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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.

Importance: Older age, high levels of β-amyloid (Aβ), and the presence of the apolipoprotein E (APOE) ε4 allele are risk factors for Alzheimer disease (AD). However, the extent to which increasing age, Aβ, and ε4 are associated with memory decline remains unclear, and the age at which memory decline begins for Aβ-positive ε4 carriers and noncarriers has not been determined. Objective: To determine the association of age, Aβ level, and APOE ε4 with memory decline in a large group of cognitively healthy older adults. Design, setting, and participants: This longitudinal observational study included cognitively healthy older adults (age >60 years) enrolled in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study from March 31, 2006, through March 31, 2017; of 1583 individuals enrolled, 1136 refused or were excluded owing to other criteria (eg, having mild cognitive impairment or AD). Participants underwent Aβ imaging in research clinics in Perth and Melbourne and more than 72 months of follow-up (at 18-month intervals). The association of age with memory was fitted to a quadratic model. Age was treated as a continuous, time-dependent variable. Exposures: β-Amyloid imaging using positron emission tomography, genotyping for APOE ɛ4, and longitudinal neuropsychological assessments of episodic memory during the 72-month follow-up. Main outcomes and measures: Episodic memory composite score. Results: Of the 447 participants, 203 (45.4%) were men and 244 (54.6%) were women; mean (SD) age was 72.5 (6.6) years. Equal proportions of female participants were observed in each Aβ-ɛ4 group (24 of 51 Aβ-positive ε4 noncarriers [47.1%] ; 35 of 64 Aβ-negative ε4 carriers [54.7%]; 40 of 72 Aβ-positive ε4 carriers [55.6%]; and 145 of 260 Aβ-negative ε4 noncarriers [55.8%]). Adults with Aβ findings (mean [SD] age, 74.4 [6.8] years) were approximately 4 years older than those negative for Aβ (mean [SD] age, 69.8 [6.1] years). Memory decline diverged significantly from Aβ-negative ɛ

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 Hypothalamic-pituitary-adrenal axis dysregulation, which is typically assessed by measuring cortisol levels, is associated with cognitive dysfunction, hippocampal atrophy, and increased risk for mild cognitive impairment and Alzheimer’s disease (AD). However, little is known about the role of hypothalamic-pituitary-adrenal axis dysregulation in moderating the effect of high levels of amyloid-β (Aβ+) on cognitive decline in the preclinical phase of AD, which is often protracted, and thus offers opportunities for prevention and early intervention. Methods Using data from a 6-year multicenter prospective cohort study, we evaluated the relation between Aβ level, plasma cortisol level, and cognitive decline in 416 cognitively normal older adults. Results Results revealed that Aβ+ older adults experienced faster decline than Aβ− older adults in all cognitive domains (Cohen’s d at 6-year assessment = 0.37–0.65). They further indicated a significant interaction between Aβ and cortisol levels for global cognition (d = 0.32), episodic memory (d = 0.50), and executive function (d = 0.59) scores, with Aβ+ older adults with high cortisol levels having significantly faster decline in these domains compared with Aβ+ older adults with low cortisol levels. These effects were independent of age, sex, APOE genotype, anxiety symptoms, and radiotracer type. Conclusions In cognitively healthy older adults, Aβ+ is associated with greater cognitive decline and high plasma cortisol levels may accelerate the effect of Aβ+ on decline in global cognition, episodic memory, and executive function. These results suggest that therapies targeted toward lowering plasma cortisol and Aβ levels may be helpful in mitigating cognitive decline in the preclinical phase of AD.

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 Aβ 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.

Background: In cognitively normal (CN) older adults, carriage of the apolipoprotein E (APOE) ɛ4 allele is associated with increased risk for dementia of the Alzheimer type (AD-dementia). It is unclear whether this occurs solely through APOEɛ4 increasing amyloid-β (Aβ) accumulation or through processes independent of Aβ. Objective: To determine the extent and nature to which APOEɛ4 increases risk for clinical disease progression in CN older adults. Methods: Data from the total (n = 765) and Aβ-imaged (n = 423) CN cohort in the Australian Imaging, Biomarker and Lifestyle (AIBL) Study of Ageing was analyzed using Cox proportional hazard models to estimate ɛ4 risk for clinical disease progression over a 72-month follow-up. Results: With Aβ status unknown and risk from demographic characteristics controlled, ɛ4 carriage increased risk for clinical disease progression over 72 months by 2.66 times compared to risk of non-ɛ4 carriage. Re-analysis with Aβ status included showed that abnormally high Aβ increased risk for clinical disease progression over 72 months by 2.11 times compared to risk of low Aβ. However, with Aβ level known, ɛ4 carriage was no longer predictive of clinical disease progression. Conclusion: In CN older adults, the risk of ɛ4 for clinical disease progression occurs through the effect of ɛ4 increasing Aβ levels.

Objective Several studies have reported that non‐demented older adults with clinical depression show changes in amyloid‐β (Aβ) levels in blood, cerebrospinal fluid and on neuroimaging that are consistent with those observed in patients with Alzheimer's disease. These findings suggest that Aβ may be one of the mechanisms underlying the relation between the two conditions. We sought to determine the relation between elevated cerebral Aβ and the presence of depression across a 54‐month prospective observation period. Methods Cognitively normal older adults from the Australian Imaging Biomarkers and Lifestyle study who were not depressed and had undergone a positron emission tomography scan to classify them as either high Aβ (n = 81) or low Aβ (n = 278) participated. Depressive symptoms were assessed using the Geriatric Depression Scale — Short Form at 18‐month intervals over 54 months. Results Whilst there was no difference in probable depression between groups at baseline, incidence was 4.5 (95% confidence interval [CI] 1.3–16.4) times greater within the high Aβ group (9%) than the low Aβ group (2%) by the 54‐month assessment. Conclusions Results of this study suggest that elevated Aβ levels are associated with a 4.5‐fold increased likelihood of developing clinically significant depressive symptoms on follow‐up in preclinical Alzheimer's disease. This underscores the importance of assessing, monitoring and treating depressive symptoms in older adults with elevated Aβ.

In a group of older adults with very mild dementia, we aimed to characterize the nature and magnitude of cognitive decline as measured by the Cogstate Brief Battery, in relation to Aβ levels and hippocampal volume. Participants were characterized according to their status on the Clinical Dementia Rating (CDR) scale. A total of 308 individuals who were CDR 0 and had low cerebral Aβ levels (Aβ−), 32 individuals who were Aβ− and CDR 0.5, and 43 individuals who were Aβ+ and CDR 0.5 were included in this study. Participants completed the CogState brief battery at baseline, and at 18-, 36-, 54- and 72-month follow-up. Linear mixed model analyses indicated that relative to the Aβ− CDR 0 group, the Aβ+ CDR 0.5 group showed increased rates of memory decline and hippocampal volume loss. However, compared to the Aβ− CDR 0 group, the Aβ− CDR 0.5 group showed no changes in cognitive function or hippocampal volume over 72 months. The results of this study confirm that in individuals with very mild dementia, who also have biomarker confirmation of Aβ+, changes in cognitive function manifest primarily as deterioration in memory processing, and this is associated with hippocampal volume loss. Conversely, the absence of any cognitive decline or loss in hippocampal volume in individuals with very mild dementia but who are Aβ− suggests that some other non-AD disease process may underlie any static impairment in cognitive function.

Objective: As the absence of Aβ-related memory decline in APOE ε4 noncarriers may be due to the relative brevity of previous studies, we aimed to characterize Aβ-related cognitive decline over 72 months in APOE ε4 carriers and noncarriers who were cognitively normal (CN). Methods: CN older adults (n = 423) underwent Aβ imaging and APOE genotyping. Participants completed comprehensive neuropsychological testing at baseline 18-, 36-, 54-, and 72-month assessments. Results: Relative to Aβ− CN ε4 noncarriers, both Aβ+ CN ε4 carriers and noncarriers showed significantly increased decline in measures of memory, language, and executive function as well as higher rates of progression to a clinical classification of mild cognitive impairment. Memory decline was greater in Aβ+ CN ε4 carriers than in Aβ+ CN ε4 noncarriers. No cognitive decline was evident in Aβ− CN ε4 carriers. Conclusions: In CN older adults, Aβ+ is associated with memory decline in ε4 noncarriers; however, the rate of this decline is much slower than that observed in ε4 carriers. These data indicate that the processes by which ε4 carriage increases the rate of Aβ-related cognitive decline occur in the preclinical stage of Alzheimer disease.

Objective To examine how β-amyloid (Aβ), APOE and BDNF genotypes, and cortisol relate to depressive and anxiety symptoms in cognitively normal older women and men. Methods Cross-sectional data were analyzed from 423 older adults from the Australian Imaging Biomarkers and Lifestyle study. Analyses of covariance evaluated associations between Aβ, APOE and BDNF genotype, and cortisol in relation to severity of depressive and anxiety symptoms. Results Among Aβ+ older adults, APOE ε4 carriage was associated with greater severity of anxiety symptoms (d = 0.55); and in the full sample, APOE ε4 carriage was linked to greater severity of depressive (d = 0.26) and anxiety (d = 0.21) symptoms. Among Aβ+ women, ε4 carriers reported greater anxiety symptoms than non-ε4 carriers (d = 0.83), and female BDNF rs6265 Val66 Met allele carriers reported greater depressive symptoms (d = 0.29). Conclusion Sex moderated the relationship between Aβ, APOE genotype, and BDNF genotype in predicting severity of anxiety and depressive symptoms in cognitively normal older adults.