Belinda Brown

Background
Sarcopenia, an age-related loss of skeletal muscle strength, mass and function, is linked with dementia and Alzheimer's disease (AD). Current guideline-recommended tools to diagnose sarcopenia, such as appendicular skeletal muscle mass (ASM), calculated as the sum of lean muscle mass in the arms and legs via dual-energy X-ray absorptiometry (DXA), are not commonly done in AD studies. However, brain magnetic resonance imaging (MRI) is regularly performed in AD studies, and temporalis muscle thickness (TMT) has been suggested as a potential sarcopenia biomarker. As a first step in evaluating whether TMT could be a useful sarcopenia diagnostic tool, we aimed to ascertain if TMT correlates with ASM in healthy older adults.

Method
We conducted a retrospective study of healthy cognitively-unimpaired older adults in the Intense Physical Activity and Cognition study, in whom MRI and DXA had been performed on the same visit. TMT was measured on axial T1-weighted MRIs bilaterally perpendicular to the long-axis of the temporalis muscle using the orbital roof and Sylvian fissure as anatomical landmarks, and average TMT used for analysis. ASM was adjusted for body size (height2). Sarcopenia was defined as ASM< 7.0 kg/m2 for males and <5.5 kg/m2 for females as per the 2019 European working group on sarcopenia in older people criteria. Pearson correlation assessed the relationship between TMT and ASM or age.

Result
There were 95 participants (mean±standard deviation [SD] age 69.1±5.2 years, 53% female, median Montreal Cognitive Assessment score 27 [Interquartile range 25 – 28],11% had sarcopenia). The mean±SD ASM was 7.0±1.2 kg/m2 and TMT was 7.3±1.2 mm. TMT and ASM were moderately correlated (r = 0.41, 95% confidence interval 0.23 – 0.56). TMT did not correlate with age but differed significantly between those with (mean±SD 7.4±1.2) and without sarcopenia (mean±SD 6.2±0.8, p = 0.004).

Conclusion
Among a cohort of cognitively-unimpaired older adults, TMT demonstrated moderate correlation with ASM. While futher studies are needed, these findings suggest that MRI-based assessement of TMT could be a practical tool to diagnose sarcopenia in AD studies. Future studies in AD patients should explore the relationship between TMT and long-term clinical and functional outcomes.

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
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.

Background
Currently post-mortem autopsy is the only definitive diagnosis for Alzheimer's disease (AD), while pre-mortem biomarkers in the cerebrospinal fluid and neuroimaging are invasive and uneconomical. This study compares plasma phospholipid profiles in individuals destined to develop AD (carry a mutation responsible for autosomal dominant AD; MC) with those who are non-carriers of the mutations (NC). In addition to providing insight into the pathogenesis of AD, this study allows monitoring of pathogenic phospholipid changes several years before the onset of AD; thus enabling identification of candidate phospholipids as potential diagnostic biomarkers.

Methods
Participants belonged to Perth and Melbourne sites of the multicentre Dominantly Inherited Alzheimer Network (DIAN) study. The plasma phospholipid profiles of twenty-eight mutation carriers were compared against sixteen non-carriers. Plasma phospholipids were extracted by the modified Bligh and Dyer method and run on a QTRAP 4000 mass spectrometer via targeted flow injection using multiple reaction monitoring method.

Results
Two-hundred and forty phospholipid species were detected, belonging to six major phospholipid classes. Phospholipid species primarily belonging to the lysophosphatidylcholine group were significantly increased in mutation carriers compared to non-carriers (p<0.05).

Conclusions
Increased lysophosphatidylcholine in AD pathology corroborate previous reports on altered phosphatidylcholine metabolism in AD brain (Nitsch RM, 1992) and decreased plasma phosphatidylcholine levels (Whiley L, 2014). Phospholipids observed to be significantly altered between MC and NC need to be validated with liquid chromatography coupled with mass spectrometry.

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.