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Background: The Australian Imaging, Biomarkers and Lifestyle (AIBL) Study commenced in 2006 as a prospective study of 1,112 individuals (768 cognitively normal (CN), 133 with mild cognitive impairment (MCI), and 211 with Alzheimer’s disease dementia (AD)) as an ‘Inception cohort’ who underwent detailed ssessments every 18 months. Over the past decade, an additional 1247 subjects have been added as an ‘Enrichment cohort’ (as of 10 April 2019). Objective: Here we provide an overview of these Inception and Enrichment cohorts of more than 8,500 person-years of investigation. Methods: Participants underwent reassessment every 18 months including comprehensive cognitive testing, neuroimaging (magnetic resonance imaging, MRI; positron emission tomography, PET), biofluid biomarkers and lifestyle evaluations. Results: AIBL has made major contributions to the understanding of the natural history of AD, with cognitive and biological definitions of its three major stages: preclinical, prodromal and clinical. Early deployment of Aβ-amyloid and tau molecular PET imaging and the development of more sensitive and specific blood tests have facilitated the assessment of genetic and environmental factors which affect age at onset and rates of progression. Conclusion: This fifteen-year study provides a large database of highly characterized individuals with longitudinal cognitive, imaging and lifestyle data and biofluid collections, to aid in the development of interventions to delay onset, prevent or treat AD. Harmonization with similar large longitudinal cohort studies is underway to further these aims.

Background: Previous research has identified a small subgroup of older adults that maintain a high level of cognitive functioning well into advanced age. Investigation of those with superior cognitive performance (SCP) for their age is important, as age-related decline has previously been thought to be inevitable. Objective: Preservation of cortical thickness and volume was evaluated in 76 older adults with SCP and 100 typical older adults (TOAs) assessed up to five times over six years. Methods: Regions of interest (ROIs) found to have been associated with super-aging status (a construct similar to SCP status) in previous literature were investigated, followed by a discovery phase analyses of additional regions. SCPs were aged 70 + at baseline, scoring at/above normative memory (CVLT-II) levels for demographically similar individuals aged 30–44 years old, and in the unimpaired range for all other cognitive domains over the course of the study. Results: In linear mixed models, following adjustment for multiple comparisons, there were no significant differences between rates of thinning or volume atrophy between SCPs and TOAs in previously identified ROIs, or the discovery phase analyses. With only amyloid-β negative individuals in the analyses, again there were no significant differences between SCPs and TOAs. Conclusion: The increased methodological rigor in classifying groups, together with the influence of cognitive reserve, are discussed as potential factors accounting for our findings as compared to the extant literature on those with superior cognitive performance for their age.

Background: Genetic variation in Spondin-1, specifically rs11023139, has been associated with reduced rates of cognitive decline in individuals with Alzheimer’s disease. Objective: The aim of this study was to assess whether the association was present in cognitively normal older adults. Methods: Longitudinal cognitive decline was investigated using linear mixed modelling in a cohort of 590 cognitively normal older adults enrolled in the Australian Imaging, Biomarkers and Lifestyle Study. Results: No independent effect of Spondin-1 rs11023139 on cognitive decline was observed. However, significant associations were observed for the interaction between Apolipoprotein E (APOE) ɛ4 and rs11023139 in individuals with high amyloid-β burden. APOE ɛ4/rs11023139-A carriers declined significantly faster than APOE ɛ4/rs11023139-G_G carriers in measures of global cognition (p = 0.011) and verbal episodic memory (p = 0.020). Conclusion: These results suggest that carriage of the Spondin-1 rs11023139-A allele significantly contributes to a worsening of cognitive performance in APOE ɛ4 cognitively normal older adults with a high neocortical amyloid-β burden.

This prospective cohort study, "Prospective Imaging Study of Ageing: Genes, Brain and Behaviour" (PISA) seeks to characterise the phenotype and natural history of healthy adult Australians at high future risk of Alzheimer's disease (AD). In particular, we are recruiting midlife and older Australians with high and low genetic risk of dementia to discover biological markers of early neuropathology, identify modifiable risk factors, and establish the very earliest phenotypic and neuronal signs of disease onset. PISA utilises genetic prediction to recruit and enrich a prospective cohort and follow them longitudinally. Online surveys and cognitive testing are used to characterise an Australia-wide sample currently totalling over 3800 participants. Participants from a defined at-risk cohort and positive controls (clinical cohort of patients with mild cognitive impairment or early AD) are invited for onsite visits for detailed functional, structural and molecular neuroimaging, lifestyle monitoring, detailed neurocognitive testing, plus blood sample donation. This paper describes recruitment of the PISA cohort, study methodology and baseline demographics.

Cerebral microbleeds (CMB) are increasingly present with aging and can reveal vascular pathologies associated with neurodegeneration. Deep learning-based classifiers can detect and quantify CMB from MRI, such as susceptibility imaging, but are challenging to train because of the limited availability of ground truth and many confounding imaging features, such as vessels or infarcts. In this study, we present a novel generative adversarial network (GAN) that has been trained to generate three-dimensional lesions, conditioned by volume and location. This allows one to investigate CMB characteristics and create large training datasets for deep learning-based detectors. We demonstrate the benefit of this approach by achieving state-of-the-art CMB detection of real CMB using a convolutional neural network classifier trained on synthetic CMB. Moreover, we showed that our proposed 3D lesion GAN model can be applied on unseen dataset, with different MRI parameters and diseases, to generate synthetic lesions with high diversity and without needing laboriously marked ground truth.

Personality factors have been associated with Alzheimer’s disease (AD) and dementia, but they have not been examined against markers of regional brain glucose metabolism (a primary measure of brain functioning) in older adults without clinically diagnosed cognitive impairment. The relationship between personality factors derived from the five-factor model and cerebral glucose metabolism determined using positron emission tomography (PET) with [18F]-2-fluoro-2-deoxy-D-glucose (18F-FDG-PET) was examined in a cohort of 237 non-demented, community-dwelling older adults aged 60–89 years (M ± SD = 73.76 ± 6.73). Higher neuroticism and lower scores on extraversion and conscientiousness were significantly associated with decreased glucose metabolism in brain regions typically affected by AD neuropathological processes, including the hippocampus and entorhinal cortex. Furthermore, while there were significant differences between apolipoprotein E (APOE) ε4 allele carriers and non-carriers on 18F-FDG-PET results in the neocortex and other brain regions (p < 0.05), there was no significant difference between carriers and non-carriers on personality factors and no significant interactions were found between APOE ε4 carriage and personality factors on brain glucose metabolism. In conclusion, we found significant relationships between personality factors and glucose metabolism in neural regions more susceptible to AD neuropathology in older adults without clinically significant cognitive impairment. These findings support the need for longitudinal research into the potential mechanisms underlying the relationship between personality and dementia risk, including measurement of change in other AD biomarkers (amyloid and tau imaging) and how they correspond to change in personality factors. Future research is also warranted to determine whether timely psychological interventions aimed at personality facets (specific aspects or characteristics of personality factors) can affect imagin

Background:Cerebrovascular disease often coexists with Alzheimer’s disease (AD). While both diseases share common risk factors, their interrelationship remains unclear. Increasing the understanding of how cerebrovascular changes interact with AD is essential to develop therapeutic strategies and refine biomarkers for early diagnosis. Objective:We investigate the prevalence and risk factors for the comorbidity of amyloid-β (Aβ) and cerebrovascular disease in the Australian Imaging, Biomarkers and Lifestyle Study of Ageing, and further examine their cross-sectional association. Methods:A total of 598 participants (422 cognitively normal, 89 with mild cognitive impairment, 87 with AD) underwent positron emission tomography and structural magnetic resonance imaging for assessment of Aβ deposition and cerebrovascular disease. Individuals were categorized based on the comorbidity status of Aβ and cerebrovascular disease (V) as Aβ–V–, Aβ–V+, Aβ+V–, or Aβ+V+. Results:Advancing age was associated with greater likelihood of cerebrovascular disease, high Aβ load and their comorbidity. Apolipoprotein E ɛ4 carriage was only associated with Aβ positivity. Greater total and regional WMH burden were observed in participants with AD. However, no association were observed between Aβ and WMH measures after stratification by clinical classification, suggesting that the observed association between AD and cerebrovascular disease was driven by the common risk factor of age. Conclusion:Our observations demonstrate common comorbid condition of Aβ and cerebrovascular disease in later life. While our study did not demonstrate a convincing cross-sectional association between Aβ and WMH burden, future longitudinal studies are required to further confirm this.

Objective To determine the effect of β-amyloid (Aβ) level on progression risk to mild cognitive impairment (MCI) or dementia and longitudinal cognitive change in cognitively normal (CN) older individuals. Methods All CN from the Australian Imaging Biomarkers and Lifestyle study with Aβ PET and ≥3 years follow-up were included (n = 534; age 72 ± 6 years; 27% Aβ positive; follow-up 5.3 ± 1.7 years). Aβ level was divided using the standardized 0–100 Centiloid scale: <15 CL negative, 15–25 CL uncertain, 26–50 CL moderate, 51–100 CL high, >100 CL very high, noting >25 CL approximates a positive scan. Cox proportional hazards analysis and linear mixed effect models were used to assess risk of progression and cognitive decline. Results Aβ levels in 63% were negative, 10% uncertain, 10% moderate, 14% high, and 3% very high. Fifty-seven (11%) progressed to MCI or dementia. Compared to negative Aβ, the hazard ratio for progression for moderate Aβ was 3.2 (95% confidence interval [CI] 1.3–7.6; p < 0.05), for high was 7.0 (95% CI 3.7–13.3; p < 0.001), and for very high was 11.4 (95% CI 5.1–25.8; p < 0.001). Decline in cognitive composite score was minimal in the moderate group (−0.02 SD/year, p = 0.05), while the high and very high declined substantially (high −0.08 SD/year, p < 0.001; very high −0.35 SD/year, p < 0.001). Conclusion The risk of MCI or dementia over 5 years in older CN is related to Aβ level on PET, 5% if negative vs 25% if positive but ranging from 12% if 26–50 CL to 28% if 51–100 CL and 50% if >100 CL. This information may be useful for dementia risk counseling and aid design of preclinical AD trials.

White matter hyperintensities (WMH) are regions of high signal intensity typically identified on fluid attenuated inversion recovery (FLAIR). Although commonly observed in elderly individuals, they are more prevalent in Alzheimer's disease (AD) patients. Given that WMH appear relatively homogeneous on FLAIR, they are commonly partitioned into location- or distance-based classes when investigating their relevance to disease. Since pathology indicates that such lesions are often heterogeneous, probing their microstructure in vivo may provide greater insight than relying on such arbitrary classification schemes. In this study, we investigated WMH in vivo using an advanced diffusion MRI method known as single-shell 3-tissue constrained spherical deconvolution (SS3T-CSD), which models white matter microstructure while accounting for grey matter and CSF compartments. Diffusion MRI data and FLAIR images were obtained from AD (n = 48) and healthy elderly control (n = 94) subjects. WMH were automatically segmented, and classified: (1) as either periventricular or deep; or (2) into three distance-based contours from the ventricles. The 3-tissue profile of WMH enabled their characterisation in terms of white matter-, grey matter-, and fluid-like characteristics of the diffusion signal. Our SS3T-CSD findings revealed substantial heterogeneity in the 3-tissue profile of WMH, both within lesions and across the various classes. Moreover, this heterogeneity information indicated that the use of different commonly used WMH classification schemes can result in different disease-based conclusions. We conclude that future studies of WMH in AD would benefit from inclusion of microstructural information when characterising lesions, which we demonstrate can be performed in vivo using SS3T-CSD.

Poster presentation

The non-synonymous single nucleotide polymorphism (SNP), Val158Met within the Catechol-O-methyltransferase (COMT) gene has been associated with altered levels of cognition and memory performance in cognitively normal adults. This study aimed to investigate the independent and interactional effects of COMT Val158Met on cognitive performance. In particular, it was hypothesised that COMT Val158Met would modify the effect of neocortical Aβ-amyloid (Aβ) accumulation and carriage of the apolipoprotein E (APOE) ε4 allele on cognition in preclinical Alzheimer’s disease (AD). In 598 cognitively normal older adults with known neocortical Aβ levels, linear mixed modelling revealed no significant independent or interactional associations between COMT Val158Met and cognitive decline. These findings do not support previous associations between COMT Val158Met and cognitive performance and suggest this variant does not influence Aβ-amyloid or APOE ε4 driven cognitive decline in a well characterised cohort of cognitively normal older adults.

Introduction Superior cognitive performance in older adults may reflect underlying resistance to age‐associated neurodegeneration. While elevated amyloid β (Aβ) deposition (Aβ+) has been associated with increased cortical atrophy, it remains unknown whether “SuperAgers” may be protected from Aβ‐associated neurodegeneration. Methods Neuropsychologically defined SuperAgers (n = 172) and cognitively normal for age (n = 172) older adults from the Australian Imaging, Biomarkers and Lifestyle study were case matched. Rates of cortical atrophy over 8 years were examined by SuperAger classification and Aβ status. Results Of the case‐matched SuperAgers and cognitively normal for age older adults, 40.7% and 40.1%, respectively, were Aβ+. Rates of age‐ and Aβ‐associated atrophy did not differ between the groups on any measure. Aβ− individuals displayed the slowest rates of atrophy. Discussion Maintenance of superior memory in late life does not reflect resistance to age‐ or Aβ‐associated atrophy. However, those individuals who reached old age without cognitive impairment nor elevated Aβ deposition (i.e. Aβ−) displayed reduced rates of cortical atrophy.

The longevity gene Klotho (KL), specifically the functional KL-VS variant, has previously been associated with cognition and rates of cognitive decline. This study aimed to determine whether KL-VS associations with cognition were observable in preclinical Alzheimer's disease (AD). The study also aimed to determine whether there was a combined influence of KL-VS, neocortical amyloid-β (Aβ) burden, and carriage of the apolipoprotein E (APOE) ε4 allele on cognitive decline. This study involved 581 Aβ-imaged, cognitively normal older adults, enrolled in the Australian Imaging, Biomarkers and Lifestyle Study of Aging. Linear mixed effects models revealed no significant associations between KL-VS and cognitive decline independently or in combination with Aβ burden and APOE ε4 genotype. Overall, previous associations reported between KL-VS and cognitive decline are not observed at the preclinical stages of AD. Furthermore, the results do not support the hypothesis that KL-VS has a modifying effect on Aβ burden and APOE ε4–driven cognitive decline in preclinical AD.

© 2019 Elsevier Inc. The longevity gene Klotho (KL), specifically the functional KL-VS variant, has previously been associated with cognition and rates of cognitive decline. This study aimed to determine whether KL-VS associations with cognition were observable in preclinical Alzheimer's disease (AD). The study also aimed to determine whether there was a combined influence of KL-VS, neocortical amyloid-ß (Aß) burden, and carriage of the apolipoprotein E (APOE) e4 allele on cognitive decline. This study involved 581 Aß-imaged, cognitively normal older adults, enrolled in the Australian Imaging, Biomarkers and Lifestyle Study of Aging. Linear mixed effects models revealed no significant associations between KL-VS and cognitive decline independently or in combination with Aß burden and APOE e4 genotype. Overall, previous associations reported between KL-VS and cognitive decline are not observed at the preclinical stages of AD. Furthermore, the results do not support the hypothesis that KL-VS has a modifying effect on Aß burden and APOE e4–driven cognitive decline in preclinical AD.

Studies of Alzheimer's disease risk-weighted polygenic risk scores (PRSs) for cognitive performance have reported inconsistent associations. This inconsistency is particularly evident when PRSs are assessed independent of APOE genotype. As such, the development and assessment of phenotype-specific weightings to derive PRSs for cognitive decline in preclinical AD is warranted. To this end a episodic memory-weighted PRS (emPRS) was derived and assessed against decline in cognitive performance in 226 healthy cognitively normal older adults with high brain Aβ-amyloid burden participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. The effect size for decline in a verbal episodic memory was determined individually for 27 genetic variants in a reference sample (n = 151). These were then summed to generate a emPRS either including APOE (emPRSc̅APOE) or excluding APOE (emPRSs̅APOE ). Resultant emPRS were then evaluated, in a test sample (n = 75), against decline in global cognition, verbal episodic memory and a pre-Alzheimer's cognitive composite (AIBL-PACC) over 7.5 years. The mean (SD) age of the 226 participants was 72.2 (6.6) years and 116 (51.3%) were female. Reference and test samples did not differ significantly demographically. Whilst no association of emPRSs were observed with baseline cognition, the emPRSc̅ APOE was associated with longitudinal global cognition (-0.237, P = 0.0002), verbal episodic memory (-0.259, P = 0.00003) and the AIBL-PACC (-0.381, P = 0.02). The emPRSs̅ APOE was also associated with global cognition (-0.169, P = 0.021) and verbal episodic memory (-0.208, P = 0.004). Stratification by APOE ε4 revealed that the association between the emPRS and verbal episodic memory was limited to carriage of no ε4 or one ε4 allele. This was also observed for global cognition. The emPRS and rates of decline in AIBL-PACC were associated in those carrying one ε4 allele. Overall, the described novel emPRS has utility for the prediction of

Accumulating research has linked Mediterranean diet (MeDi) adherence with slower cognitive decline and reduced Alzheimer's disease (AD) risk. However, no study to-date has examined the relationship between MeDi adherence and accumulation of cerebral Aβ-amyloid (Aβ; a pathological hallmark of AD) in older adults. Cognitively normal healthy control participants of the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study of Ageing completed the Cancer Council of Victoria Food Frequency Questionnaire at baseline, which was used to construct a MeDi score for each participant (score range 0-9; higher score indicating higher adherence). Cerebral Aβ load was quantified by Pittsburgh Compound B positron emission tomography at baseline, 18 and 36 months: Only individuals categorised as "Aβ accumulators", and thus considered to be on the AD pathway, were included in the analysis (N = 77). The relationship between MeDi adherence, MeDi components, and change in cerebral Aβ load (baseline to 36 months) was evaluated using Generalised Linear Modelling, accounting for age, gender, education, Apolipoprotein E ε4 allele status, body mass index and total energy intake. Higher MeDi score was associated with less Aβ accumulation in our cohort (β = -0.01 ± 0.004, p = 0.0070). Of the individual MeDi score components, a high intake of fruit was associated with less accumulation of Aβ (β = -0.04 ± 0.01, p = 0.00036). Our results suggest MeDi adherence is associated with reduced cerebral AD pathology accumulation over time. When our results are considered collectively with previous data linking the MeDi to slower cognitive decline, it is apparent that MeDi adherence warrants further investigation in the quest to delay AD onset.

Worldwide there are over 46 million people living with dementia, and this number is expected to double every 20 years reaching about 131 million by 2050. The cost to the community and government health systems, as well as the stress on families and carers is incalculable. Over three decades of research into this disease have been undertaken by several research groups in Australia, including work by our original research group in Western Australia which was involved in the discovery and sequencing of the amyloid-β peptide (also known as Aβ or A4 peptide) extracted from cerebral amyloid plaques. This review discusses the journey from the discovery of the Aβ peptide in Alzheimer’s disease (AD) brain to the establishment of pre-clinical AD using PET amyloid tracers, a method now serving as the gold standard for developing peripheral diagnostic approaches in the blood and the eye. The latter developments for early diagnosis have been largely achieved through the establishment of the Australian Imaging Biomarker and Lifestyle research group that has followed 1,100 Australians for 11 years. AIBL has also been instrumental in providing insight into the role of the major genetic risk factor apolipoprotein E ɛ4, as well as better understanding the role of lifestyle factors particularly diet, physical activity and sleep to cognitive decline and the accumulation of cerebral Aβ.

The glymphatic system is postulated to be a mechanism of brain Aβ-amyloid clearance and to be most effective during sleep. Ablation of the astrocytic end-feet expressed water-channel protein, Aquaporin-4, in mice, results in impairment of this clearance mechanism and increased brain Aβ-amyloid deposition, suggesting that Aquaporin-4 plays a pivotal role in glymphatic function. Currently there is a paucity of literature regarding the impact of AQP4 genetic variation on sleep, brain Aβ-amyloid burden and their relationship to each other in humans. To address this a cross-sectional observational study was undertaken in cognitively normal older adults from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. Genetic variants in AQP4 were investigated with respect to self-reported Pittsburgh Sleep Quality Index sleep parameters, positron emission tomography derived brain Aβ-amyloid burden and whether these genetic variants moderated the sleep-Aβ-amyloid burden relationship. One AQP4 variant, rs72878776, was associated with poorer overall sleep quality, while several SNPs moderated the effect of sleep latency (rs491148, rs9951307, rs7135406, rs3875089, rs151246) and duration (rs72878776, rs491148 and rs2339214) on brain Aβ-amyloid burden. This study suggests that AQP4 genetic variation moderates the relationship between sleep and brain Aβ-amyloid burden, which adds weight to the proposed glymphatic system being a potential Aβ-amyloid clearance mechanism and suggests that AQP4 genetic variation may impair this function. Further, AQP4 genetic variation should be considered when interpreting sleep-Aβ relationships.

Accumulating evidence suggests a diet high in protein and fiber may confer some protection against Alzheimer’s disease (AD). However, no human studies to-date have assessed the relationship between protein and fiber intake, and plasma and brain amyloid-β (Aβ). Consequently, this cross-sectional study, investigated the association of self-reported dietary intakes of protein and fiber, with plasma and brain Aβ burden (n = 541, and n = 162 respectively), in a well-characterized cohort of cognitively normal older adults, drawn from the larger Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging. We observed 12.59 and 8.43 higher odds of ‘high’ brain Aβ burden (PiB PET SUVR≥1.5) if protein intake fell in the lowest and middle tertile, respectively, compared to the highest tertile (p = 0.008; p = 0.013). Thus, in this cohort, the more protein consumed, the less likelihood of ‘high’ Aβ burden in the brain. No other significant associations were observed. The results of this study highlight the potentially protective impact of high dietary protein intake on brain Aβ burden in older adults, before objective memory decline is apparent. While longitudinal validation is required, these findings may assist in the development of dietary approaches aimed at preventing or delaying AD onset.

Cognitive decline is considered an inevitable consequence of aging; however, estimates of cognitive aging may be influenced negatively by undetected preclinical Alzheimer's disease (AD). This study aimed to determine the extent to which estimates of cognitive aging were biased by preclinical AD. Cognitively normal older adults (n = 494) with amyloid-β status determined from positron emission tomography neuroimaging underwent serial neuropsychological assessment at 18-month intervals over 72 months. Estimates of the effects of age on verbal memory, working memory, executive function, and processing speed were derived using linear mixed models. The presence of preclinical AD and clinical progression to mild cognitive impairment or dementia during the study were then added to these models as covariates. Initially, age was associated with decline across all 4 cognitive domains. With the effects of elevated amyloid-β and clinical progression controlled, age was no longer associated with decline in verbal or working memory. However, the magnitude of decline was reduced only slightly for executive function and was unchanged for processing speed. Thus, considered together, the results of the study indicate that undetected preclinical AD negatively biases estimates of age-related cognitive decline for verbal and working memory.

Objective To prospectively examine 8-year risk of clinical disease progression to mild cognitive impairment (MCI)/dementia in older adults ≥60 with superior episodic memory (SuperAgers) compared to those cognitively normal for their age (CNFA). Additionally, to determine the extent to which SuperAgers were resilient to the negative effects of elevated amyloid-beta (Aβ+) on cognition. Method Participants were classified as SuperAgers based on episodic memory performance consistent with younger adults aged 30–44 and no impairment on non-memory tests (n = 179), and were matched with CNFA on age, sex, education, and follow-up time (n = 179). Subdistribution hazard models examined risk of clinical progression to MCI/dementia. Linear mixed models assessed the effect of Aβ on cognition over time. Results Prevalence of Aβ+ and APOE ε4 was equivalent between SuperAgers and CNFA. SuperAgers had 69%–73% reduced risk of clinical progression to MCI/dementia compared to CNFA (HR: 0.27–0.31, 95% CI: 0.11–0.73, p < .001). Aβ+ was associated with cognitive decline in verbal memory and executive function, regardless of SuperAger/CNFA classification. In the absence of Aβ+, equivalent age-related changes in cognition were observed between SuperAgers and CNFA. Conclusions SuperAgers displayed resilience against clinical progression to MCI/dementia compared to CNFA despite equivalent risk for Alzheimer’s disease (AD); however, SuperAgers had no greater protection from Aβ+ than CNFA. The deleterious effects of Aβ on cognition persist regardless of baseline cognitive ability. Thus, superior cognitive performance does not reflect resistance against the neuropathological processes associated with AD, and the observed resilience for SuperAgers may instead reflect neuropsychological criteria for cognitive impairment.

Background: Preclinical Alzheimer’s disease (AD) is defined by cerebral amyloid-β positivity (Aβ+) in cognitively normal (CN) older adults. Objective:To estimate the risk of progression to the symptomatic stages of AD due to PET Aβ+ and the extent that progression was influenced by other demographic, genetic, and clinical characteristics in a large prospective study. Methods: Fine-Gray subdistribution modeling was used to examine the risk of progression from CN to MCI/dementia due to Aβ+, APOE ɛ4 carriage, and their interaction in the Australian Imaging, Biomarkers and Lifestyle (AIBL) flagship study of aging CN cohort (n = 599) over 8 years. Results: 17.7% Aβ+ and 8.1% Aβ–progressed over 8 years (OR: 2.43). Risk of progression for Aβ+ was 65–104% greater than Aβ–. Aβ+ APOE ɛ4 carriers were at 348% greater risk than all other participants. Significant risk factors of progression in Aβ+ were age (HR: 1.05), PET SUVR (HR: 2.49) and APOE ɛ4 carriage (HR: 2.63); only age was a significant risk factor in Aβ–(HR: 1.09). Aβ–progressors were not near the threshold for Aβ+. These relationships were not moderated by hypertension, diabetes, obesity, or stroke/TIA. Conclusion: Aβ+ is an important prognostic marker for progression from CN to MCI/dementia in older adults and APOE ɛ4 carriage provides further predictive value in the presence of Aβ+. These data suggest that Aβ-associated clinical progression is consistent with clinical-pathological models of AD, whereas progression in the absence of elevated Aβ deposition may be the result of neuropathological processes other than AD that accumulate with age.

Background Relationships between depression and Alzheimer's disease (AD) may become clearer if studied in preclinical AD where dementia is not present. Method The aim of this study was to evaluate prospectively, relationships between brain amyloid-β (Aβ), depressive symptoms and screen positive depression in cognitively normal (CN) older adults. Depressive symptoms were measured with the Geriatric Depression Inventory (GDS-15) in CN adults from the Australian Imaging Biomarkers and Lifestyle (AIBL) study without depression at baseline and classified as having abnormally high (Aβ+; n = 136) or low (Aβ−; n = 449) Aβ according to positron emission tomography at 18-month intervals over 72 months. Results Incident cases of screen positive depression were not increased in Aβ+ CN adults although small increases in overall depressive symptoms severity (d = − 0.25; 95% CI, − 0.45, − 0.05) and apathy-anxiety symptoms (d = − 0.28; 95% CI − 0.48, − 0.08) were. Limitations As the AIBL sample is an experimental sample, no individuals had severe medical illnesses or significant psychiatric disorders. Additionally, individuals who had evidence of screen-positive depression at screening were excluded from enrolment in the AIBL study. Thus, the current data can be considered only as providing a foundation for understanding relationships between Aβ and depression in preclinical AD. Conclusions These results suggest that the presence of a depressive disorder or even increased depressive symptoms are themselves unlikely to be a direct consequence of increasing Aβ. New depressive disorders presenting in CN older adults could therefore be investigated for aetiologies beyond AD.

Background It is possible that estimates of normal age-related decline in intellectual function have been biased negatively by undetected preclinical Alzheimer's disease (AD). This prospective study aimed to determine the nature and magnitude of changes in crystallized and fluid intelligence, as well as their relationship to one another, in normal aging, taking into account the effects of preclinical AD. Methods Cognitively normal older adults (n = 494) aged between 60 and 84 years underwent serial assessment of fluid and crystallized intelligence at 18-month intervals over 72 months and PET neuroimaging for the presence of abnormal amyloid-β (Aβ+; n = 184). The effects of age and Aβ + on changes in fluid and crystallized intelligence were analysed using linear mixed models. An intelligence discrepancy score was developed from linear regression analysis of the extent to which fluid intelligence could be predicted from crystallized intelligence. The predictive validity of the intelligence discrepancy score for Aβ status or clinical disease progression was evaluated. Results Relative to the Aβ- group, the Aβ + group showed greater age-related decline on fluid, but not crystallized, intelligence. The intelligence discrepancy score predicted progression to clinically recognized disease (i.e., mild cognitive impairment or dementia), but was unrelated to Aβ status. Conclusions Preclinical AD is associated with more rapid age-related decline in fluid, but not crystallized, intelligence. Accordingly, a discrepancy between fluid and crystallized intelligence does indicate risk of progression to early AD.

Background:With the exception of APOE, genetic variants associated with increased Alzheimer’s disease (AD) risk are characterized by small effect sizes. Polygenic risk scores (PRS) have shown utility in predicting AD risk; however, their utility for predicting decline in cognition at preclinical stages of AD is poorly understood. Objective:To validate associations of a 22-variant AD-risk-weighted PRS with AD risk and related biomarkers and to assess its utility to predict cognitive decline. Methods:The PRS was evaluated with respect to brain amyloid-β (Aβ) burden, cerebrospinal fluid (CSF) Aβ42, total-tau, and phospho-tau, and decline in cognition in 643 (570 cognitively normal (CN), 73 AD) PET-imaged participants from the longitudinal Australian Imaging, Biomarkers and Lifestyle (AIBL) Study of Ageing. Cognition was assessed using three composite measures; global cognition, verbal episodic memory, and a Pre-Alzheimer’s Cognitive Composite (PACC). Results:PRS, both with and without APOE, were positively correlated with brain Aβ burden, CSF total-tau, and phospho-tau in CN older adults. Further, in CN biomarker positive (Aβhigh) participants, significant associations were observed with baseline and longitudinal cognition. However, this association was not observed after the removal of APOE. Partitioning the PRS into quartiles revealed that the PRS associations with cognitive decline in Aβhigh CN older adults is due to a saturating effect of APOE genotype. Conclusions:An AD-risk-weighted PRS is associated with cognitive decline in CN older adults. However, this association is absent when APOE genotype is excluded from the PRS, suggesting that associations with cognitive decline in this model of polygenic risk are driven by APOE genotype alone. Further research is needed to define appropriate PRSs with greater utility for predicting preclinical AD cognitive decline.

Copyright © 2017 John Wiley & Sons, Ltd. Objective: Depressive and anxiety symptoms are common in older adults, significantly affect quality of life, and are risk factors for Alzheimer's disease. We sought to identify the determinants of predominant trajectories of depressive and anxiety symptoms in cognitively normal older adults. Method: Four hundred twenty-three older adults recruited from the general community underwent Aß positron emission tomography imaging, apolipoprotein and brain-derived neurotrophic factor genotyping, and cognitive testing at baseline and had follow-up assessments. All participants were cognitively normal and free of clinical depression at baseline. Latent growth mixture modeling was used to identify predominant trajectories of subthreshold depressive and anxiety symptoms over 6 years. Binary logistic regression analysis was used to identify baseline predictors of symptomatic depressive and anxiety trajectories. Results: Latent growth mixture modeling revealed two predominant trajectories of depressive and anxiety symptoms: a chronically elevated trajectory and a low, stable symptom trajectory, with almost one in five participants falling into the elevated trajectory groups. Male sex (relative risk ratio (RRR) = 3.23), lower attentional function (RRR = 1.90), and carriage of the brain-derived neurotrophic factor Val66Met allele in women (RRR = 2.70) were associated with increased risk for chronically elevated depressive symptom trajectory. Carriage of the apolipoprotein epsilon 4 allele (RRR = 1.92) and lower executive function in women (RRR = 1.74) were associated with chronically elevated anxiety symptom trajectory. Conclusion: Our results indicate distinct and sex-specific risk factors linked to depressive and anxiety trajectories, which may help inform risk stratification and management of these symptoms in older adults at risk for Alzheimer's disease. Copyright © 2017 John Wiley & Sons, Ltd.

© 2018-IOS Press and the authors. All rights reserved. Worldwide there are over 46 million people living with dementia, and this number is expected to double every 20 years reaching about 131 million by 2050. The cost to the community and government health systems, as well as the stress on families and carers is incalculable. Over three decades of research into this disease have been undertaken by several research groups in Australia, including work by our original research group in Western Australia which was involved in the discovery and sequencing of the amyloid-β peptide (also known as Aβ or A4 peptide) extracted from cerebral amyloid plaques. This review discusses the journey from the discovery of the Aβ peptide in Alzheimer's disease (AD) brain to the establishment of pre-clinical AD using PET amyloid tracers, a method now serving as the gold standard for developing peripheral diagnostic approaches in the blood and the eye. The latter developments for early diagnosis have been largely achieved through the establishment of the Australian Imaging Biomarker and Lifestyle research group that has followed 1,100 Australians for 11 years. AIBL has also been instrumental in providing insight into the role of the major genetic risk factor apolipoprotein E ϵ4, as well as better understanding the role of lifestyle factors particularly diet, physical activity and sleep to cognitive decline and the accumulation of cerebral Aβ.