, Aβ42/40, age, gender, and APOE ε4) in the ITTC (95% accuracy).

Conclusion
The general performance of the Lumipulse assays was similar across both the ADCC and ITTC, indicating strong repeatability independent of clinical stage. Focusing on only participants eligible for DMTs increased sensitivity and improved accuracy for the Aβ-containing pTau217/Aβ42 ratio and linear combination of markers, and resulted in small numbers of unclassified participants by the test.

Background: CSF and blood soluble TREM2 (sTREM2) levels have been found to increase at early stage of Alzheimer's disease (AD). The relationships between sTREM2, AD-related biomarkers, and other neuroinflammation biomarkers remain unclear. Moreover, the impact of rare variants in TREM2 gene (R47H/R62H), which are associated with increased risk of AD, on plasma sTREM2 has not been elucidated.

Objective: Investigate the association of plasma sTREM2 levels with brain amyloid-beta (A beta) load and AD-related blood biomarkers, i.e., phosphorylated tau (pTau)-181, pTau-231, GFAP, NFL, and other neuroinflammation and peripheral inflammation markers in cognitively normal (CN) older adults at risk of AD (CN A beta+) compared to CN A beta-, including the effect of AD-linked TREM2 rare variants.

Methods: Plasma sTREM2 concentrations were measured by MesoScale Discovery (MSD) assay from the KARVIAH cohort. Participants underwent cognitive tests and PET amyloid imaging. Genetic data and blood biomarkers were included for correlation analysis. Associations with plasma sTREM2 were investigated upon stratification by PET-A beta load SUVR ((CN A beta- (n = 65) and CN A beta+ (n = 35)) as the main analysis. A subgroup analysis based on the TREM2 R47H and R62H genotype was conducted as exploratory analysis.

Results: Plasma sTREM2 positively correlated with plasma pTau181, and pTau231 in CN A beta+ group. Plasma sTREM2 positively correlated with serum microglial kynurenine pathway metabolites. Plasma sTREM2 and brain A beta load were higher in R47H TREM2 carriers compared to non-carriers.

Conclusions: Our findings suggest plasma sTREM2 relates to downstream tau processes in amyloid-positive individuals, providing novel insights into the roles of peripheral TREM2 signaling that reflects microglial activity in early AD neuropathological development.

INTRODUCTION
Dietary nitrate, through conversion to nitric oxide, which supports vascular and nervous system function, may lower dementia risk but may also form neurodegenerative N‐nitrosamines, depending on the nitrate source.

METHODS
We investigated associations between source‐specific nitrate and nitrite intake and incident and early‐onset dementia (<65 years) in 54,804 dementia‐free participants from the Danish Diet, Cancer and Health Cohort Study over ∼27 years. Nitrate and nitrite intakes were derived from food frequency questionnaires and nitrate and nitrite databases.

RESULTS
Higher plant‐sourced nitrate intake was non‐linearly associated with lower rates of incident dementia (fifth vs first quintile hazard ratio 95% confidence interval: 0.90 [0.83, 0.98]), while increased risk was seen for higher intakes of animal‐sourced, additive‐permitted meat‐sourced, and tap water‐sourced nitrate. Similar associations were seen for source‐specific nitrite intake and were more pronounced for early‐onset dementia. No clear effect modification was observed.

DISCUSSION
These findings highlight the importance of nitrate source in dementia risk and warrant further investigation. Highlights Plant nitrate is associated with a lower risk of incident and early‐onset dementia. Animal and tap water nitrate are associated with an increased risk of dementia. Encouraging consumption of plant‐based nitrate sources may lower risk of dementia.

Background
Type 2 diabetes is associated with increased Alzheimer’s disease risk and brain beta amyloid (Aβ) burden, suggesting an underlying mechanistic relationship between Alzheimer’s disease and type 2 diabetes. Animal studies show exercise reduces levels of brain Aβ and tau, and while human studies are somewhat limited, some studies have reported physical activity is associated with lower brain Aβ and tau levels. Exercise has well established links to reductions in insulin resistance; thus, as physical activity can impact both insulin resistance and Alzheimer’s disease pathology and/or biomarkers, it is reasonable to hypothesise that a mediating relationship may exist. The objective of this review was to identify what evidence exists that examines the association between insulin, physical activity, Aβ and tau in research conducted on animal models and in human cohorts. We specifically aimed to identify whether insulin resistance has a mediating role in the relationship between physical activity and Aβ and tau.

Methods
A systematic search was performed in Cochrane library, PsycINFO, PubMed and World of Science to identify publications. The search identified 343 articles with 20 articles meeting the full inclusion criteria.

Results
Most animal studies showed that exercise could simultaneously reduce insulin resistance and Alzheimer’s disease pathology and/or biomarkers. We found limited evidence from human research that physical activity was associated with both reduced insulin resistance and Aβ or tau levels. We did not find any evidence that insulin resistance mediates the physical activity – Aβ or tau relationship.

Conclusion
Exercise can simultaneously impact insulin resistance and Alzheimer’s disease pathology in animal models. Results from human research are limited, and no robust evaluation of the potential mediating role of insulin resistance in the physical activity – Aβ or tau relationship exists. Future research should focus on identifying the mediating pathways that may link physical activity to biomarkers of Alzheimer’s disease.

Introduction
Research in the field of sleep, aging, and dementia is rapidly growing. Consensus guidance is needed to facilitate high-quality research, comparability, and consistency.

Methods
A modified Delphi consensus study was conducted by the Sleep and Circadian Rhythms Professional Interest Area of the International Society to Advance Alzheimer's Research and Treatment (ISTAART) and an international panel of experts to establish recommendations for future research.

Results
After two voting rounds, the group (1) determined by consensus the most relevant sleep and circadian features to assess in the context of aging and dementia research, (2) established recommendations on data acquisition and report for future studies, and (3) identified high-priority future directions.

Discussion
This expert consensus study provides guidance to develop high-quality sleep and circadian research in the context of aging and dementia. Similar recommendations will need to be established for clinical practice.

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.

BACKGROUND
Healthy lifestyle factors, including diet, may affect brain amyloid beta (Aβ) load. This study examines dietary patterns as moderators of the relationships among symptoms of depression, anxiety, and brain Aβ load.

METHOD
A cross-sectional study of cognitively unimpaired older adults (n = 524) from the Australian Imaging, Biomarkers, and Lifestyle study assessed dietary patterns, depressive and anxiety symptoms, and brain Aβ load. Moderation and simple slope analyses were conducted.

RESULTS
The Dietary Approaches to Stop Hypertension (DASH) diet moderated the relationship between depressive and anxiety symptoms and brain Aβ load. Higher symptoms were associated with greater Aβ load in individuals with lower DASH adherence. This effect was also observed for anxiety symptoms in apolipoprotein E ε4 carriers. The Mediterranean and Western diets did not moderate these relationships.

CONCLUSION
The DASH diet adherence may mitigate the impact of depressive and anxiety symptoms on brain Aβ load, supporting genotype-specific dietary interventions in mental and brain health.

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.