Dataset Information

Inter-network connectivity and amyloid-beta linked to cognitive decline in preclinical Alzheimer's disease: a longitudinal cohort study.

ABSTRACT:

Background

Amyloid-beta (A?) has a dose-response relationship with cognition in healthy adults. Additionally, the levels of functional connectivity within and between brain networks have been associated with cognitive performance in healthy adults. Aiming to explore potential synergistic effects, we investigated the relationship of inter-network functional connectivity, A? burden, and memory decline among healthy individuals and individuals with preclinical, prodromal, or clinical Alzheimer's disease.

Methods

In this longitudinal cohort study (ADNI2), participants (55-88 years) were followed for a maximum of 5 years. We included cognitively healthy participants and patients with mild cognitive impairment (with or without elevated A?) or Alzheimer's disease. Associations between memory decline, A? burden, and connectivity between networks across the groups were investigated using linear and curvilinear mixed-effects models.

Results

We found a synergistic relationships between inter-network functional connectivity and A? burden on memory decline. Dose-response relationships between A? and memory decline varied as a function of directionality of inter-network connectivity across groups. When inter-network correlations were negative, the curvilinear mixed-effects models revealed that higher A? burden was associated with greater memory decline in cognitively normal participants, but when inter-network correlations were positive, there was no association between the magnitude of A? burden and memory decline. Opposite patterns were observed in patients with mild cognitive impairment. Combining negative inter-network correlations with A? burden can reduce the required sample size by 88% for clinical trials aiming to slow down memory decline.

Conclusions

The direction of inter-network connectivity provides additional information about A? burden on the rate of expected memory decline, especially in the preclinical phase. These results may be valuable for optimizing patient selection and decreasing study times to assess efficacy in clinical trials.

SUBMITTER: Van Hooren RWE

PROVIDER: S-EPMC6114059 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Publications

Inter-network connectivity and amyloid-beta linked to cognitive decline in preclinical Alzheimer's disease: a longitudinal cohort study.

Van Hooren Roy W E RWE Riphagen Joost M JM Jacobs Heidi I L HIL

Alzheimer's research & therapy 20180828 1

<h4>Background</h4>Amyloid-beta (Aβ) has a dose-response relationship with cognition in healthy adults. Additionally, the levels of functional connectivity within and between brain networks have been associated with cognitive performance in healthy adults. Aiming to explore potential synergistic effects, we investigated the relationship of inter-network functional connectivity, Aβ burden, and memory decline among healthy individuals and individuals with preclinical, prodromal, or clinical Alzhei ...[more]

PMID: 30153858

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Project description:As Alzheimer disease (AD) research moves to intervene in presymptomatic phases of the disease, we must develop outcome measures sensitive to the earliest disease-related changes.To demonstrate the feasibility of a cognitive composite outcome for clinically normal elderly participants with evidence of AD pathology using the ADCS Preclinical Alzheimer Cognitive Composite (ADCS-PACC). The ADCS-PACC combines tests that assess episodic memory, timed executive function, and global cognition. The ADCS-PACC is the primary outcome measure for the first clinical trial in preclinical AD (ie, the Anti-Amyloid Treatment in Asymptomatic Alzheimer's study).With the ADCS-PACC, we derive pilot estimates of amyloid-related decline using data from 2 observational studies conducted in North America and another conducted in Australia. The participants analyzed had normal cognition and mean ages of 75.81, 71.37, and 79.42 years across the 3 studies.For the 2 studies that collected data on A? levels (ADNI and AIBL), we estimate decline in a preclinical AD "A?-positive" placebo group and compare them with an "A?-negative" group. For the study that did not include data on A? levels (the ADCS Prevention Instrument [ADCS-PI] study), we grouped participants by the presence of APOE-?4 and by clinical progression.In ADNI, A?-positive participants showed more decline than did A?-negative participants with regard to the ADCS-PACC score at 24 months (mean [SE] difference, -1.239 [0.522] [95% CI, -2.263 to -0.215]; P?=?.02). In AIBL, the mean (SE) difference is significant at both 18 months (-1.009 [0.406] [95% CI, -1.805 to -0.213]; P?=?.01) and 36 months (-1.404 [0.452] [95% CI, -2.290 to -0.519]; P?=?.002). In the ADCS-PI study, APOE-?4 allele carriers performed significantly worse on the ADCS-PACC at 24 months (mean [SE] score, -0.742 [0.294] [95% CI, -1.318 to -0.165]; P?=?.01) and 36 months (-1.531 [0.469] [95% CI, -2.450 to -0.612]; P?=?.001). In the ADCS-PI study, cognitively normal participants who progress from a global Clinical Dementia Rating score of 0 are significantly worse on the ADCS-PACC than cognitively normal participants who are stable with a global Clinical Dementia Rating score of 0 at months 12, 24, and 36 (mean [SE] ADCS-PACC score, -4.471 [0.702] [95% CI, -5.848 to -3.094]; P?<?.001). Using pilot estimates of variance and assuming 500 participants per group with 30% attrition and a 5% ? level, we project 80% power to detect effects in the range of ??=?0.467 to 0.733 on the ADCS-PACC.Analyses of at-risk cognitively normal populations suggest that we can reliably measure the first signs of cognitive decline with the ADCS-PACC. These analyses also suggest the feasibility of secondary prevention trials.

Dataset Information

Inter-network connectivity and amyloid-beta linked to cognitive decline in preclinical Alzheimer's disease: a longitudinal cohort study.

Background

Methods

Results

Conclusions

Publications

Inter-network connectivity and amyloid-beta linked to cognitive decline in preclinical Alzheimer's disease: a longitudinal cohort study.

Similar Datasets

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