Non-linear Relationship Between Plasma Amyloid-? 40 Level and Cognitive Decline in a Cognitively Normal Population
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ABSTRACT:
SUBMITTER: Gao F
PROVIDER: S-EPMC7516983 | biostudies-literature | 2020 Jan
REPOSITORIES: biostudies-literature
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Project description:Among cognitively normal individuals, elevated brain amyloid (defined by cerebrospinal fluid assays or positron emission tomography regional summaries) can be related to risk for later Alzheimer-related cognitive decline.To characterize and quantify the risk for Alzheimer-related cognitive decline among cognitively normal individuals with elevated brain amyloid.Exploratory analyses were conducted with longitudinal cognitive and biomarker data from 445 cognitively normal individuals in the United States and Canada. Participants were observed from August 23, 2005, to June 7, 2016, for a median of 3.1 years (interquartile range, 2.0-4.2 years; maximum follow-up, 10.3 years) as part of the Alzheimer's Disease Neuroimaging Initiative (ADNI).Individuals were classified at baseline as having normal (n?=?243) or elevated (n?=?202) brain amyloid using positron emission tomography amyloid imaging or a cerebrospinal fluid assay of amyloid ?.Outcomes included scores on the Preclinical Alzheimer Cognitive Composite (PACC; a sum of 4 baseline standardized z scores, which decreases with worse performance), Mini-Mental State Examination (MMSE; 0 [worst] to 30 [best] points), Clinical Dementia Rating Sum of Boxes (CDR-Sum of Boxes; 0 [best] to 18 [worst] points), and Logical Memory Delayed Recall (0 [worst] to 25 [best] story units).Among the 445 participants (243 with normal amyloid, 202 with elevated amyloid), mean (SD) age was 74.0 (5.9) years, mean education was 16.4 (2.7) years, and 52% were women. The mean score for PACC at baseline was 0.00 (2.60); for MMSE, 29.0 (1.2); for CDR-Sum of Boxes, 0.04 (0.14); and for Logical Memory Delayed Recall, 13.1 (3.3). Compared with the group with normal amyloid, those with elevated amyloid had worse mean scores at 4 years on the PACC (mean difference, 1.51 points [95% CI, 0.94-2.10]; P?<?.001), MMSE (mean difference, 0.56 points [95% CI, 0.32-0.80]; P?<?.001), and CDR-Sum of Boxes (mean difference, 0.23 points [95% CI, 0.08-0.38]; P?=?.002). For Logical Memory Delayed Recall, between-group score was not statistically significant at 4 years (mean difference, 0.73 story units [95% CI, -0.02 to 1.48]; P?=?.056).Exploratory analyses of a cognitively normal cohort followed up for a median of 3.1 years suggest that elevation in baseline brain amyloid level, compared with normal brain amyloid level, was associated with higher likelihood of cognitive decline, although the findings are of uncertain clinical significance. Further research is needed to assess the clinical importance of these differences and measure longer-term associations.
| S-EPMC5736301 | biostudies-literature
Project description:OBJECTIVE:Public health recommendations promote social engagement to reduce risk of cognitive decline and dementia. The objective of this study was to evaluate the longitudinal associations of social engagement and cognition in cognitively normal older adults with varying levels of neocortical amyloid-β, the Alzheimer's disease (AD) pathologic marker. METHODS:Two hundred seventeen men and women, age 63-89 underwent assessments for social engagement and cognitive performance at baseline and 3 years later using the Community Healthy Activities Model Program for Seniors questionnaire and the Preclinical Alzheimer Cognitive Composite (PACC). Amyloid-β was measured using Pittsburgh compound B-PET. Multivariable regression models estimated main and interactive effects of baseline social engagement and amyloid-β on cognitive change. Reciprocal models estimated main and interactive effects of baseline cognitive performance and amyloid-β on change in social engagement. RESULTS:Baseline social engagement was associated with PACC change as a modifier but not as a main effect. Lower baseline social engagement was associated with greater amyloid-β-related PACC decline, while higher baseline social engagement was associated with relative preservation of PACC scores (β = 0.05, p = 0.03). Reciprocally, lower baseline PACC score was associated with decline in social engagement score (β = 1.1, p = 0.02). This association was not modified by amyloid-β, and there was no direct association of amyloid-β with change in social engagement. CONCLUSIONS:Low social engagement may be a marker of neurocognitive vulnerability in older adults who are cognitively normal but have evidence of AD pathophysiologic change. Understanding changes in social engagement in older adults may lead to earlier diagnosis of AD and advances in evidence-based prevention and treatment.
| S-EPMC6778491 | biostudies-literature
Project description:ObjectiveTo investigate the relationship between amyloid-β (Aβ) deposition and markers of brain structure on cognitive decline in oldest-old individuals with initial normal cognition.MethodsWe studied cognitive functioning in four domains at baseline and change over time in fifty-seven cognitively intact individuals from the EMIF-AD 90+ study. Predictors were Aβ status determined by [18 F]-flutemetamol PET (normal = Aβ - vs. abnormal = Aβ+), cortical thickness in 34 regions and hippocampal volume. Mediation analyses were performed to test whether effects of Aβ on cognitive decline were mediated by atrophy of specific anatomical brain areas.ResultsSubjects had a mean age of 92.7 ± 2.9 years, of whom 19 (33%) were Aβ+. Compared to Aβ-, Aβ+ individuals showed steeper decline on memory (β ± SE = -0.26 ± 0.09), and processing speed (β ± SE = -0.18 ± 0.08) performance over 1.5 years (P < 0.05). Furthermore, medial and lateral temporal lobe atrophy was associated with steeper decline in memory and language across individuals. Mediation analyses revealed that part of the memory decline observed in Aβ+ individuals was mediated through parahippocampal atrophy.InterpretationThese results show that Aβ abnormality even in the oldest old with initially normal cognition is not part of normal aging, but is associated with a decline in cognitive functioning. Other pathologies may also contribute to decline in the oldest old as cortical thickness predicted cognitive decline similarly in individuals with and without Aβ pathology.
| S-EPMC7886045 | biostudies-literature
Project description:Plasma amyloid ? (A?) peptides have been previously studied as candidate biomarkers to increase recruitment efficiency in secondary prevention clinical trials for Alzheimer's disease.Free and total A?42/40 plasma ratios (FP42/40 and TP42/40, respectively) were determined using ABtest assays in cognitively normal subjects from the Australian Imaging, Biomarker and Lifestyle Flagship Study. This population was followed-up for 72 months and their cortical A? burden was assessed with positron emission tomography.Cross-sectional and longitudinal analyses showed an inverse association of A?42/40 plasma ratios and cortical A? burden. Optimized as a screening tool, TP42/40 reached 81% positive predictive value of high cortical A? burden, which represents 110% increase over the population prevalence of cortical A? positivity.These findings support the use of plasma A?42/40 ratios as surrogate biomarkers of cortical A? deposition and enrichment tools, reducing the number of subjects submitted to invasive tests and, consequently, recruitment costs in clinical trials targeting cognitively normal individuals.
| S-EPMC5602863 | biostudies-other
Project description:IntroductionThis meta-analysis aimed to characterize the nature and magnitude of amyloid (Aβ)-related cognitive impairment and decline in cognitively normal (CN) older individuals.MethodMEDLINE Ovid was searched from 2012 to June 2016 for studies reporting relationships between cerebrospinal fluid or positron emission tomography (PET) Aβ levels and cognitive impairment (cross-sectional) and decline (longitudinal) in CN older adults. Neuropsychological data were classified into domains of episodic memory, executive function, working memory, processing speed, visuospatial function, semantic memory, and global cognition. Type of Aβ measure, how Aβ burden was analyzed, inclusion of control variables, and clinical criteria used to exclude participants, were considered as moderators. Random-effects models were used for analyses with effect sizes expressed as Cohen's d.ResultsA total of 38 studies met inclusion criteria contributing 30 cross-sectional (N = 5005) and 14 longitudinal (N = 2584) samples. Aβ-related cognitive impairment was observed for global cognition (d = 0.32), visuospatial function (d = 0.25), processing speed (d = 0.18), episodic memory, and executive function (both d's = 0.15), with decline observed for global cognition (d = 0.30), semantic memory (d = 0.28), visuospatial function (d = 0.25), and episodic memory (d = 0.24). Aβ-related impairment was moderated by age, amyloid measure, type of analysis, and inclusion of control variables and decline moderated by amyloid measure, type of analysis, inclusion of control variables, and exclusion criteria used.DiscussionCN older adults with high Aβ show a small general cognitive impairment and small to moderate decline in episodic memory, visuospatial function, semantic memory, and global cognition.
| S-EPMC5315443 | biostudies-literature
Project description:ImportancePlasma measurement of amyloid-β (Aβ) peptides has been associated with cognitive function, but evidence of its ability to identify cognitive decline is still scarce.ObjectiveTo investigate the associations between plasma Aβ42/40 and cognitive decline over time among community-dwelling older adults with subjective memory concerns.Design, setting, and participantsThis multicenter cohort study used data from volunteers in the 5-year study Multidomain Alzheimer Preventive Trial (MAPT). Participants were aged 70 years or older and observed for a median (interquartile range) of 3.9 (2.0-4.0) years. Recruitment of participants started in May 2008 and ended in February 2011. Follow-up ended in April 2016. Data analysis was conducted from April to October 2020.ExposurePlasma Aβ42 and Aβ40 were measured at 12 months for 448 participants (92.8%) and at 24 months for the rest. The moment of Aβ assessment was defined as the baseline for this study.Main outcomes and measuresCognitive function was assessed at 12, 24, 36, 48, and 60 months by a composite cognitive score based on 4 tests; Mini Mental State Examination (MMSE); Clinical Dementia Rating, sum of boxes; and Alzheimer Disease Cooperative Study-Activities of Daily Living. Mixed-effect linear regressions were performed.ResultsA total of 483 participants (median [IQR] age, 76.0 [73.0-80.0]; 286 [59.2%] women) were analyzed. Of them, 161 (33.3%) were classified as low plasma Aβ42/40 (≤0.107). After adjusting for age, sex, education, body mass index, Geriatric Depression Scale score, apolipoprotein E ε4 genotype, and MAPT intervention groups, low plasma Aβ42/40 was associated with more pronounced decline in composite cognitive score (adjusted between-group mean difference: -0.20, 95% CI, -0.34 to -0.07; P = .004) and decline in MMSE score (adjusted between-group mean difference: -0.59; 95% CI, -1.07 to -0.11; P = .02) during the follow-up period compared with the group with an Aβ42/40 ratio greater than 0.107.Conclusions and relevanceIn this study, low plasma Aβ42/40 was associated with more pronounced decline in cognitive function (measured by multiple outcomes) over time. Findings suggest that plasma Aβ42/40 may be used to identify people at risk of cognitive decline, being an alternative to more complex and expensive measures, such as positron emission tomography imaging or cerebrospinal fluid measurement.
| S-EPMC7747018 | biostudies-literature
Project description:.BackgroundGenetic variation in Spondin-1, specifically rs11023139, has been associated with reduced rates of cognitive decline in individuals with Alzheimer's disease.ObjectiveThe aim of this study was to assess whether the association was present in cognitively normal older adults.MethodsLongitudinal cognitive decline was investigated using linear mixed modelling in a cohort of 590 cognitively normal older adults enrolled in the Australian Imaging, Biomarkers and Lifestyle Study.ResultsNo independent effect of Spondin-1 rs11023139 on cognitive decline was observed. However, significant associations were observed for the interaction between Apolipoprotein E (APOE) ɛ4 and rs11023139 in individuals with high amyloid-β burden. APOE ɛ4/rs11023139-A carriers declined significantly faster than APOE ɛ4/rs11023139-G_G carriers in measures of global cognition (p = 0.011) and verbal episodic memory (p = 0.020).ConclusionThese results suggest that carriage of the Spondin-1 rs11023139-A allele significantly contributes to a worsening of cognitive performance in APOE ɛ4 cognitively normal older adults with a high neocortical amyloid-β burden.
| S-EPMC7990462 | biostudies-literature
Project description:IntroductionUnderstanding the associations among depression, subjective cognitive decline, and prodromal Alzheimer's disease (AD) has important implications for both depression and dementia screening in older adults. The Geriatric Depression Scale (GDS) is a depression screening tool for older adults that queries memory concerns. To determine whether depression symptoms on the GDS (15-item version), including self-reported memory problems, differ by levels of brain amyloid beta (Aβ), a pathological hallmark of early stage AD, we investigated potential measurement bias with regard to Aβ level. We also examined measurement bias attributable to level of cognitive functioning and sex as positive controls.MethodsWe examined 3961 cognitively normal older adults from the A4/LEARN Study. We used the MIMIC (multiple indicators, multiple causes) approach to detect measurement bias.ResultsWe found measurement bias with small-to-moderate range effect sizes in several GDS-15 items with respect to Aβ level, cognitive functioning, and sex. There was negligible impact of measurement bias attributable to Aβ level on overall depressive symptom level.DiscussionGDS-15 item responses are sensitive to Aβ burden, cognitive functioning, and sex over and above what would be expected given the effect of those factors on depressive symptom severity overall. However, these direct effects for GDS item measurement bias are of small magnitude and do not appreciably impact the validity of inferences about depression based on the GDS-15.
| S-EPMC7521597 | biostudies-literature
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.
| S-EPMC7099624 | biostudies-literature
Project description:Blood-based biomarkers could prove useful to predict Alzheimer's disease core pathologies in advance of clinical symptoms. Implementation of such biomarkers requires a solid understanding of their long-term dynamics and the contribution of confounding to their association with Alzheimer's disease pathology. Here we assess the value of plasma amyloid-β1-42/1-40, phosphorylated-tau181 and glial fibrillary acidic protein to detect early Alzheimer's disease pathology, accounting for confounding by genetic and early environmental factors. Participants were 200 monozygotic twins, aged ≥60 years with normal cognition from the european medical information framework for Alzheimer's disease study. All twins had amyloid-β status and plasma samples available at study enrolment. For 80 twins, additional plasma samples were available that had been collected approximately 10 years prior to amyloid-β status assessment. Single-molecule array assays were applied to measure amyloid-β1-42/1-40, phosphorylated-tau181 and glial fibrillary acidic protein. Predictive value of and longitudinal change in these biomarkers were assessed using receiver operating characteristic curve analysis and linear mixed models. Amyloid pathology could be predicted using blood-based biomarkers obtained at the time of amyloid status assessment (amyloid-β1-42/1-40: area under the curve = 0.65, P = 0.01; phosphorylated-tau181: area under the curve = 0.84, P < 0.001; glial fibrillary acidic protein: area under the curve = 0.74, P < 0.001), as well as using those obtained 10 years prior to amyloid status assessment (amyloid-β1-42/1-40: area under the curve = 0.69, P = 0.03; phosphorylated-tau181: area under the curve = 0.92, P < 0.001; glial fibrillary acidic protein: area under the curve = 0.84, P < 0.001). Longitudinally, amyloid-β1-42/1-40 levels decreased [β (SE) = -0.12 (0.01), P < 0.001] and phosphorylated-tau181 levels increased [β (SE) = 0.02 (0.01), P = 0.004]. Amyloid-β-positive individuals showed a steeper increase in phosphorylated-tau181 compared with amyloid-β-negative individuals [β (SE) = 0.06 (0.02), P = 0.004]. Also amyloid-β-positive individuals tended to show a steeper increase in glial fibrillary acidic protein [β (SE) = 0.04 (0.02), P = 0.07]. Within monozygotic twin pairs, those with higher plasma phosphorylated-tau181 and lower amyloid-β1-42/1-40 levels were more likely to be amyloid-β positive [β (SE) = 0.95 (0.26), P < 0.001; β (SE) = -0.28 (0.14), P < 0.05] indicating minimal contribution of confounding by genetic and early environmental factors. Our data support the use of amyloid-β1-42/1-40, phosphorylated-tau181 and glial fibrillary acidic protein as screening tools for Alzheimer's disease pathology in the normal aging population, which is of importance for enrolment of high-risk subjects in secondary, or even primary, prevention trials. Furthermore, these markers show potential as low-invasive monitoring tool of disease progression and possibly treatment effects in clinical trials.
| S-EPMC9942541 | biostudies-literature