Australian Alzheimer’s Research Foundation

BackgroundDementia is currently the second leading cause of death in Australia and the seventh leading cause of death worldwide. Diagnosis of Alzheimer's disease (AD), the major cause of dementia, is difficult and time consuming. Current clinical imaging technologies are costly to use for widespread early screening of AD and have limited availability. In contrast, the retina is unique, where blood vessels and neural tissue can be viewed and imaged non‐invasively and relatively inexpensively. As part of the central nervous system, the retina exhibits similarities to the brain and can display indicators of various neurological disorders, including AD. We aimed to image the retina and analyse its spectral features to develop a robust machine learning (ML) classification model that distinguishes between brain amyloid‐beta (Aβ) positive and negative individuals.MethodSixty‐eight consenting volunteers with varying levels of brain Aβ protein underwent non‐invasive imaging using a hyperspectral retinal camera and illumination of wavelengths from 450 to 905 nm. Multiple retina features from the central and superior views were selected and analysed to identify their variability among individuals with different brain amyloid loads. Eight ML models were evaluated for their performance in predicting brain Aβ levels using the retina images and systemic factors like age, gender and apolipoprotein E (APOE) genotype.ResultThe retinal reflectance spectra in the 405–585 nm wavelengths exhibited a significant difference in individuals with increasing brain amyloid. The retinal features in the superior view showed higher inter‐subject variability. Our comparison of eight different ML algorithms revealed that the Multi‐Layer Perceptron (MLP) model exhibited superior classification performance, achieving an accuracy of 0.86, precision of 0.88, recall of 0.82, F1‐score of 0.85, and area under curve (AUC) of 0.90.ConclusionThis study indicates that there are spectral variations of retinal features associated with brain amyloid loads. It also demonstrates the feasibility of the retinal hyperspectral imaging (rHSI) technique as a potential non‐invasive, inexpensive screening method to identify individuals in the preclinical phase of AD.

ObjectiveMobile health technologies offer scalable opportunities to promote public health, including cognitive health, via education, engagement, and personalized health approach. This study describes the features of the Terrapino mobile application and its users to date, and provide initial evaluation of the ARA score.MethodsBetween December 2022 and December 2024, 8,395 users completed the Alzheimer's Risk Assessment survey, a comprehensive questionnaire developed to collect comprehensive, evidence-based information about Alzheimer's disease risk and protective factors including sociodemographics, health and health history information, lifestyle habits, subjective memory complaints and perceived stress. Most (95%) used the original, Czech version, but English and Spanish versions are also available.ResultsUsers were 18–103 years old (mean 57.1 ± 14.5 years), with 46.4% aged 60 years or older. Most (72%) were women and nearly half held a college degree. Despite relatively high education, lifestyle and health characteristics resembled general population trends, suggesting broad accessibility and reach. In a random forest machine learning models, hypertension, going for walks, playing sports and exercising, education, depression, memory complaints, meditation, vegetable intake and the use of olive oil emerged as most influential variables predicting the overall Alzheimer's Risk Assessment score, whether estimated for the entire sample or for those aged 60 + years. The models explained upwards of 80% of variance in the risk score.ConclusionsThis initial examination suggests good feasibility to engage large numbers of individuals in cognitive health promotion through a mobile platform. The early data also suggests good validity of the Alzheimer's Risk Assessment score collected within the application. The initial findings support future efforts to test the application's capacity to contribute to efforts to cognitive health promotion which can be tested through longitudinal research in the upcoming years.

BackgroundCSF 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.ObjectiveInvestigate the association of plasma sTREM2 levels with brain amyloid-β (Aβ) 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 Aβ+) compared to CN Aβ-, including the effect of AD-linked TREM2 rare variants.MethodsPlasma 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-Aβ load SUVR ((CN Aβ- (n = 65) and CN Aβ+ (n = 35)) as the main analysis. A subgroup analysis based on the TREM2 R47H and R62H genotype was conducted as exploratory analysis.ResultsPlasma sTREM2 positively correlated with plasma pTau181, and pTau231 in CN Aβ+ group. Plasma sTREM2 positively correlated with serum microglial kynurenine pathway metabolites. Plasma sTREM2 and brain Aβ load were higher in R47H TREM2 carriers compared to non-carriers.ConclusionsOur 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.

BackgroundCurrently a definitive diagnosis for Alzheimer’s disease (AD) is not readily available to the wider community as the gold standard markers of AD are either invasive and/or expensive. Therefore, there is an urgent need for a relatively low‐cost blood test that can be readily used in clinical settings. This study aims to address this gap by developing a reliable and cost‐effective in‐house blood‐based biomarkers panel for routine use in clinical labs for early detection of AD. Our team have shown that specific proteins in the blood, namely phosphorylated tau and Glial Fibrillary Acidic Protein (GFAP) as biomarker for early AD diagnosis. However, only a combination of selected blood biomarkers can reliably predict who is at risk of AD. To achieve a combination diagnostic assay based on robust blood biomarkers, this study will first develop singleplex diagnostic Single Molecule Array (Simoa) blood biomarkers assays for phosphorylated Tau: p ‐Tau217 and pTau205, as well as the N‐ and C‐terminus of GFAP. A novel panel of the best 3 biomarkers will then be selected to establish a blood test for preclinical diagnosis of AD.MethodMonoclonal antibodies against p ‐Tau217, p ‐Tau205, N‐ and C‐terminus of GFAP were generated in collaboration with GenScript, Singapore. These antibodies have undergone initial characterisation with controlled primary assessment of specificity and affinity (i.e immunostaining, immunoprecipitation‐Western Blot, and immunoprecipitation‐mass spectrometry) using various tissues such as human cells expressing phospho‐site‐deficient tau as negative controls, human brain, CSF, and plasma from healthy controls and AD. Finally, these antibodies were developed for Simoa assay in collaboration with University of Gothenburg.ResultWe have successfully generated specific high affinity monoclonal antibodies against p ‐Tau217, p ‐Tau205, and N‐terminus GFAP and have confirmed that these antibodies have the necessary specificity and sensitivity for the Simoa platform.ConclusionThe development of Simoa assays will be validated in a highly characterised control and Alzheimer cohort The Australian Imaging, Biomarker, and Lifestyle (AIBL) and a novel panel of the best 3 biomarkers established.

INTRODUCTIONFor 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.METHODSIn 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.RESULTSTesting 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.DISCUSSIONCombinations of plasma p‐tau217 and Aβ42 demonstrate recommended performance, confirming the presence of Aβ positivity prior to selection for disease‐modifying therapies.HighlightsThe 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.

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. 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. 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. 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. The Dietary Approaches to Stop Hypertension (DASH) diet moderates the links among depression, anxiety, and brain amyloid load. Higher symptoms were linked to greater amyloid load in those with low DASH adherence. This effect was observed for anxiety symptoms in apolipoprotein E ε4 allele carriers. Mediterranean and Western diets did not moderate these relationships. Findings support genotype-specific dietary interventions for brain and mental health.

Abstract BackgroundRecently, there has been substantial interest in investigating the role of short‐chain fatty acids (SCFAs) and, medium chain fatty acids (MCFA) in the neuroinflammation associated with Alzheimer’s disease (AD). Specifically, butyrate (SCFA) and lauric acid (MCFA) have demonstrated potential in alleviating neuroinflammation and reducing toxicity associated with amyloid proteins. Additionally, they have been found to enhance mitochondrial function and reduce neuronal hyperactivity. However, the mechanisms by which butyrate and lauric acid either suppress or activate astrocytes and neurons, as well as how they influence Aβ‐mediated activation of astrocytes and neurons, remain unclear. This study aims to address this knowledge gap by investigating the independent and synergistic effects of butyrate and lauric acid on AD pathogenesis—a research endeavour not undertaken previously.MethodButyrate and lauric acid were administered independently and synergistically to cultures of astrocytes, neurons derived from induced pluripotent stem cells (iPSCs) obtained from healthy human control subjects. Inflammatory responses of astrocytes and neurons were measured under synthetic amyloid beta stimulating conditions similar to AD. Legend Plex Human Inflammatory Panel was used to quantify the response of inflammatory cytokines (Interleukin IL‐1β, IL‐6, IL‐8, IL‐18, IL‐33, etc.) to inflammatory stimuli. The statistical analysis was carried out using the GraphPad Prism version 10.1.2. One‐way ANOVA was used to analyse the data.ResultButyrate and lauric acid, independently and synergistically demonstrate a positive association with pro‐inflammatory cytokines. There were negative association with anti‐inflammatory cytokines in neuron, astrocytes and spontaneous co‐cultures of astrocytes and neurons.ConclusionThe findings indicate that both butyrate and lauric acid inhibit inflammation in Alzheimer’s‐induced astrocytes and neurons. Ongoing investigations aim to evaluate their effects on various cytokines and determine the responsible genes through qPCR analysis.

Abstract BackgroundEvidence suggests that diet may play a modifiable role in reducing Alzheimer’s disease (AD) risk. Higher adherence to the Mediterranean diet (MeDi) is linked to a lower incidence of mild cognitive impairment (MCI) and AD. Increasing evidence indicates the potential utility of a cytoskeletal protein found in astrocytes, plasma Glial Fibrillary Acidic Protein (GFAP), as a marker specific for AD pathogenesis. However, the relationship between plasma GFAP level and the MeDi has not been fully determined. This cross‐sectional study examined whether MeDi diet as a whole or the individual components, were associated with plasma GFAP levels in an Australian older adult cohort drawn from the larger Australian Imaging, Biomarkers and Lifestyle (AIBL) study of ageing.MethodsCognitively unimpaired participants (n = 116) and individuals with MCI (n = 47) (mean age 75.37 ± 6.31; 44% male) completed a self‐reported food frequency questionnaire and had plasma GFAP levels measured using SIMOA platform. A score for the MeDi was generated for each individual. Linear regression models evaluated the association between plasma GFAP and the MeDi score, as well as individual MeDi components, including sex and age as covariates.ResultsMeDi score was not associated with plasma GFAP level. However, for individual MeDi components, dairy intake was positively associated with GFAP level (β = 0.107±0.039, p = 0.007).ConclusionsThis study is one of the first to report an association of plasma GFAP level with dietary components in an older adult cohort. The results suggest that dairy intake influences astrocyte reactivity. Further studies will include evaluation of plasma GFAP levels with additional dietary patterns, and individual dietary components to fully investigate the modifiable effect of diet on AD process.

Abstract BackgroundResearch on cognitive reserve (CR) in individuals aged 80 years old and above has resulted in inconsistent findings, mostly showing a relationship with baseline cognitive abilities but not follow up assessments. The effects of amyloid burden on the relationship between CR, cognitive decline and dementia in oldest old warrants further study in the presence of APOE e4. We hypothesised that CR in oldest old (≥80 yrs old) adults will result in different trajectories, depending on being amyloid PET positive or negative. Specifically, this study was to determine whether the relationship between CR and cognition is mediated by amyloid load in very old individuals.MethodData of 115 participants aged 80 years and above at baseline and one follow‐up was analysed for this study. Participants were recruited from the Western Australia Memory Study (WAMS, Perth) and the Kerr Anglican Retirement Village Initiative in Ageing Health (KARVIAH) Study (Sydney, Australia). In both sites participants have undergone amyloid imaging, as well as a comprehensive neuropsychological assessment, APOE genotyping and AD‐related blood‐based biomarkers analysis.ResultPreliminary results indicated a non‐significant relationship between education years, as the proxy for CR, and baseline cognition. Similar not‐significant findings was observed between CR and amyloid load. Individuals positive or negative for amyloid burden on the brain at baseline, as well as carriage of APOE e4 did not differ on years of education. Of interest, APOE e4 allele carriers were not different from not‐carriers on amyloid load in the brain. Due to nonsignificant relationships between the variables of interest, in both cross‐sectional as well as longitudinal data, further mediation analysis was not carried out.ConclusionOur nonsignificant results indicated that the commonly reported relationship between CR, cognitive function, amyloid load in older adults may not be present in individuals aged 80 years old and above. Although these findings are consistent with previous reports, other factors including longevity genetic factors that promote preserving cognition in oldest adults as well as lifestyle factors should be considered. Further analysis of such factors is currently ongoing and may result in interesting outcomes for this cohort.

This narrative review evaluates the role of diet in the relationship between depression and Alzheimer's disease (AD). AD and depression are often comorbid, and depression appears to independently increase the future risk of AD. Evidence suggests diet influences the risk of both conditions directly and indirectly. Diet impacts neurochemical and biological processes that may affect the development and progression of depression and cognitive dysfunction. The dietary components offering the greatest protection against depression and AD are yet to be determined. Current evidence highlights the importance of polyphenolic compounds, folate, B vitamins, and polyunsaturated fatty acids, along with adherence to dietary patterns like the Mediterranean diet, which includes multiple beneficial dietary factors. The investigation of dietary factors in the prevention of depression and AD is a comparatively young field of research. Comprehensive highly characterised longitudinal datasets and advanced analytical approaches are required to further examine the complex relationship between diet, depression, and AD. There is a critical need for more research in this area to develop effective preventive strategies aimed at maintaining mental and physical health with advancing age.