Stephanie Rainey-Smith

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
Genetic variation in Spondin-1 (SPON1), specifically rs11023139, has been associated with reduced rates of cognitive decline in individuals with Alzheimer's disease. The aim of this study was to assess whether the association was present in cognitively normal (CN) older adults.

Methods
Longitudinal cognitive decline was investigated using linear mixed modelling in a cohort of 590 CN older adults enrolled in the Australian Imaging, Biomarkers and Lifestyle Study.

Results
No independent effect of rs11023139 on cognitive decline was observed. However, significant associations were observed for the interaction between APOE ε4 and rs11023139 in individuals with high Aβ-amyloid burden. APOE ε4/rs11023139-A carriers declined significantly faster than APOE ε4/rs11023139-G_G carriers in measures of global cognition (p=0.011) and verbal episodic memory (p=0.020).

Conclusions
These results suggest that carriage of the SPON1 rs11023139-A allele significantly contributes to a worsening of cognitive performance in APOE ε4 CN older adults with a high neocortical Aβ-amyloid burden.

Background
There has been increased interest in the role of dietary patterns and future risk of Alzheimer's disease (AD). However, the specific relationship between protein and fibre intake on cognitive function in older adults at higher risk of AD remains to be determined. This study investigated the association of protein and fibre intake, with cognition using data from the Australian Imaging, Biomarkers and Lifestyle study of ageing (AIBL) cohort.

Methods
Neuropsychological data derived from AIBL (734) were grouped into two cognitive domains (PACC and the Boston non-memory score). Composite scores, calculated by averaging the normalised individual cognitive measure Z scores, were assessed between levels of fibre and protein intake (binary, below/above the recommended daily intake (RDI) age, gender, APOE e4 allele status, total energy intake, education and BMI.

Results
Average values for the AIBL Study Preclinical Alzheimer cognitive (AIBL PACC) score (but not the non-memory) were significantly higher in participants with high protein intake (PACC:0.11 vs PACC:0.68, p=0.046) but not for those with high fibre intake (PACC:0.51 vs PACC:0.53, p>0.05). Adjusted for all confounding variables, this difference was abrogated (p>0.05). Given the level of education as a covariate was strongly related to the PACC score (p<0.0001), we further tested the interaction between education level (<12/12+ years) with low/high protein and fibre intakes. We saw a significant interaction for both protein and fibre groups with education level for the PACC score (education*protein: p=0.014, education*fibre: p=0.051), with those participants with high protein/fibre intakes and 12+ years of education having higher PACC scores as compared to those with <12 years of education and low protein/fibre intakes. Combining both fibre and protein in one three level variable (0=low fibre/low protein, 1=at least 1 fibre/protein high, and 2=both high fibre and protein) identified a significant association with the PACC score (p=0.007), with those participants in the low group and with <12 years of education performing worse for the PACC score as compared with those in the high group with 12+years of education.

Conclusions
This study highlights the importance of adequate protein and fibre intake on cognitive performance in an elderly cognitively normal population.

Background
Accumulating evidence suggests that rather than simply manifesting as a comorbidity of Alzheimer's disease (AD), suboptimal sleep actually contributes to the pathogenesis of the disease. One postulated mechanism underlying this association involves clearance of brain Aβ-amyloid (Aβ) via the glymphatic system during sleep. The water-channel proteins, Aquaporin (AQP) -1 and -4, are proposed to play a role in glymphatic system-mediated clearance of brain Aβ. Our own work suggests that genetic variation of AQP4 moderates the relationship between sleep and brain Aβ burden in humans. However, currently, there is a paucity of literature regarding the impact of AQP1 genetic variation on sleep, brain Aβ burden and their relationship to each other: a knowledge gap that the current study sought to address.

Methods
A cross-sectional observational study was undertaken in cognitively normal older adults from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study (N = 222). Genetic variants in AQP1 were investigated with respect to self-reported Pittsburgh Sleep Quality Index sleep parameters, positron emission tomography-derived brain Aβ burden and whether these genetic variants moderated the sleep-Aβ burden relationship.

Results
The AQP1 variant, rs28362727, moderated the effect of sleep latency on brain Aβ burden. Carriage of the minor allele (rs28362727-C), in combination with longer time to fall asleep, was associated with an elevated cerebral Aβ load, to a level that would be classified as ‘high’ (PiB-like Standardized Uptake Value Ratio (SUVR) > 1.4) if time to fall asleep exceeded 30-minutes (SUVR approaching 1.7 at 35-minutes latency). This association was observably stronger in homozygotes, suggesting a potential gene-dosage effect.

Conclusions
This study suggests that AQP1 genetic variation moderates the relationship between sleep and brain Aβ burden, which adds weight to the proposed glymphatic system being a potential Aβ clearance mechanism, and suggests that AQP1 genetic variation may impair this function. Further, AQP1 genetic variation warrants consideration when interpreting sleep-Aβ relationships.

Background
Identification of lifestyle and dietary modifications which prevent or delay cognitive decline and Alzheimer's disease (AD) would confer significant social and economic benefit. Yet, there is a relative lack of large-scale longitudinal investigations of lifestyle-related factors impacting cognitive decline and AD-related pathology. The Mediterranean diet (MeDi), has been widely recognised as a healthy eating model due to its correlation with low morbidity and mortality for many chronic diseases. In the context of AD, accumulating research including our own has linked MeDi adherence with slower cognitive decline and reduced risk of AD. However, only one study to date has examined the relationship between MeDi adherence and cerebral amyloid load, with the authors reporting reduced cerebral amyloid load cross-sectionally among individuals with high MeDi adherence. There is a critical need to further explore the relationship between MeDi and brain amyloid levels using longitudinal data collected from a well-characterised ageing cohort.

Methods
We report on data collected over 36 months from cognitively healthy control participants (n=119) of the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study of Ageing. The Cancer Council of Victoria Food Frequency Questionnaire was used to generate a MeDi score for each participant at baseline. Cerebral amyloid load was quantified by Pittsburgh Compound B positron emission tomography at baseline, 18 and 36 months. The relationship between MeDi adherence and cerebral amyloid load was evaluated longitudinally using Analysis of Variance, correlations and Generalised Linear Models (age, gender, education and Apolipoprotein E ε4 carriage were included in the models).

Results
Individuals with high MeDi adherence demonstrated less cerebral amyloid accumulation over 36 months compared to those with low adherence (0.04 vs. 0.08 mean change cerebral amyloid load respectively; p=0.008).

Conclusions
To our knowledge, this is the first study to assess the relationship between MeDi adherence and cerebral amyloid burden longitudinally. Our results suggest that MeDi adherence is associated with reduced cerebral AD pathology. When our results are considered collectively with previous data linking the MeDi to slower cognitive decline, it appears that MeDi adherence warrants further investigation in the quest to delay AD onset.

Project Description: Identification of lifestyle and dietary modifications which prevent or delay cognitive decline and Alzheimer's disease (AD) onset would confer significant social and economic benefit. However, there is a relative lack of large-scale investigations of lifestyle-related factors impacting cognitive decline and AD-related pathology. There is a critical need for longitudinal data collected from well-characterised ageing cohorts, and assessment of lifestyle in the context of Apolipoprotein E (APOE) genotype to facilitate development of strategies tailored to the needs of APOE ε4 allele carriers for whom prognosis is currently poorest. We report on dietary and physical activity data collected from healthy control participants of the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study of Ageing. The Cancer Council of Victoria Food Frequency Questionnaire was used to evaluate dietary pattern adherence (n=527), and physical activity levels were determined by self-report using the International Physical Activity Questionnaire (n=124). These measures were subsequently analysed in conjunction with APOE genotype, Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism, neuroimaging and comprehensive neuropsychological assessment data. Linear mixed model analyses revealed that higher baseline adherence to a 'healthy' Mediterranean diet pattern was associated with reduced decline in the executive function cognitive domain after 36 months amongst APOE Ɛ4 allele carriers (p<0.01). Conversely, higher adherence to an 'unhealthy' western diet pattern at baseline was associated with greater decline after 36 months in the visuospatial cognitive domain in APOE Ɛ4 allele non-carriers (p<0.01).Hierarchical regressions demonstrated an association between higher levels of physical activity and larger hippocampal volume as determined by Magnetic Resonance Imaging (β=0.19;p<0.05). When stratified by BDNF Val66Met polymorphism and APOE Ɛ4 allele, physical activity was associated with larger hippocampal and temporal lobe volumes in the Val/Val homozygote group for the BDNF Val66Met polymorphism, and the relationship between physical activity and temporal lobe volume amongst Val/Val homozygotes was dependent on APOE ε4 allele carriage (β=-0.38;p<0.05). We have previously reported that brain and blood Aβ levels are modulated by physical activity by APOE genotype-dependent mechanisms. Taken together, our results are suggestive of differential effects of lifestyle factors on aspects of cognitive decline and AD-related pathology that are contingent on APOE Ɛ4 allele carriage.