Epigenetic Age Acceleration and Chronological Age: Associations With Cognitive Performance in Daily Life.

DNA methylation-derived epigenetic clocks offer the opportunity to examine aspects of age acceleration (ie, the difference between an individual's biological age and chronological age), which vary among individuals and may better account for age-related changes in cognitive function than chronological age. Leveraging existing ambulatory cognitive assessments in daily life from a genetically diverse sample of 142 adults in midlife, we examined associations between 5 measures of epigenetic age acceleration and performance on tasks of processing speed and working memory. Covarying for chronological age, we used multilevel models to examine associations of epigenetic age acceleration (Horvath 1, Horvath 2, Hannum, PhenoAge, and GrimAge clocks) with both average level and variability of cognitive performance. Positive age acceleration (ie, epigenetic age greater than chronological age) was associated with poorer mean processing speed (Horvath 1 and 2) and working memory (GrimAge). Higher chronological age was also associated with poorer mean processing speed and working memory performance. Further, positive age acceleration was generally associated with greater intraindividual variability in working memory and processing speed tasks, whereas being chronologically older was associated with less intraindividual variability. Although further work is needed, our results indicate age acceleration effects have comparable or greater size as those for chronological age differences, suggesting that epigenetic age acceleration may account for additional risk and interindividual variation in cognitive performance above chronological age.

Remote and in-clinic digital cognitive screening tools outperform the MoCA to distinguish cerebral amyloid status among cognitively healthy older adults.

INTRODUCTION: We evaluated the accuracy of remote and in-person digital tests to distinguish between older adults with and without AD pathological change and used the Montreal Cognitive Assessment (MoCA) as a comparison test. METHODS: Participants were 69 cognitively normal older adults with known beta-amyloid (Aß) PET status. Participants completed smartphone-based assessments 3×/day for 8 days, followed by TabCAT tasks, DCTclock™, and MoCA at an in-person study visit. We calculated the area under the curve (AUC) to compare task accuracies to distinguish Aß status. RESULTS: Average performance on the episodic memory (Prices) smartphone task showed the highest accuracy (AUC = 0.77) to distinguish Aß status. On in-person measures, accuracy to distinguish Aß status was greatest for the TabCAT Favorites task (AUC = 0.76), relative to the DCTclockTM (AUC = 0.73) and MoCA (AUC = 0.74). DISCUSSION: Although further validation is needed, our results suggest that several digital assessments may be suitable for more widespread cognitive screening application.

Epigenetic age acceleration as a biomarker for impaired cognitive abilities in adulthood following early life adversity and psychiatric disorders.

Background: Early life adversity and psychiatric disorders are associated with earlier declines in neurocognitive abilities during adulthood. These declines may be preceded by changes in biological aging, specifically epigenetic age acceleration, providing an opportunity to uncover genome-wide biomarkers that identify individuals most likely to benefit from early screening and prevention. Methods: Five unique epigenetic age acceleration clocks derived from peripheral blood were examined in relation to latent variables of general and speeded cognitive abilities across two independent cohorts: 1) the Female Growth and Development Study (FGDS; n = 86), a 30-year prospective cohort study of substantiated child sexual abuse and non-abused controls, and 2) the Biological Classification of Mental Disorders study (BeCOME; n = 313), an adult community cohort established based on psychiatric disorders. Results: A faster pace of biological aging (DunedinPoAm) was associated with lower general cognitive abilities in both cohorts and slower speeded abilities in the BeCOME cohort. Acceleration in the Horvath clock was significantly associated with slower speeded abilities in the BeCOME cohort but not the FGDS. Acceleration in the Hannum clock and the GrimAge clock were not significantly associated with either cognitive ability. Accelerated PhenoAge was associated with slower speeded abilities in the FGDS but not the BeCOME cohort. Conclusions: The present results suggest that epigenetic age acceleration has the potential to serve as a biomarker for neurocognitive decline in adults with a history of early life adversity or psychiatric disorders. Estimates of epigenetic aging may identify adults at risk of cognitive decline that could benefit from early neurocognitive screening.

Examining the Bidirectional Nature of Loneliness and Anxiety Among Older Adults in Daily Life.

OBJECTIVES: Loneliness in later life increases the risk for adverse health outcomes; however, less is known about how loneliness is maintained. Anxiety may play an important role in maintaining loneliness, but little is known about how this connection plays out over time in daily life. This study thus focused on the within-person associations between momentary loneliness and anxiety among older adults. METHODS: Participants were 317 diverse older adults (40% Black; 13% Hispanic, mean age = 77.45 years, 67% women) systematically recruited from the Bronx, NY, who completed ecological momentary assessments 5 times daily for 14 consecutive days. Multilevel models tested bidirectional contemporaneous, momentary cross-lagged (t - 1), day-level cross-lagged (average day to end of day), and day-to-day cross-lagged associations between loneliness and anxiety. Separate sensitivity analyses controlled for concurrent overall mood valence or depressed state. Gender and mild cognitive impairment (MCI) status were tested as moderators at all timescales. RESULTS: Significant bidirectional associations between loneliness and anxiety were found at the contemporaneous and momentary cross-lagged (t - 1) timescales. Higher average daily loneliness predicted higher end-of-day anxiety, but not vice versa. Loneliness and anxiety were not significantly associated from day to day. Sensitivity analyses revealed some associations varied depending on inclusion of either concurrent mood valence or depressed state. Neither gender nor MCI status moderated associations at any timescale. DISCUSSION: Findings shed light on the complex temporal ordering of loneliness and anxiety in daily life and extend contemporary theoretical notions of loneliness, including the possibility of interventions that target key moments in daily life.

Loneliness and Cognitive Function in Older Adults Without Dementia: A Systematic Review and Meta-Analysis.

BACKGROUND: Loneliness has been highlighted as a risk factor for dementia. However, the nature of the relationship between loneliness and cognitive function prior to onset of dementia is unclear. OBJECTIVE: The aim of this systematic review and meta-analysis was to examine the relationship between loneliness and cognitive function in samples screened for dementia at study commencement. METHODS: Five electronic databases (PubMed, PsycNET, Web of Science, EBSCOhost, Scopus) were searched from inception to August 31, 2021. A narrative review and random-effects meta-analysis were conducted on studies meeting search criteria. PROSPERO registration number: CRD42020155539. RESULTS: The sixteen studies that met inclusion criteria involved 30,267 individuals, with mean age ranging from 63.0 to 84.9 years. Studies varied in dementia screening criteria, measurement of loneliness and cognitive function, and statistical modeling approach. The narrative review indicated that loneliness was associated with poorer global cognition, episodic memory, working memory, visuospatial function, processing speed, and semantic verbal fluency. Results of the meta-analysis indicated that loneliness was negatively associated with global cognitive function (overall r = -0.08; 95% CI = -0.14, -0.02; n = 6). Due to lack of sufficient data and heterogeneity between studies, we were unable to explore associations with other cognitive domains or longitudinal associations. CONCLUSION: Loneliness is associated with subtle impairment across multiple cognitive domains in older adults who were screened for dementia. Better characterization of this relationship will provide important information about how loneliness contributes to the clinical and pathological sequalae of AD and be informative for risk reduction and early detection strategies.

Receptive Language Abilities for Females Exposed to Early Life Adversity: Modification by Epigenetic Age Acceleration at Midlife in a 30-Year Prospective Cohort Study.

OBJECTIVES: Deviations from normative trajectories of receptive language abilities following early life adversity (ELA) may indicate an elevated risk for advanced cognitive aging and related morbidities. Accelerated epigenetic aging at midlife may further identify those at greatest risk for advanced cognitive aging following ELA. We examined whether accelerations in epigenetic aging at midlife can identify those individuals who demonstrated the greatest change in receptive language abilities following ELA. METHODS: Data were drawn from the Female Growth and Development Study (n = 86), a 30-year prospective cohort study of females exposed to substantiated child sexual abuse (CSA), a severe ELA, and a non-CSA comparison condition. The Peabody Picture Vocabulary Test-Revised (PPVT-R) measured receptive language abilities on 6 occasions from childhood to mid-life. Interindividual differences in PPVT-R trajectories were examined in relation to CSA exposure and across 5 independent measures of epigenetic age acceleration derived from first (Horvath DNAmAge, Hannum DNAmAge) and second (GrimAge, PhenoAge, Dunedin Pace of Aging) generation epigenetic clocks. RESULTS: Quadratic growth models revealed that PPVT-R scores were significantly lower at age 25 for females exposed to CSA. Specifically, CSA exposed females had lower intercepts when GrimAge was accelerated and a smaller quadratic trend when PhenoAge was accelerated. DISCUSSION: ELA is associated with significant differences in development of receptive language abilities with the most pronounced differences observed for females with accelerated epigenetic ages at mid-life. These findings suggest that epigenetic age acceleration could serve as an indicator of differences in cognitive aging and portend to later adulthood cognitive functioning.

Accounting for retest effects in cognitive testing with the Bayesian double exponential model via intensive measurement burst designs.

Monitoring early changes in cognitive performance is useful for studying cognitive aging as well as for detecting early markers of neurodegenerative diseases. Repeated evaluation of cognition via a measurement burst design can accomplish this goal. In such design participants complete brief evaluations of cognition, multiple times per day for several days, and ideally, repeat the process once or twice a year. However, long-term cognitive change in such repeated assessments can be masked by short-term within-person variability and retest learning (practice) effects. In this paper, we show how a Bayesian double exponential model can account for retest gains across measurement bursts, as well as warm-up effects within a burst, while quantifying change across bursts in peak performance. We also highlight how this approach allows for the inclusion of person-level predictors and draw intuitive inferences on cognitive change with Bayesian posterior probabilities. We use older adults' performance on cognitive tasks of processing speed and spatial working memory to demonstrate how individual differences in peak performance and change can be related to predictors of aging such as biological age and mild cognitive impairment status.

Daily Social Interactions and Momentary Loneliness: The Role of Trait Loneliness and Neuroticism.

OBJECTIVES: Loneliness has been linked to poor mental and physical health outcomes in later life. Little is known about how daily social interactions relate to older adults' everyday experiences of loneliness. This study examined the dynamic associations between social interactions and the momentary feelings of loneliness in older adults' daily lives. We further examined whether individual differences in trait loneliness and neuroticism influenced the extent to which daily social interactions were related to moment-to-moment changes in loneliness. METHOD: Participants were 317 community-dwelling older adults (aged 70-90 years) who reported their social interactions and momentary feelings of loneliness 5 times daily for 14 consecutive days using smartphones. RESULTS: Having more frequent, more pleasant, and in-person social interactions, as well as interactions with family and friends specifically, significantly predicted lower momentary loneliness a few hours later. Higher levels of momentary loneliness, in turn, predicted less likelihood of engaging in these types of social interactions subsequently. In addition, older adults with higher (vs lower) traits of loneliness and neuroticism experienced greater decreases in momentary feelings of loneliness after having more frequent or pleasant social interactions, or interactions with family members. DISCUSSION: These results expand our understanding of the dynamic associations between daily social interactions and loneliness in later life and provide insights to inform future research, including the possibility of behavioral interventions that target social interactions to reduce the risk for loneliness.

A highly feasible, reliable, and fully remote protocol for mobile app-based cognitive assessment in cognitively healthy older adults.

Introduction: The early detection of cognitive impairment is one of the most important challenges in Alzheimer's disease (AD) research. The use of brief, short-term repeated test sessions via mobile app has demonstrated similar or better reliability and validity compared to standard in-clinic assessments in adult samples. The present study examined adherence, acceptability, and reliability for a remote, app-based cognitive screening protocol in healthy older adults. Methods: Cognitively unimpaired older adults (N = 52, ages 60-80) completed three brief cognitive testing sessions per day within morning, afternoon, and evening time windows, for 8 consecutive days using a mobile app-based cognitive testing platform. Cognitive tasks assessed visual working memory, processing speed, and episodic memory. Results: Participants completed an average of 93% (M = 22.3 sessions, standard deviation = 10.2) of the 24 assigned sessions within 8 to 9 days. Average daily adherence ranged from 95% of sessions completed on day 2 to 88% of sessions completed on day 8. There was a statistically significant effect of session time on adherence between the morning and afternoon sessions only F (1, 51) = 9.15, P  = .004, η p  2   = 0.152, with fewer afternoon sessions completed on average. The within-person reliabilities of average scores, aggregated across all 24 sessions, were exceptionally high, ranging from 0.89 to 0.97. Performance on the episodic memory task was positively and significantly associated with total score and word list recall score on the Telephone Interview for Cognitive Status. In an exit survey, 65% of participants reported that they "definitely" would complete the sessions again. Discussion: These findings suggests that remote, mobile app-based cognitive testing in short bursts is both highly feasible and reliable in a motivated sample of cognitively normal older adults. Limitations include the limited diversity and generalizability of the sample; this was a largely White, highly educated, and motivated sample self-selected for AD research.

The where and when of COVID-19: Using ecological and Twitter-based assessments to examine impacts in a temporal and community context.

In March 2020, residents of the Bronx, New York experienced one of the first significant community COVID-19 outbreaks in the United States. Focusing on intensive longitudinal data from 78 Bronx-based older adults, we used a multi-method approach to (1) examine 2019 to early pandemic (February-June 2020) changes in momentary psychological well-being of Einstein Aging Study (EAS) participants and (2) to contextualize these changes with community distress scores collected from public Twitter posts posted in Bronx County. We found increases in mean loneliness from 2019 to 2020; and participants that were higher in neuroticism had greater increases in thought unpleasantness and feeling depressed. Twitter-based Bronx community scores of anxiety, depressivity, and negatively-valenced affect showed elevated levels in 2020 weeks relative to 2019. Integration of EAS participant data and community data showed week-to-week fluctuations across 2019 and 2020. Results highlight how community-level data can characterize a rapidly changing environment to supplement individual-level data at no additional burden to individual participants.

The Support Person's Preferences and Perspectives of Physical Activity Programs for Older Adults With Cognitive Impairment.

Objectives: Physical activity (PA) is beneficial for older adults' cognition. There is limited research investigating perspectives of support persons (SPs) of next-of-kins (NOKs) with cognitive impairment. This exploratory study aimed to investigate perspectives of SPs of older adults with Alzheimer's Dementia (AD) or Mild Cognitive Impairment (MCI). Methods: A telephone survey of 213 SPs of NOKs from the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing (AIBL) was undertaken to quantitatively assess SPs' beliefs and knowledge about PA benefits, current PA level of their NOK, and PA program preferences. The contribution of age, gender, diagnosis and mental health symptoms was assessed using multiple logistic regression analyses. Results: Many SPs were aware of PA benefits for memory (64%) and believed it would help their NOK (72%). Older SP age was associated with less awareness of benefits (p = 0.016). SPs caring for male NOKs were more likely to believe that PA would be helpful than those caring for female NOKs (p = 0.049). NOK AD diagnosis (rather than MCI) (p = 0.014), older age (p = 0.005) and female gender (p = 0.043) were associated with lower PA levels. SPs were mixed regarding preference for their NOKs to participate in individual (45%) or group (54%) PA. Many SPs wanted to participate in PA with their NOK (63%). Conclusions: The results highlight that SPs have high levels of awareness of the cognitive benefits of PA, and describe their preferences regarding PA programs. The findings provide new information to inform targeted public health messaging, PA prescribers and providers, and future research directions.

Undetected Neurodegenerative Disease Biases Estimates of Cognitive Change in Older Adults.

Neurodegenerative disease is highly prevalent among older adults and, if undetected, may obscure estimates of cognitive change among aging samples. Our aim in this study was to determine the nature and magnitude of cognitive change in the absence of common neuropathologic markers of neurodegenerative disease. Cognitively normal older adults (ages 65-89 years, N = 199) were classified as normal or abnormal using neuroimaging and cerebrospinal-fluid biomarkers of ß-amyloid, tau, and neurodegeneration. When cognitive change was modeled without accounting for biomarker status, significant decline was evident for semantic memory, processing speed, and working memory. However, after adjusting for biomarker status, we found that the rate of change was attenuated and that the biomarker-normal group demonstrated no decline for any cognitive domain. These results indicate that estimates of cognitive change in otherwise healthy older adults will be biased toward decline when the presence of early neurodegenerative disease is not accounted for.

Loneliness in older age: What is it, why is it happening and what should we do about it in Australia?

Loneliness is an important health issue facing older people due to its association with poor quality of life and poor health outcomes. This paper aimed to clarify key issues around loneliness among older adults and draw attention to innovative programs and the translation of emerging research into practice. Loneliness is a mismatch between a person's actual and desired social connections, experienced as negative emotions. Older adults are vulnerable to loneliness because of changes associated with ageing. As such, identifying as older is often seen as a burden, negatively impacting self-esteem, sense of purpose and relevance, culminating in loneliness. Interventions combatting loneliness can target individuals, relationships, communities or societies. We advocate for an intersectoral approach to support healthy ageing and reduce loneliness. This will require further research to evaluate new approaches with loneliness as the primary outcome, and additional funding to translate evidence into an integrated multi-level approach to addressing loneliness.

The Association Between Loneliness and Inflammation: Findings From an Older Adult Sample.

Loneliness has been linked to poor mental and physical health outcomes. Past research suggests that inflammation is a potential pathway linking loneliness and health, but little is known about how loneliness assessed in daily life links with inflammation, or about linkages between loneliness and inflammation among older adults specifically. As part of a larger investigation, we examined the cross-sectional associations between loneliness and a panel of both basal and LPS-stimulated inflammatory markers. Participants were 222 socioeconomically and racially diverse older adults (aged 70-90 years; 38% Black; 13% Hispanic) systematically recruited from the Bronx, NY. Loneliness was measured in two ways, with a retrospective trait measure (the UCLA Three Item Loneliness Scale) and an aggregated momentary measure assessed via ecological momentary assessment (EMA) across 14 days. Inflammatory markers included both basal levels of C-reactive protein (CRP) and cytokines (IL-1ß, IL-4, IL-6, IL-8, IL-10, TNF-α) and LPS-stimulated levels of the same cytokines. Multiple regression analyses controlled for age, body-mass index, race, and depressive symptoms. Moderation by gender and race were also explored. Both higher trait loneliness and aggregated momentary measures of loneliness were associated with higher levels of CRP (ß = 0.16, p = 0.02; ß = 0.15, p = 0.03, respectively). There were no significant associations between loneliness and basal or stimulated cytokines and neither gender nor race were significant moderators. Results extend prior research linking loneliness with systemic inflammation in several ways, including by examining this connection among a sample of older adults and using a measure of aggregated momentary loneliness.

The Web-Based Uprise Program for Mental Health in Australian University Students: Protocol for a Pilot Randomized Controlled Trial.

BACKGROUND: University students are vulnerable to poor mental health, psychological distress, and loneliness relative to nonuniversity student peers. However, the rate of seeking mental health treatment among university students is low. Web-based psychological interventions may provide an opportunity for supporting vulnerable university students who are unlikely to otherwise seek support. OBJECTIVE: The aim of this study is to examine the feasibility, acceptability, safety, and efficacy of an existing web-based transdiagnostic cognitive behavioral therapy (CBT) mental health program for use among Australian university students. METHODS: This is a pilot randomized controlled trial comparing a self-directed web-based CBT mental health program with a waitlist control. The self-directed modules will be augmented with optional webchat or telephone coaching with a therapist. The recruitment target is 70 university students who do not present with a clinical mental health disorder. Allocation will be made in a 1:1 ratio and will occur after the initial baseline assessment. Assessments will be completed at baseline, upon completion of a 4-week waitlist (waitlist group only), upon completion of the program, and at 3 months after completion of the program. RESULTS: The trial was funded in June 2018, and the protocol was approved by the Swinburne University Human Research Ethics Committee in September 2018. Recruitment commenced in October 2018, with the first participant allocated in November 2018. A total of 70 participants were recruited to the trial. The trial recruitment ceased in June 2019, and data collection was finalized in December 2019. We expect the final data analysis to be completed by November 2020 and results to be published early in 2021. The primary outcomes are feasibility, acceptability, safety, and symptoms of depression, anxiety, and stress. The secondary outcomes are psychological wellbeing, quality of life, loneliness, self-reported physical health status, emotion regulation, and cognitive and mindfulness processes. CONCLUSIONS: The acceptability, feasibility, safety, and efficacy of a web-based mental health program in university students will be evaluated. Web-based mental health programs offer the opportunity to engage university students who may be reluctant to seek support through traditional face-to-face mental health services, and the transdiagnostic approach of the program has the potential to address the breadth of mental health concerns of university students. TRIAL REGISTRATION: Australian New Zealand Clinical Trial Registry ACTRN12618001604291; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12618001604291. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/21307.

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.

Rates of age- and amyloid ß-associated cortical atrophy in older adults with superior memory performance.

INTRODUCTION: Superior cognitive performance in older adults may reflect underlying resistance to age-associated neurodegeneration. While elevated amyloid ß (Aß) deposition (Aß+) has been associated with increased cortical atrophy, it remains unknown whether "SuperAgers" may be protected from Aß-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 Aß status. RESULTS: Of the case-matched SuperAgers and cognitively normal for age older adults, 40.7% and 40.1%, respectively, were Aß+. Rates of age- and Aß-associated atrophy did not differ between the groups on any measure. Aß- individuals displayed the slowest rates of atrophy. DISCUSSION: Maintenance of superior memory in late life does not reflect resistance to age- or Aß-associated atrophy. However, those individuals who reached old age without cognitive impairment nor elevated Aß deposition (i.e. Aß-) displayed reduced rates of cortical atrophy.

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.

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.

Amyloid burden and incident depressive symptoms in preclinical Alzheimer's disease.

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-ß (Aß), 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 (Aß+; n = 136) or low (Aß-; n = 449) Aß according to positron emission tomography at 18-month intervals over 72 months. RESULTS: Incident cases of screen positive depression were not increased in Aß+ 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 Aß 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 Aß. New depressive disorders presenting in CN older adults could therefore be investigated for aetiologies beyond AD.