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ImportanceCerebral amyloid-β aggregation is an early pathological event in Alzheimer disease (AD), starting decades before dementia onset. Estimates of the prevalence of amyloid pathology in persons without dementia are needed to understand the development of AD and to design prevention studies.ObjectiveTo use individual participant data meta-analysis to estimate the prevalence of amyloid pathology as measured with biomarkers in participants with normal cognition, subjective cognitive impairment (SCI), or mild cognitive impairment (MCI).Data sourcesRelevant biomarker studies identified by searching studies published before April 2015 using the MEDLINE and Web of Science databases and through personal communication with investigators.Study selectionStudies were included if they provided individual participant data for participants without dementia and used an a priori defined cutoff for amyloid positivity.Data extraction and synthesisIndividual records were provided for 2914 participants with normal cognition, 697 with SCI, and 3972 with MCI aged 18 to 100 years from 55 studies.Main outcomes and measuresPrevalence of amyloid pathology on positron emission tomography or in cerebrospinal fluid according to AD risk factors (age, apolipoprotein E [APOE] genotype, sex, and education) estimated by generalized estimating equations.ResultsThe prevalence of amyloid pathology increased from age 50 to 90 years from 10% (95% CI, 8%-13%) to 44% (95% CI, 37%-51%) among participants with normal cognition; from 12% (95% CI, 8%-18%) to 43% (95% CI, 32%-55%) among patients with SCI; and from 27% (95% CI, 23%-32%) to 71% (95% CI, 66%-76%) among patients with MCI. APOE-ε4 carriers had 2 to 3 times higher prevalence estimates than noncarriers. The age at which 15% of the participants with normal cognition were amyloid positive was approximately 40 years for APOE ε4ε4 carriers, 50 years for ε2ε4 carriers, 55 years for ε3ε4 carriers, 65 years for ε3ε3 carriers, and 95 years for ε2ε3 carriers. Amyloid positivity was more common in highly educated participants but not associated with sex or biomarker modality.Conclusions and relevanceAmong persons without dementia, the prevalence of cerebral amyloid pathology as determined by positron emission tomography or cerebrospinal fluid findings was associated with age, APOE genotype, and presence of cognitive impairment. These findings suggest a 20- to 30-year interval between first development of amyloid positivity and onset of dementia.

White matter hyperintensities (WMHs) are associated with vascular risk and Alzheimer's disease. In this study, we examined relations between WMH load and distribution, amyloid pathology and vascular risk in 339 controls and cases with either subjective (SCD) or mild cognitive impairment (MCI). Regional deep (DWMH) and periventricular (PWMH) WMH loads were determined using an automated algorithm. We stratified on Aβ1-42 pathology (Aβ+/−) and analyzed group differences, as well as associations with Framingham Risk Score for cardiovascular disease (FRS-CVD) and age. Occipital PWMH (p = 0.001) and occipital DWMH (p = 0.003) loads were increased in SCD-Aβ+ compared with Aβ− controls. In MCI-Aβ+ compared with Aβ− controls, there were differences in global WMH (p = 0.003), as well as occipital DWMH (p = 0.001) and temporal DWMH (p = 0.002) loads. FRS-CVD was associated with frontal PWMHs (p = 0.003) and frontal DWMHs (p = 0.005), after adjusting for age. There were associations between global and all regional WMH loads and age. In summary, posterior WMH loads were increased in SCD-Aβ+ and MCI-Aβ+ cases, whereas frontal WMHs were associated with vascular risk. The differences in WMH topography support the use of regional WMH load as an early-stage marker of etiology. [ABSTRACT FROM AUTHOR]

Introduction: Amyloid beta 1-43 (Aβ43), with its additional C-terminal threonine residue, is hypothesized to play a role in early Alzheimer's disease pathology possibly different from that of amyloid beta 1-42 (Aβ42). Cerebrospinal fluid (CSF) Aβ43 has been suggested as a potential novel biomarker for predicting conversion from mild cognitive impairment (MCI) to dementia in Alzheimer's disease. However, the relationship between CSF Aβ43 and established imaging biomarkers of Alzheimer's disease has never been assessed. Materials and Methods: In this observational study, CSF Aβ43 was measured with ELISA in 89 subjects; 34 with subjective cognitive decline (SCD), 51 with MCI, and four with resolution of previous cognitive complaints. All subjects underwent structural MRI; 40 subjects on a 3T and 50 on a 1.5T scanner. Forty subjects, including 24 with SCD and 12 with MCI, underwent 18F-Flutemetamol PET. Seventy-eight subjects were assessed with 18F-fluorodeoxyglucose PET (21 SCD/7 MCI and 11 SCD/39 MCI on two different scanners). Ten subjects with SCD and 39 with MCI also underwent diffusion tensor imaging. Results: Cerebrospinal fluid Abβ3 was both alone and together with p-tau a significant predictor of the distinction between SCD and MCI. There was a marked difference in CSF Aβ43 between subjects with 18F-Flutemetamol PET scans visually interpreted as negative (37 pg/ml, n = 27) and positive (15 pg/ml, n = 9), p < 0.001. Both CSF Aβ43 and Aβ42 were negatively correlated with standardized uptake value ratios for all analyzed regions; CSF Aβ43 average rho -0.73, Aβ42 -0.74. Both CSF Aβ peptides correlated significantly with hippocampal volume, inferior parietal and frontal cortical thickness and axial diffusivity in the corticospinal tract. There was a trend toward CSF Aβ42 being better correlated with cortical glucose metabolism. None of the studied correlations between CSF Aβ43/42 and imaging biomarkers were significantly different for the two Aβ peptides when controlling for multiple testing. Conclusion: Cerebrospinal fluid Aβ43 appears to be strongly correlated with cerebral amyloid deposits in the same way as Aβ42, even in non-demented patients with only subjective cognitive complaints. Regarding imaging biomarkers, there is no evidence from the present study that CSF Aβ43 performs better than the classical CSF biomarker Aβ42 for distinguishing SCD and MCI. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) neuropathology is associated with neuroinflammation, but there are few useful biomarkers. Mutant variants of triggering receptor expressed on myeloid cells 2 (TREM2) have recently been linked to late-onset AD and other neurodegenerative disorders. TREM2, a microglial receptor, is involved in innate immunity. A cleaved fragment, soluble TREM2 (sTREM2), is present in the cerebrospinal fluid (CSF). Methods: We developed and used a novel enzyme-linked immunosorbent assay to investigate the potential value of CSF sTREM2 as an AD biomarker in two independent cohorts: an AD/mild cognitive impairment (MCI)/control cohort (n = 100) and an AD/control cohort (n =5 0 ) . Results: We found no significant difference in sTREM2 levels between groups of controls and patients with AD or MCI. However, among all controls there was a positive correlation between sTREM2 and age (Spearman rho = 0.50; p < 0.001; n = 75). In the AD/MCI/control cohort, CSF sTREM2 correlated positively with total Tau (T-tau) (Spearman rho 0.57; p < 0.001; n = 50), phosphorylated Tau (P-tau) (Spearman rho 0.63; p < 0.001; n = 50) and amyloid-β1-42 (Aβ42) (Spearman rho 0.35; p = 0.01; n = 50) in control subjects. Among controls with a CSF Aβ42 above a cut-off value (700 pg/ml) in this cohort, the positive correlation between sTREM2 and Aβ42 was stronger (Spearman rho = 0.44; p = 0.002; n = 46). Conclusions: sTREM2 in CSF correlates with aging in controls, and with the neurodegenerative markers CSF T-tau/P-tau among controls who are negative for AD CSF core biomarkers Aβ42, T-tau or P-tau. [ABSTRACT FROM AUTHOR]