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The A4 study: ?-amyloid and cognition in 4432 cognitively unimpaired adults.

ABSTRACT: OBJECTIVE:To clarify the preclinical stage of Alzheimer's disease by estimating when ?-amyloid accumulation first becomes associated with changes in cognition. METHODS:Here we studied a large group (N = 4432) of cognitively unimpaired individuals who were screened for inclusion in the A4 trial (age 65-85) to assess the effect of subthreshold levels of ?-amyloid on cognition and to identify which cognitive domains first become affected. RESULTS:?-amyloid accumulation was linked to significant cognitive dysfunction in cognitively unimpaired participants with subthreshold levels of ?-amyloid in multiple measures of memory (Logical Memory Delayed Recall, P = 0.03; Free and Cued Selective Reminding Test, P < 0.001), the Preclinical Alzheimer's Cognitive Composite (P = 0.01), and was marginally associated with decreased executive function (Digit Symbol Substitution, P = 0.07). Significantly, decreased cognitive scores were associated with suprathreshold levels of ?-amyloid, across all measures (P < 0.05). The Free and Cued Selective Reminding Test, a list recall memory test, appeared most sensitive to ?-amyloid -related decreases in average cognitive scores, outperforming all other cognitive domains, including the narrative recall memory test, Logical Memory. INTERPRETATION:Clinical trials for cognitively unimpaired ?-amyloid-positive individuals will include a large number of individuals where mechanisms downstream from ?-amyloid pathology are already activated. These findings have implications for primary and secondary prevention of Alzheimer's disease.

SUBMITTER: Insel PS

PROVIDER: S-EPMC7261742 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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The A4 study: β-amyloid and cognition in 4432 cognitively unimpaired adults.

Insel Philip S PS Donohue Michael C MC Sperling Reisa R Hansson Oskar O Mattsson-Carlgren Niklas N

Annals of clinical and translational neurology 20200421 5

<h4>Objective</h4>To clarify the preclinical stage of Alzheimer's disease by estimating when β-amyloid accumulation first becomes associated with changes in cognition.<h4>Methods</h4>Here we studied a large group (N = 4432) of cognitively unimpaired individuals who were screened for inclusion in the A4 trial (age 65-85) to assess the effect of subthreshold levels of β-amyloid on cognition and to identify which cognitive domains first become affected.<h4>Results</h4>β-amyloid accumulation was lin ...[more]

PMID: 32315118

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Project description:IntroductionSystemic inflammation has been increasingly implicated in the pathogenesis of Alzheimer's disease (AD), yet the mechanistic and temporal specificity of this relationship is poorly understood. We aimed to characterize the cross-sectional and longitudinal associations between peripheral inflammatory biomarkers, cognition, and Aβ deposition in oldest-old cognitively unimpaired (CU) adults.MethodsA large sample of 139 CU older adults (mean age (range) = 85.4 (82-95)) underwent neuropsychological testing, Pittsburgh compound-B (PiB)-PET imaging and structural MRI. Hierarchical regression models examined associations between circulating inflammatory biomarkers (Interleukin-6 (IL-6), soluble Tumor Necrosis Factor receptors 1 and 2 (sTNFr1 and sTNFr2), soluble cluster of differentiation 14 (sCD14), C-reactive protein (CRP)), cognition, and global and regional Aβ deposition at baseline and over follow-up. Indices of preclinical disease, including pathologic Aβ status and hippocampal volume, were incorporated to assess conditional associations.ResultsAt baseline evaluation, higher concentrations of IL-6 and sTNFr2 were associated with greater global Aβ burden in those with lower hippocampal volume. In longitudinal models, IL-6 predicted subsequent conversion to MCI and both IL-6 and CRP predicted greater change in global and regional Aβ deposition specifically among participants PiB-positive at baseline. These relationships withstood adjustment for demographic factors, anti-hypertensive medication use, history of diabetes, heart disease, APOE ε4 carrier status, and white matter lesions.DiscussionIn a large prospective sample of CU adults aged 80 and over, peripheral inflammatory biomarkers were associated with and predictive of the progression of Aβ deposition. This was specific to those with biomarker evidence of preclinical AD at baseline, supporting recent evidence of disease-state-dependent differences in inflammatory expression profiles. Chronic, low-level systemic inflammation may exacerbate the deposition of Aβ pathology among those with emerging disease processes, and place individuals at a higher risk of developing clinically significant cognitive impairment.

Project description:ImportanceClinical guidelines currently recommend against amyloid imaging for cognitively unimpaired persons. The goal of Alzheimer's disease (AD) prevention, together with advances in understanding the pathophysiology of AD, however, has led to trials testing drugs in cognitively unimpaired persons who show evidence of AD biomarkers. Assuming the eventual success of such trials, millions of patients will be affected. There is a need to understand the effects of biomarker disclosure on those individuals.DesignThe Study of Knowledge and Reactions to Amyloid Testing (SOKRATES) involved 2 semi-structured telephone interviews with individuals who received amyloid PET scan results as part of screening for research participation. Post-disclosure interviews were conducted at 4 to 12 weeks and again 1 year later. Data were collected from November 5, 2014 to November 30, 2016. Interviews were transcribed and coded in NVivo 12.0.Participants80 adults aged 65 and older: 50 who received "elevated" and 30 who received "not-elevated" amyloid PET scan results.Main outcomesInterviews examined four domains: (1) comprehension of the amyloid PET scan result; (2) implications of the result for sense of self, memory, and future; (3) sharing of results with others; and (4) AD risk-reduction behaviors.ResultsParticipants who received an elevated amyloid PET scan result viewed the result as more serious and sensitive than other medical test results given its unique implications for identity, self-determination, and stigma. In contrast, participants who received a not-elevated amyloid PET scan result described feeling relief and reinterpreted perceived memory impairments as normal aging. Participants with elevated amyloid reported contemplating and making more changes to health behaviors and future plans than their peers with not-elevated amyloid.ConclusionsClinical practice in the diagnosis and treatment of persons with preclinical AD, a stage of the disease defined by the presence of biomarkers in the absence of cognitive impairment, will need to address matters of identity, stigma, and life-planning.

Project description:Importance:To reduce the rising incidence of clinical impairment due to Alzheimer disease, it is essential to define older adults at highest risk. Widowhood may be an unrecognized factor contributing to accelerated clinical progression along the Alzheimer disease pathway among cognitively unimpaired older adults. Objective:To determine whether widowhood status and level of brain ?-amyloid (ie, the Alzheimer disease pathologic protein) are additively or interactively associated with cognitive decline among cognitively unimpaired older adults. Design, Setting, and Participants:In this cohort study, 257 married, widowed, and unmarried (ie, never married, divorced, or separated) participants from the Harvard Aging Brain Study longitudinal cohort underwent baseline evaluation of neocortical ?-amyloid levels using Pittsburgh compound B positron emission tomography and 4 annual cognitive assessments. Data were collected from September 2010 to February 2017 and analyzed from July 2018 to July 2019. Main Outcomes and Measures:Cognitive performance was measured using the Preclinical Alzheimer Cognitive Composite. Results:Of the 257 participants, 153 (59.5%) were women, and the mean (SD) age was 73.5 (6.1) years; 145 participants (56.4%) were married (66 [45.5%] women), 77 (30.0%) were unmarried (56 [72.7%] women), and 35 (13.6%) were widowed (31 [88.6%] women). Compared with married participants, widowed participants demonstrated worsening cognitive performance after adjusting for age, sex, socioeconomic status, depression, and ?-amyloid levels (??=?-0.11; 95% CI, -0.19 to -0.04; P?=?.002) with no difference observed between married and unmarried participants. Furthermore, widowed participants with higher baseline ?-amyloid levels exhibited steeper cognitive decline (??=?-0.22; 95% CI, -0.42 to -0.03; P?=?.02), indicating both independent and interactive associations of ?-amyloid levels and widowhood with cognition. In a secondary model using dichotomous ?-amyloid-marital status groupings, the rate of cognitive decline among widowed participants with high ?-amyloid was nearly 3 times faster than among married participants with high ?-amyloid (widowed, high ?-amyloid: ?, -0.33; 95% CI, -0.46 to -0.19; P?<?.001; married, high ?-amyloid: ?, -0.12; 95% CI, -0.18 to -0.01; P?<?.001). Conclusions and Relevance:In a sample of cognitively unimpaired older adults, being widowed was associated with accelerated ?-amyloid-related cognitive decline during 3 years. Cognitively unimpaired, widowed older adults were particularly susceptible to Alzheimer disease clinical progression, emphasizing the need for increased research attention and evidenced-based interventions for this high-risk group.

Project description:ObjectiveResearch in animals has shown that chronic stress exacerbates tau pathology. In humans, psychological stress has been associated with higher risk of Alzheimer disease clinical syndrome. The objective of this cross-sectional study was to assess the hypothesis that stress coping ability (assessed via the Brief Resilience Scale [BRS]) is associated with tau burden and to evaluate whether these associations differed by sex and amyloid status (A+/A-) in cognitively unimpaired (CU) older adults.MethodsWe included 225 CU participants (mean age 70.4 ± 10.2 years, 48% female) enrolled in the population-based Mayo Clinic Study of Aging who completed the BRS and underwent amyloid-PET (Pittsburgh compound B-PET) and tau-PET (AV1451-PET). We fitted multiple regression and analysis of covariance models to assess the associations between BRS and tau-PET and the interaction with amyloid status and sex. We focused on entorhinal cortex (ERC) tau burden and also performed voxel-wise analyses. Age, sex, education, depression, and anxiety were considered as covariates.ResultsHigher stress coping ability was associated with lower tau burden in the medial temporal lobe (including ERC) and occipito-temporal and cuneal/precuneal cortices. The association was present in both A+ and A- but weaker in A- CU older adults. There was an interaction between amyloid status and stress coping ability that was restricted to the medial temporal lobe tau such that A+ CU older adults with lower stress coping abilities showed higher tau. There were no significant interactions between stress coping and sex.ConclusionsA faster termination of the stress response (higher coping ability) may limit the negative effects of stress on tau deposition. Conversely, lower stress coping ability may be an early sign of accumulating tau pathology. Longitudinal studies are warranted to clarify whether stress mechanisms act to exacerbate tau pathology or tau influences stress-related brain mechanisms and lowers the ability to cope with stress.

Dataset Information

The A4 study: ?-amyloid and cognition in 4432 cognitively unimpaired adults.

Publications

The A4 study: β-amyloid and cognition in 4432 cognitively unimpaired adults.

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