Tackling Dementia Together via The Australian Dementia Network (ADNeT): A Summary of Initiatives, Progress and Plans.

In 2018, the Australian Dementia Network (ADNeT) was established to bring together Australia's leading dementia researchers, people with living experience and clinicians to transform research and clinical care in the field. To address dementia diagnosis, treatment, and care, ADNeT has established three core initiatives: the Clinical Quality Registry (CQR), Memory Clinics, and Screening for Trials. Collectively, the initiatives have developed an integrated clinical and research community, driving practice excellence in this field, leading to novel innovations in diagnostics, clinical care, professional development, quality and harmonization of healthcare, clinical trials, and translation of research into practice. Australia now has a national Registry for Mild Cognitive Impairment and dementia with 55 participating clinical sites, an extensive map of memory clinic services, national Memory and Cognition Clinic Guidelines and specialized screening for trials sites in five states. This paper provides an overview of ADNeT's achievements to date and future directions. With the increase in dementia cases expected over coming decades, and with recent advances in plasma biomarkers and amyloid lowering therapies, the nationally coordinated initiatives and partnerships ADNeT has established are critical for increased national prevention efforts, co-ordinated implementation of emerging treatments for Alzheimer's disease, innovation of early and accurate diagnosis, driving continuous improvements in clinical care and patient outcome and access to post-diagnostic support and clinical trials. For a heterogenous disorder such as dementia, which is now the second leading cause of death in Australia following cardiovascular disease, the case for adequate investment into research and development has grown even more compelling.

Rates of regional tau accumulation in ageing and across the Alzheimer's disease continuum: an AIBL 18F-MK6240 PET study.

BACKGROUND: Tau positron emission tomography (PET) imaging enables longitudinal observation of tau accumulation in Alzheimer's disease (AD). 18F-MK6240 is a high affinity tracer for the paired helical filaments of tau in AD, widely used in clinical trials, despite sparse longitudinal natural history data. We aimed to evaluate the natural history of tau accumulation, and the impact of disease stage and reference region on the magnitude and effect size of regional change. METHODS: One hundred and eighty-four participants: 89 cognitively unimpaired (CU) beta-amyloid negative (Aß-), 44 CU Aß+, 51 cognitively impaired Aß+ (26 with mild cognitive impairment [MCI] and 25 with dementia) had follow-up 18F-MK6240 PET for one to four years (median 1.48). Regional standardised uptake value ratios (SUVR) were generated. Two reference regions were examined: cerebellar cortex and eroded subcortical white matter. FINDINGS: CU Aß- participants had very low rates of tau accumulation in the mesial temporal lobe (MTL). In CU Aß+, significantly higher rate of accumulation was seen in the MTL (particularly the amygdala), extending into the inferior temporal lobes. In MCI Aß+, the rate of accumulation was greatest in the lateral temporal, parietal and lateral occipital cortex, and plateaued in the MTL. Accumulation was global in AD Aß+, except for a plateau in the MTL. The eroded subcortical white matter reference region showed no significant advantage over the cerebellar cortex and appeared prone to spill-over in AD participants. Data fitting suggested approximately 15-20 years to accumulate tau to typical AD levels. INTERPRETATION: Tau accumulation occurs slowly. Rates vary according to brain region, disease stage and tend to plateau at high levels. Rates of tau accumulation are best measured in the MTL and inferior temporal cortex in preclinical AD and in large neocortical areas, in MCI and AD. FUNDING: NHMRC; Cerveau Technologies.

Childhood Abuse, Goal-Striving Stress and Self-Esteem: An Explanatory Role for Perceptions of Divine Control?

Early life course events and experiences affect lifelong processes of human development, and at the forefront of life course research, is how negative conditions during childhood compromise adult well-being. In the current study, we propose that individuals who experience early life adversity may be more susceptible to the effect of stressors that are also very much rooted in the self-concept, namely goal-striving stress, the feeling of falling short of one's expectations. Using data from the 2014 Nashville Stress and Health Study from the United States (NSAHS), we examine this process and consider how elements of religiosity, particularly beliefs in God's causal influence in human life (divine control) explain why goal-striving stress takes a larger toll on the self-esteem of individuals who experienced childhood abuse. Our findings indicate that (1) childhood abuse was positively associated with goal-striving stress and inversely associated with self-esteem, (2) goal-striving stress was inversely associated with self-esteem, (3) goal-striving stress exacerbated the association between childhood abuse and lower self-esteem. Mediated-moderation analyses also revealed that (4) lower perceptions of divine control explain why goal-striving stress was more damaging for victims of childhood abuse. Taken together, this study contributes to a growing body of work on anticipatory stressors and linkages to the self-concept for victims of early life adversity, and how adversity early in the life course might undermine key religious resources like divine control that may otherwise mitigate the noxious effects of stress.

Religion and Pandemic Weight Gain: A Refuge from the Storm?

The COVID-19 pandemic was an inherently stressful global crisis that was associated with weight gain for over 40% of the American public. Building on previous research, we draw on recently collected national survey data from the United States to examine the effects of religious attendance (both in-person and virtual), the sense of divine control, and religious/spiritual (R/S) struggles on pandemic weight gain. A series of logistic regression models were conducted. Our findings suggest that divine control and monthly in-person religious attendance were associated with a lower risk of pandemic weight gain, while R/S struggles were associated with a higher risk of weight gain. Our results reveal the complex role that religiosity can play with respect to pandemic weight gain.

Visually Identified Tau 18F-MK6240 PET Patterns in Symptomatic Alzheimer's Disease.

BACKGROUND: In Alzheimer's disease, heterogeneity has been observed in the postmortem distribution of tau neurofibrillary tangles. Visualizing the topography of tau in vivo may facilitate clinical trials and clinical practice. OBJECTIVE: This study aimed to investigate whether tau distribution patterns that are limited to mesial temporal lobe (MTL)/limbic regions, and those that spare MTL regions, can be visually identified using 18F-MK6240, and whether these patterns are associated with different demographic and cognitive profiles. METHODS: Tau 18F-MK6240 PET images of 151 amyloid-ß positive participants with mild cognitive impairment (MCI) and dementia were visually rated as: tau negative, limbic predominant (LP), MTL-sparing, and Typical by two readers. Groups were evaluated for differences in age, APOE ɛ4 carriage, hippocampal volumes, and cognition (MMSE, composite memory and non-memory scores). Voxel-wise contrasts were also performed. RESULTS: Visual rating resulted in 59.6% classified as Typical, 17.9% as MTL-sparing, 9.9% LP, and 12.6% as tau negative. Intra-rater and inter-rater reliability was strong (Cohen's kappa values of 0.89 and 0.86 respectively). Tracer retention in a "hook"-like distribution on sagittal sequences was observed in the LP and Typical groups. The visually classified MTL-sparing group had lower APOE ɛ4 carriage and relatively preserved hippocampal volumes. Higher MTL tau was associated with greater amnestic cognitive impairment. High cortical tau was associated with greater impairments on non-memory domains of cognition, and individuals with high cortical tau were more likely to have dementia than MCI. CONCLUSION: Tau distribution patterns can be visually identified using 18F-MK6240 PET and are associated with differences in APOE ɛ4 carriage, hippocampal volumes, and cognition.

Changes in Spiritual but Not Religious Identity and Well-Being in Emerging Adulthood in the United States: Pathways to Health Sameness?

The "spiritual but not religious" (SBNR) are a growing group in the religious landscape of the United States. Thousands of studies to date have been devoted to the study of religion and health, but far less attention has been given to the study of the "spiritual but not religious." In this study, we address this gap by using two waves of longitudinal data from the National Study of Youth and Religion (2005-2008). We assess whether within-person changes in SBNR identity are associated with health and mental health in emerging adulthood and consider several pathways that may account for observed differences. Results suggest that consistently identifying as SBNR was associated with worse physical and mental health relative to youth that were consistently religious. Using parametric mediation analyses, we found evidence that three of our four proposed mediators (religious attendance, sense of closeness to God, and religious doubt, but not life meaning) partially explained these mental health differences. This study therefore makes an important advance in assessing the health implications of (non)-religion/spirituality early in the life course.

Trust in God and/or Science? Sociodemographic Differences in the Effects of Beliefs in an Engaged God and Mistrust of the COVID-19 Vaccine.

At present, COVID-19 vaccines are widely available in the USA, but large proportions of the American populace remain unvaccinated. One possible source of COVID-19 vaccine hesitancy is a lack of trust in science. In this study, drawing from the large literature at the intersection of science and religion, we ask whether beliefs in an engaged God (the belief that God is involved in daily human affairs) predict mistrust of the COVID-19 vaccine and whether any observed association differs across race, gender, and education. Using nationally representative data from Wave 6 of the Baylor Religion Survey (2021), our results suggest that beliefs in an engaged God were associated with greater mistrust in the COVID-19 vaccine. This association was amplified for Hispanic and lower educated Americans. We argue that beliefs in an engaged God may promote a distrust of science, reduce motivation to get vaccinated, and derive comfort and strength by placing control over one's life in the hands of a loving, involved deity. We also situate our findings within an emerging body of work on the "dark side" of religion and reflect on their implications for understanding the broader religion/health connection.

Give Thanks in All Circumstances? Gratitude Toward God and Health in Later Life after Major Life Stressors.

Gratitude is foundational to well-being throughout the life course, and an emerging body of work suggests that older adults may be more inclined to attribute gratitude to a non-human target (God). Drawing on life course theory and Erikson's lifespan development framework, we use data from a national sample of Christian older adults from the United States (N = 1,005) to examine whether gratitude toward God buffers the noxious health effects of the death of a loved one or personal illness. Results suggest that gratitude toward God tends to predict better age-comparative and global self-rated physical health in the aftermath of stress, a moderation effect which is partially mediated by stronger beliefs in God-mediated control (that God is a collaborative partner in dealing with problems). We conclude by proposing some interventions for clinicians and counselors centered around gratitude and religiosity that may assist older adults in coping with major life stressors.

Using imputation to provide harmonized longitudinal measures of cognition across AIBL and ADNI.

To improve understanding of Alzheimer's disease, large observational studies are needed to increase power for more nuanced analyses. Combining data across existing observational studies represents one solution. However, the disparity of such datasets makes this a non-trivial task. Here, a machine learning approach was applied to impute longitudinal neuropsychological test scores across two observational studies, namely the Australian Imaging, Biomarkers and Lifestyle Study (AIBL) and the Alzheimer's Disease Neuroimaging Initiative (ADNI) providing an overall harmonised dataset. MissForest, a machine learning algorithm, capitalises on the underlying structure and relationships of data to impute test scores not measured in one study aligning it to the other study. Results demonstrated that simulated missing values from one dataset could be accurately imputed, and that imputation of actual missing data in one dataset showed comparable discrimination (p < 0.001) for clinical classification to measured data in the other dataset. Further, the increased power of the overall harmonised dataset was demonstrated by observing a significant association between CVLT-II test scores (imputed for ADNI) with PET Amyloid-ß in MCI APOE-ε4 homozygotes in the imputed data (N = 65) but not for the original AIBL dataset (N = 11). These results suggest that MissForest can provide a practical solution for data harmonization using imputation across studies to improve power for more nuanced analyses.

Fifteen Years of the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study: Progress and Observations from 2,359 Older Adults Spanning the Spectrum from Cognitive Normality to Alzheimer's Disease.

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 Aß-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.

Aggregation of Abnormal Memory Scores and Risk of Incident Alzheimer's Disease Dementia: A Measure of Objective Memory Impairment in Amnestic Mild Cognitive Impairment.

OBJECTIVES: The criteria for objective memory impairment in mild cognitive impairment (MCI) are vaguely defined. Aggregating the number of abnormal memory scores (NAMS) is one way to operationalise memory impairment, which we hypothesised would predict progression to Alzheimer's disease (AD) dementia. METHODS: As part of the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing, 896 older adults who did not have dementia were administered a psychometric battery including three neuropsychological tests of memory, yielding 10 indices of memory. We calculated the number of memory scores corresponding to z ≤ -1.5 (i.e., NAMS) for each participant. Incident diagnosis of AD dementia was established by consensus of an expert panel after 3 years. RESULTS: Of the 722 (80.6%) participants who were followed up, 54 (7.5%) developed AD dementia. There was a strong correlation between NAMS and probability of developing AD dementia (r = .91, p = .0003). Each abnormal memory score conferred an additional 9.8% risk of progressing to AD dementia. The area under the receiver operating characteristic curve for NAMS was 0.87 [95% confidence interval (CI) .81-.93, p < .01]. The odds ratio for NAMS was 1.67 (95% CI 1.40-2.01, p < .01) after correcting for age, sex, education, estimated intelligence quotient, subjective memory complaint, Mini-Mental State Exam (MMSE) score and apolipoprotein E ϵ4 status. CONCLUSIONS: Aggregation of abnormal memory scores may be a useful way of operationalising objective memory impairment, predicting incident AD dementia and providing prognostic stratification for individuals with MCI.

Mesial temporal tau is related to worse cognitive performance and greater neocortical tau load in amyloid-ß-negative cognitively normal individuals.

We examined whether mesial temporal (Me) tau relates to cognitive performance in 47 amyloid-ß (Aß)-negative, cognitively normal older adults (>60 years old). Me-tau was measured using [18F]flortaucipir-positron emission tomography standardized uptake value ratio. The effect of continuous and categorical (stratified at standardized uptake value ratio = 1.2 [21% Me-positive]) Me-tau on cognition (mini-mental state examination, pre-Alzheimer's cognitive composite, a memory composite, and a nonmemory composite score) was examined using general linear models, and associations between Me-tau and [18F]flortaucipir signal in the neocortex were assessed using voxelwise regressions (continuous) and voxelwise contrasts (categorical). In addition, we assessed the effect of age and Aß burden on Me-tau. Both continuous and categorical Me-tau was associated with worse cognitive performance across all tests and with higher lateral temporal and parietal [18F]flortaucipir signal. Furthermore, we observed a marginal association between Me-tau and age, whereas there was no association with Aß burden. Our findings indicate that Me-tau in Aß-negative cognitively normal individuals, which is likely age-related (i.e., primary age-related tauopathy), might not be as benign as commonly thought.

Association of ß-Amyloid Level, Clinical Progression, and Longitudinal Cognitive Change in Normal Older Individuals.

OBJECTIVE: To determine the effect of ß-amyloid (Aß) 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 Aß PET and ≥3 years follow-up were included (n = 534; age 72 ± 6 years; 27% Aß positive; follow-up 5.3 ± 1.7 years). Aß 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: Aß 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 Aß, the hazard ratio for progression for moderate Aß 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 Aß 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.

Superior Memory Reduces 8-year Risk of Mild Cognitive Impairment and Dementia But Not Amyloid ß-Associated Cognitive Decline in Older Adults.

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 (Aß+) 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 Aß on cognition over time. RESULTS: Prevalence of Aß+ 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). Aß+ was associated with cognitive decline in verbal memory and executive function, regardless of SuperAger/CNFA classification. In the absence of Aß+, 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 Aß+ than CNFA. The deleterious effects of Aß 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.

Relationship Between Amyloid-ß Positivity and Progression to Mild Cognitive Impairment or Dementia over 8 Years in Cognitively Normal Older Adults.

BACKGROUND: Preclinical Alzheimer's disease (AD) is defined by cerebral amyloid-ß positivity (Aß+) in cognitively normal (CN) older adults. OBJECTIVE: To estimate the risk of progression to the symptomatic stages of AD due to PET Aß+ 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 Aß+, APOEɛ4 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% Aß+ and 8.1% Aß-progressed over 8 years (OR: 2.43). Risk of progression for Aß+ was 65-104% greater than Aß-. Aß+ APOEɛ4 carriers were at 348% greater risk than all other participants. Significant risk factors of progression in Aß+ 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 Aß-(HR: 1.09). Aß-progressors were not near the threshold for Aß+. These relationships were not moderated by hypertension, diabetes, obesity, or stroke/TIA. CONCLUSION: Aß+ is an important prognostic marker for progression from CN to MCI/dementia in older adults and APOEɛ4 carriage provides further predictive value in the presence of Aß+. These data suggest that Aß-associated clinical progression is consistent with clinical-pathological models of AD, whereas progression in the absence of elevated Aß deposition may be the result of neuropathological processes other than AD that accumulate with age.

Episodic Memory and Learning Dysfunction Over an 18-Month Period in Preclinical and Prodromal Alzheimer's Disease.

Recent meta-analyses suggest that episodic memory impairment associated with preclinical Alzheimer's disease (AD) equates to 0.15-0.24 standard deviations below that of cognitively healthy older adults. The current study aimed to characterize impairments in verbal acquisition and recall detectable at a single assessment, and investigate how verbal learning and episodic memory deteriorates in preclinical AD. A verbal list-learning task, the International Shopping List Test (ISLT), was administered multiple times over an 18-month period, to three groups of participants: amyloid-beta negative healthy older adults (Aß- CN; n = 50); Aß+ positive healthy older adults (preclinical AD; n = 25); and Aß+ positive individuals diagnosed with mild cognitive impairment (prodromal AD; n = 22). At baseline, there was no significant difference between the preclinical AD and control groups rate of acquisition, or total and delayed recall, however all indices were impaired in prodromal AD. Performance on ISLT total score improved in the control group over the 18-month period, but showed a moderate magnitude decline in the preclinical AD group (Cohen's d = - 0.63, [- 1.12, - 0.14]) and the prodromal AD group (Cohen's d = - 0.36, [- 0.94, 0.22]). No significant impairment in acquisition associated with preclinical AD was seen at baseline. Individuals with preclinical AD showed a significantly different performance on the ISLT total score over an 18-month period, compared to those without abnormal Aß. Individuals with prodromal AD showed substantial impairment on the ISLT at baseline and declined to a greater extent over time.

Estimates of age-related memory decline are inflated by unrecognized Alzheimer's disease.

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-ß 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-ß 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.

Trajectories of irregular word reading ability as a proxy for premorbid intelligence in Alzheimer's disease, mild cognitive impairment, and healthy aging: A longitudinal study.

The ability to read irregularly spelled words is commonly used to estimate premorbid intelligence, as this ability has been thought to be resistant to early effects of neurodegenerative disorders. However, studies evaluating decline of this skill in Alzheimer's disease (AD) have produced conflicting results. Irregular word reading was assessed three times over 36 months in a large (N = 995) sample, including healthy control, AD, and Mild Cognitive Impairment (MCI) groups. At baseline, MCI and AD groups read correctly an average of 3.01 and 7.39 fewer words, respectively, than healthy controls. The MCI group's performance remained stable during the study, but the AD group declined. Importantly, the observed decline was likely an underestimate, as significant numbers of the AD participants (42.6%) could not complete the task at follow-up. Use of alternate (e.g., demographics-based) methods is advised to augment or replace word pronunciation in estimating premorbid intelligence in individuals with even mild AD. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Baseline Amnestic Severity Predicts Progression From Amnestic Mild Cognitive Impairment to Alzheimer Disease Dementia at 3 Years.

BACKGROUND: Given the long preclinical disease course of Alzheimer disease (AD) pathology, novel treatments may be more efficacious if administered before the emergence of dementia. Thus, accurate prediction of who will develop AD dementia is of key importance in selecting individuals for trials of treatment and may become crucial for future selection of patients for therapy. METHODS: As part of the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing, 901 individuals who did not have dementia were recruited. We assigned individuals according to Petersen criteria and Winblad criteria for Mild Cognitive Impairment (MCI) at baseline. We then stratified individuals with amnestic MCI into 2 groups according to the severity of their memory impairment on baseline neuropsychological assessment. Incident diagnosis of AD dementia was established by consensus of an expert panel at 36 months. RESULTS: At 36 months, 725 (80.5%) participants were followed up, 54 (7.4%) of whom developed AD dementia. Subjects with amnestic MCI according to Petersen criteria were more likely to develop AD dementia [positive predictive value; PPV, 24.1%; 95% confidence interval (CI), 18.4-30.6] than healthy controls (PPV, 1.0%; 95% CI, 0.3-2.3). Winblad criteria were also effective, with multiple domain amnestic MCI being most accurate at predicting AD dementia (PPV, 47.3%; 95% CI, 33.7-61.2). Finally, more severe amnestic impairment below the median was useful for predicting the development of AD dementia in single domain amnestic MCI (PPV, 28.1%; 95% CI, 17.0-41.5) and in multiple domain amnestic MCI (PPV, 65.7%; 95% CI, 47.8-80.9). CONCLUSIONS: Memory impairment per se, impairment in multiple cognitive domains and severity of memory impairment were all associated with greater risk of developing AD dementia in this sample. Characterizing the severity of memory impairment may provide prognostic stratification within Petersen or Winblad taxonomies of amnestic MCI.