Stephanie Rainey-Smith

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.

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
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
Gut microbiota and their metabolites, particularly short‐chain fatty acids (SCFAs), play a vital role in the gut‐brain axis, and have been associated with neurodegenerative diseases like Alzheimer's disease (AD). However, the changes in gut microbiota composition and SCFA levels during the progression of AD are not yet well understood. This study seeks to investigate these variations to gain deeper insights into their potential role in disease development.

Method
This study examined changes in gut microbiota and SCFA across three groups; Cognitively unimpaired individuals with low amyloid‐beta ((CU) Aβ Low (n = 71)), CU Aβ High (n = 19), and those diagnosed with mild cognitive impairment (MCI) or AD (Disease Group (DG), n = 10). Participants were selected from well characterised cohorts and underwent Pittsburg compound B‐positron emission tomography to determine cerebral amyloid status. Faecal microbiota composition was assessed using shotgun metagenomics, while faecal SCFA concentrations were quantified via Gas Chromatography‐Mass Spectrometry (GC‐MS). Associations between taxa and SCFAs were assessed using Spearman correlation and MaAsLin2.

Result
Firmicutes, Proteobacteria, and Bacteroidetes exhibited significant correlations with SCFAs across all groups. In the CU Aβ Low and Disease Group (DG), Firmicutes showed Positive correlations with butyric acid. Group‐specific patterns included negative correlations between Bacteroidetes and propionic acid in the DG group, a positive correlation between Firmicutes and total SCFAs in the CU Aβ Low group, and a positive correlations between Proteobacteria and Actinobacteria with butyric acid in the CU Aβ High group, alongside notable interactions with isovaleric acid. Furthermore, specific taxa such as Corynebacterium falsenii (Phylum: Actinobacteria), Ruthenibacterium lactatiformans (Phylum: Firmicutes), and Streptomyces capitiformicae (Phylum: Actinobacteria) showed significant associations with SCFAs, particularly propionic acid and butyric acid.

Conclusion
These findings suggest that changes in gut bacteria and their metabolites vary at different stages of AD. Key results show that certain bacteria, such as Firmicutes, Bacteroidetes, and Proteobacteria, are linked to SCFAs, especially butyric acid, which plays a role in gut and brain health. This suggests that modifying gut bacteria could help regulate SCFA levels and potentially slow the progression of AD. However, more research is needed to fully understand this connection.

Background
Alzheimer's disease (AD), the most common form of dementia, is marked by significant reductions in glucose metabolism. Such hypometabolism reflects underlying synaptic dysfunction, correlating with cognitive decline. Our study aimed to explore the impact of dietary patterns—specifically, the Western Diet and Prudent Diet—on change in glucose metabolism in brain regions associated with AD risk, [18F]Fluorodeoxyglucose positron emission tomography (FDG‐PET) imaging as a biomarker.

Method
Longitudinal data from 133 cognitively unimpaired older adults were analysed from the Western Australian Memory Study. Participants underwent dietary assessment using the Cancer Council of Victoria Food Frequency Questionnaire and completed FDG‐PET imaging up to three times over 43 months. Dietary patterns were identified through principal component analysis, yielding two patterns—named Western Diet and Prudent Diet. Pattern scores were computed by summing food group intakes weighted by their respective factor loadings. Linear mixed‐effect models evaluated the association between dietary adherence and brain glucose metabolism, including potential confounders. The cohort was stratified by apolipoprotein E (APOE) ε4 carrier status, a genetic risk factor for AD, to investigate potential differing effects.

Result
Adherence to a Western Diet, characterised by high sugars and saturated fats, was associated with a faster decline in glucose metabolism in the right fusiform gyrus among APOE ε4 carriers (β = ‐0.00012; SE = 0.00004; false discover rate adjusted p = .032), with no significant associations in APOE ε4 non‐carriers. Similarly, no significant associations were observed between the Prudent Diet, characterised by high intake of fruits, vegetables, and whole grains, and glucose metabolism, in both APOE ε4 carriers and non‐carriers.

Conclusion
Our study highlights the potential detrimental impact of a Western Diet on brain glucose metabolism, particularly for individuals at genetic risk for AD. The decline in glucose metabolism in the fusiform gyrus, a region essential for cognitive functions like facial recognition, emphasises the role of diet in brain health. Future research should examine the mechanisms linking diet to neurodegeneration and explore dietary interventions as preventive strategies against cognitive decline and dementia.

Background
Alzheimer's disease (AD) is a progressive neurodegenerative disorder, with evidence suggesting gut microbiota plays a critical role in its onset and progression. Shifts in probiotic communities during the preclinical phase may influence disease pathways through gut‐brain interactions. This study investigates how age, sex, and APOE ε4 genotype impact probiotic composition and microbial metabolite production in cognitively unimpaired individuals.

Method
Stool samples from 123 participants in the Australian Imaging Biomarkers and Lifestyle (AIBL) study and WA Memory Study (WAMS) were analysed. Participants were grouped by age (<70, ≥70 years), sex, and APOE ε4 carrier status. Metagenomic sequencing assessed gut microbial composition, focusing on probiotics like Bifidobacterium and Lactobacillus. Gas‐liquid chromatography measured short‐chain fatty acids (SCFAs), including butyrate, propionate, and acetate.

Result
Gut Microbiota Composition: Dominant bacterial phyla included Actinobacteria, Bacteroidetes, Cyanobacteria, and Firmicutes across all groups. Age‐Related Changes: Older participants (≥70 years) showed significant declines in Bacteroidetes and Firmicutes, reflecting reduced microbial diversity. Sex‐Specific Differences: Females had lower Firmicutes levels, reducing butyrate production, essential for inflammation control and brain health. APOE ε4 Carriers: Older APOE ε4 carriers showed a decline in butyrate‐producing bacteria, particularly Faecalibacterium prausnitzii, leading to reduced butyrate and elevated acetate levels. Sex and APOE ε4: Female APOE ε4 carriers ≥70 exhibited the most pronounced butyrate decline, indicating increased vulnerability to dysbiosis and inflammation. Probiotic Alterations: Key probiotics, including Bifidobacterium and Lactobacillus, were significantly reduced in older APOE ε4 carriers.

Conclusion
Age, sex, and APOE ε4 status significantly influence gut microbiota composition and SCFA production at the preclinical stage of AD. Reduced butyrate levels, particularly in older female APOE ε4 carriers, highlight the importance of gut health in mitigating AD risk. These findings suggest targeted probiotic interventions could restore gut balance and delay AD progression.

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.