Search

Background: Alzheimer's disease (AD) is a multifactorial disease characterised by a long period of neuronal loss which manifests clinically as cognitive decline and ultimately dementia. Understanding the nature and magnitude of cognitive decline prior to dementia is critical to understanding the disease course. Here we quantify change in six cognitive composite scores to compare their temporal sequence and rates of change early in the AD disease course. Method: Amyloid‐beta positive (Aβ+) cognitively unimpaired (CU), MCI and AD participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of ageing with ≥three study visits (N = 857), were used to derive composite scores for executive function, language, attention and processing, recognition, visuospatial, and a general composite used in clinical trials (AIBL‐PACC). A multivariate method for combining cognitive change trajectory curves was used to place each composite score trajectory in a common numerical space. Using the mean AIBL‐PACC scores for the prodromal group (MCI‐Aβ+) as a reference, change over a three‐year period for each composite was estimated. Given the AIBL requirement for a minimum 1.5 SD change in two or more cognitive domains to justify progression to MCI/AD, disease time was set with the zero point at a ‐1.5 AIBL‐PACC score, representing a 1.5 SD decline in AIBL‐PACC from the mean CU Ab‐ population at baseline. Result: The AIBL‐PACC, language and visuospatial functioning scores showed the steepest trajectories indicating AD related decline in these scores was fastest (Figure 1). AIBL‐PACC reached the ‐1.5 point on the y‐axis first followed closely by memory recognition, with steeper trajectory of decline for the AIBL‐PACC across the age range. Focusing on AIBL‐PACC, it took 2.15 years to transition from ‐1.5 to the mean of the prodromal group (‐1.87). At five years past the start of the prodromal stage, the data suggests a drop in the AIBL‐PACC to ‐2.54, an approximate decline of ∼0.22 points per year. Conclusion: This is the first presentation of a novel multivariate disease trajectory method examining expected change across the AD continuum among Aβ+ persons. A 3‐year change in the PACC composite demonstrated here will be relevant to measure disease progression during clinical trials. [ABSTRACT FROM AUTHOR]

Background: Cerebral microbleeds (CMBs) are common in the elderly population and are associated with cognitive decline. The aim of the current study was to examine the association between CMBs and cerebral amyloid pathology in cognitively unimpaired (CU) and cognitively impaired (CI) individuals included in the Amyloid Biomarker Study. Method: We included 2550 CU and 1002 CI participants from 12 cohorts of the Amyloid Biomarker Study. Presence of amyloid pathology was determined based on Aß42 levels in CSF (n = 2873) or amyloid‐PET (n = 679) using data‐driven or center‐specific cutoffs. CMBs were assessed on in vivo MRI and were classified as present (≥1) or absent. The association of amyloid pathology with CMBs and its dependency on age, sex, APOE‐e4 carriership and hypertension was assessed using generalized‐estimating‐equations. Result: Thirty‐seven percent of participants were amyloid positive, 38% were APOE‐e4 carrier, 54% were female, 30% had hypertension and 17% had CMBs (20% of the amyloid positive and 16% of the amyloid negative group, respectively). The mean age was 66.7 years (SD9.2). In CU participants, there was no association between amyloid pathology and CMBs. In CI individuals, CMB prevalence was associated with amyloid pathology depending on age (p = 0.044). At younger ages (<75 years), CMBs were more common in amyloid positive rather than amyloid negative participants while at older ages, amyloid negative participants had CMBs more often. However, the interaction between amyloid status and age became insignificant when hypertension was considered. CMB prevalence was associated with amyloid pathology depending on hypertension (p = 0.006). In CI participants without hypertension, CMBs were more common in those that were amyloid positive rather than amyloid negative. In CI participants with hypertension, there was no significant difference in CMB prevalence between the amyloid positive and negative groups (Figure 1). Sex and APOE‐e4 status did not affect the observed associations between amyloid pathology and CMBs in participants with CI. Conclusion: CMB prevalence is associated with amyloid pathology and this association is dependent on hypertension. Knowledge on the background prevalence of CMBs considering AD biomarker and vascular risk factor status is needed to inform clinical trial design and safety evaluation of AD therapies. [ABSTRACT FROM AUTHOR]

Background: Prevalence estimates of amyloid positivity in persons across the AD clinical spectrum are important to reduce screen failure rates and improve recruitment efficiency in anti‐amyloid trials. We have previously estimated the prevalence according to age, sex, education and APOE genotype. It is however unknown whether these prevalence estimates generalize to diverse ethnoracial groups. We here aim to estimate the prevalence of amyloid abnormality in Black, White and Asian persons without dementia and examine associations with age, sex, educational level and APOE‐e4 carrier status. Method: We selected 7,419 participants (6,083 with normal cognition; 1,336 with MCI) from 9 Amyloid Biomarker Study cohorts, including 291 Black, 6,310 White and 818 Asian participants. Amyloid positivity was determined with a PET (n = 5,714) or CSF (n = 1,705) biomarker, using data‐driven or study‐specific cutoffs. Generalized estimating equations were used to estimate the age‐related prevalence by ethnoracial group and to evaluate moderation by APOE‐e4 carrier status while adjusting for sex and education. Result: The mean age was 70.9+‐7.4 years, 3,848 (57%) were women, and 20% were APOE‐e4 carriers. In persons with normal cognition, the age‐related prevalence of amyloid positivity was higher for White (25%) than for Black (17%) and Asian (16%) participants (p = 0.016). Among APOE‐e4 carriers with normal cognition, the prevalence of amyloid abnormality was again higher for White (46%) than for Black (29%) and Asian (30%) participants (Asian vs Black p‐value = 0.046, Asian vs White p‐value<0.001, Black vs White p‐value<0.001). Among APOE‐e4 noncarriers, no differences among the ethnoracial groups were identified (p = 0.56). In persons with MCI, White (59%) and Asian (60%) participants had abnormal amyloid more often than Black participants (43%; p<0.001). Ethnoracial differences were similar for APOE‐e4 carriers and noncarriers with MCI. Conclusion: In persons with normal cognition, the prevalence of amyloid abnormality among APOE‐e4 carriers was ∼15% higher for White than for Black and Asian participants, while among APOE‐e4 noncarriers no ethnoracial differences were found. In persons with MCI, both White and Asian participants ∼15% more often had abnormal amyloid than Black participants, irrespective of APOE‐e4 carrier status. Ethnoracial status may be an important factor to consider in the design of AD clinical trials. [ABSTRACT FROM AUTHOR]

Background: We have updated our previous amyloid positivity prevalence estimates (Jansen, 2015; Ossenkoppele, 2015; Table 1) with data from 19,097 individuals from 85 cohorts. We tested if prevalence estimates differed for positron emission tomography (PET) or cerebrospinal fluid (CSF) amyloid. We calculated data‐driven CSF cut‐points as previous studies suggested a drift in Innotest‐assay performance. Method: We included 9,908 participants with normal cognition (CN); 1,542 with subjective cognitive decline (SCD); 5,405 with mild cognitive impairment (MCI); and 2,260 with clinical Alzheimer's disease (AD) dementia. 10,139 participants had an amyloid‐PET measure and 8,958 participants had an amyloid‐CSF measure. Amyloid‐ß aggregation was originally dichotomized as normal or abnormal according to study‐specific cut‐points, and we defined data‐driven CSF cut‐points using Gaussian mixture modelling. Generalized‐estimating‐equations adjusting for within‐study clustering of individuals were used to estimate amyloid positivity prevalence according to age, cognitive status, and biomarker modality and compared original with updated cut‐points. Result: Amyloid positivity prevalence was higher with older age and advancing disease severity. Using original cut‐points as provided by the cohort, the prevalence of amyloid positivity at the median age of 70 was similar for PET and CSF estimates for CN (24%), SCD (26%), and MCI (51%), and was higher in PET (87%) than CSF (79%) for clinical AD dementia. Using the data‐driven CSF cut‐points, the prevalence of amyloid positivity was higher for CSF‐based estimates than PET‐based estimates in CN (CSF 33%, PET 24%), SCD (CSF 36%, PET 27%), and MCI (CSF 60%, PET 49%), but comparable in CSF and PET in clinically diagnosed AD dementia (CSF 83%, PET 87) (Table 1, Figure 1). Conclusion: We provide updated amyloid positivity estimates from the Amyloid Biomarker Study. CSF‐based estimates using a data‐driven approach resulted in higher estimates (up to 11% higher) in people without clinical AD dementia than PET‐based estimates. Whether CSF‐based estimates are more sensitive than PET‐based estimates for amyloid pathology among people without dementia needs to be explored in cohorts that use both modalities. These updated estimates may be useful to understand potential eligible patient population sizes for anti‐amyloid therapies and to inform recruitment strategies for clinical trials investigating anti‐amyloid therapies. [ABSTRACT FROM AUTHOR]

Background: The relationship between lifestyle factors and Alzheimer's disease pathophysiology is not well understood. The aim of this study was to assess the cross‐sectional association between lifestyle factors and amyloid abnormality in individuals with normal cognition (NC) and mild cognitive impairment (MCI). Method: We selected 39 cohorts from the Amyloid Biomarker Study. Self‐reported lifestyle data were available for 8924 participants with NC and 2403 participants with MCI. Amyloid abnormality was determined with amyloid‐PET (center‐specific cutoffs) or with aß42 level in CSF (data‐driven or center‐specific cutoffs). Lifestyle data was harmonized across cohorts and dichotomized into ever smoked yes/no, current alcohol consumption yes/no, currently physically active yes/no and current sleep problems yes/no. Education was dichotomized into 'high' or 'low' at the median of 16 years. Generalized estimating equations with amyloid abnormality as outcome and single lifestyle factors as predictors were used. Interactions with age, sex, education, cognitive status and APOE‐e4 carrier status were assessed and these variables were added as covariates to all models. Result: Thirty‐one percent of participants were amyloid positive, 37% were ApoE‐4 carrier, and 55% were female. The mean age was 68.7 (SD8.7). Twenty‐five percent of participants smoked, 54% consumed alcohol, 30% experienced sleep problems and 25% were physically inactive. Overall, smoking was associated with a slightly increased prevalence of amyloid abnormality (2%; p = 0.03). In NC, sleep problems were unrelated to the prevalence of amyloid abnormality while in MCI, sleep problems were associated with a lower prevalence (15.3%; p<0.001). Physical activity was related to higher prevalence of amyloid abnormality in APOE‐e4 carriers (5.9%; p<0.001) while this association was not found in noncarriers. Age, sex and educational level did not modify the identified associations between lifestyle factors and amyloid abnormality. Alcohol consumption was unrelated to amyloid abnormality. Conclusion: Smoking behavior, sleep quality, and physical activity were associated with amyloid abnormality depending on cognitive and APOE‐e4 status. A better understanding of the associations between lifestyle factors and cerebral amyloid pathology in different subgroups will aid in identifying those at risk and contribute to the development of targeted intervention strategies. [ABSTRACT FROM AUTHOR]

Background: The association of amyloid abnormality with cognitive decline in persons with normal cognition (NC) and mild cognitive impairment (MCI) is important to guide AD trial design and understand prognoses. We examined the relation between amyloid abnormality and decline over time in several cognitive domains, and tested whether apolipoprotein (APOE)‐e genotype modified this association. Method: We included 3,820 persons (2,599 NC, 1,221 all‐cause MCI) from 22 Amyloid Biomarker Study cohorts, with baseline PET (n = 846) or CSF (n = 2,974) amyloid measurements available. Amyloid abnormality on PET was based on visual read or cohort‐specific cutoffs, and for CSF on cohort‐specific or data‐driven cutoffs. Global cognition was assessed by Mini‐Mental State Examination (MMSE), functional performance by Clinical Dementia Rating global scale (CDR), and memory immediate and delayed recall by verbal learning tests. We examined baseline amyloid abnormality associations with cognitive performance over time and potential modification by APOE‐e (up to 3‐way interactions) using random‐slope/random‐intercept linear mixed‐models corrected for age, sex, education with random cohort effects. Result: Mean follow‐up duration was 2.1 (range 0.5‐8) years. Baseline MMSE was worse in persons with abnormal‐amyloid compared with normal‐amyloid (NC mean difference = 0.2, p = 0.04, MCI mean difference = 2.4, p<0.001). In NC, amyloid abnormality was not associated with decline in any domain (Table 1), nor was the association influenced by APOE‐e4. In MCI, amyloid abnormality was associated with lower baseline performance and steeper decline on all domains (Table 1). In APOE‐e4‐carriers with MCI, MMSE decline was steeper than in non‐carriers (p<0.001, 1.5x steeper in amyloid‐abnormal, 3x steeper in amyloid‐normal). The rate of decline on immediate/delayed recall in MCI was higher in APOE‐e4‐carriers than non‐carriers, independent of amyloid status (p<0.001). For both NC and MCI, decline was steepest in persons with e4e4, followed by e3e4, e3e3, e2e4, and e2e3 (p = 0.001, Figure 1), independent of amyloid status. Conclusion: Amyloid abnormality was not associated with cognitive decline in persons with NC after a short‐term follow‐up. In MCI, amyloid abnormality was closely associated with cognitive decline in several domains, with an additive effect of APOE‐e on decline. These results may be relevant for future trial recruitment strategies. Future studies should examine long‐term outcomes in NC. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to assess the relationship between baseline caries experience and the restoration replacement rate in children. Methods: The 5-year New England Children's Amalgam Trial recruited 534 6- to 10-year-old children with 2 or more carious posterior teeth. The association between decay and longevity of restorations was assessed. Restorations with no follow-up (N=391) were excluded from analysis. Results: The average follow-up was 3.0±1.6 years in 489 children. Restorations with fallow-up (N=3,604) were placed in mouths with a median of 15 dfs/DFS and 8 dft/DFT The need for replacement increased significantly (P≤.001) with increasing numbers of dfs/DFS and dft/DFT After 5 years of follow-up, at least 15% of restorations in a mouth with ≥14 dfs/DFS needed replacement, compared to 9% for 2 to 5 dfs/DFS. Comparing dft/DFT after 5 years of follow-up, there was a 23% replacement rate far >12 dft/DFT compared to 10% for 2 to 3 dft/DFT Decay in the mouth had a greater association with the need for replacement due to new caries compared to replacement due to recurrent caries. Conclusion: Children with more decay at the time of restoration placement were at higher risk for replacement of restorations. [ABSTRACT FROM AUTHOR]

Case-control studies indicate that vitamins C, E, A and carotenoids decrease risk of oral premalignant lesions (OPLs) and oral cancer, but clinical trials have failed to find protective effects of β-carotene and suggest that vitamin E may increase risk. The authors prospectively evaluated the association between intake of vitamins C, E, A and carotenoids and incidence of OPL. Participants were 42,340 men in the Health Professionals Follow-up Study who provided information on supplement use and diet every 2-4 years by food frequency questionnaire. The authors confirmed 207 clinically or histopathologically diagnosed OPL events occurring between 1986 and 2002 by medical record review. Multivariate-adjusted relative risks (RR) of OPL were calculated with proportional hazards models. Total intake of vitamin C, vitamin A or carotenoids was not significantly associated with OPL risk. Dietary vitamin C was significantly associated with reduced risk (quintile 5 vs. 1, RR = 0.52, 95% CI 0.31-0.85, p [ABSTRACT FROM AUTHOR]

Background: To identify at‐risk individuals that will likely benefit from disease‐modifying treatment and improve selection for clinical trials, the role of unobjectified cognitive complaints (subjective cognitive decline, SCD) in preclinical Alzheimer's Disease (AD) needs to be refined. Although persons with SCD are at increased risk of developing dementia, it is unclear whether SCD is a symptomatic indicator of preclinical AD. We aim to identify SCD characteristics that are associative of amyloid positivity and are thus indicative of preclinical AD. Methods: We included 1,336 persons with SCD from 14 centers included in the Amyloid Biomarker Study. Amyloid‐ß deposition was measured with positron emission tomography or cerebrospinal‐fluid biomarkers and dichotomized as normal or abnormal according to study‐specific cut‐offs. SCD characteristics included were subjective decline in memory, informant confirmation of SCD, concerns about complaints, feelings of worse performance, subjective decline in attention and concentration, depression, anxiety, and setting. Generalized‐estimating‐equations adjusting for center were used to examine the association between SCD characteristics and amyloid positivity. Results: Average age was 66.5 years, 52% were female, mean education was 14.2 years, 33% was APOE‐ε4 positive, 19% was amyloid positive, 21% was t‐tau positive, and 30% was p‐tau positive. Increased age (p<0.001) and APOE‐ε4 carriership (p<0.001) were associated with a higher probability of amyloid positivity. Subjective decline in memory was associated with an increased probability of amyloid positivity (25% vs. 19% for persons without subjective decline specific to memory, mean difference 9%, p=0.036). The probability of amyloid positivity differed according to setting and was higher in a memory clinic setting (29%) compared to research setting (15%) and population setting (5%). The other SCD characteristics were not associated with amyloid positivity. Age, APOE‐ε4 carriership, subjective decline in memory, and setting remained independent predictors of amyloid positivity when analysed combined. Conclusion: Based on these analyses, age, APOE‐ε4 carriership, subjective decline in memory, and setting are characteristcs that may help identify preclinical AD in persons with SCD. [ABSTRACT FROM AUTHOR]