Search

Introduction Amyloid beta (Aβ), tau, and neurodegeneration jointly with the Alzheimer's disease (AD) risk factors affect the severity of clinical symptoms and disease progression. Methods Within 248 Aβ-positive elderly with and without cognitive impairment and dementia, partial least squares structural equation pathway modeling was used to assess the direct and indirect effects of imaging biomarkers (global Aβ-positron emission tomography [PET] uptake, regional tau-PET uptake, and regional magnetic resonance imaging-based atrophy) and risk-factors (age, sex, education, apolipoprotein E [APOE], and white-matter lesions) on cross-sectional cognitive impairment and longitudinal cognitive decline. Results Sixteen percent of variance in cross-sectional cognitive impairment was accounted for by Aβ, 46% to 47% by tau, and 25% to 29% by atrophy, although 53% to 58% of total variance in cognitive impairment was explained by incorporating mediated and direct effects of AD risk factors. The Aβ-tau-atrophy pathway accounted for 50% to 56% of variance in longitudinal cognitive decline while Aβ, tau, and atrophy independently explained 16%, 46% to 47%, and 25% to 29% of the variance, respectively. Discussion These findings emphasize that treatments that remove Aβ and completely stop downstream effects on tau and neurodegeneration would only be partially effective in slowing of cognitive decline or reversing cognitive impairment.

INTRODUCTION The Alzheimer's Disease Neuroimaging Initiative (ADNI) has accumulated 15 years of clinical, neuroimaging, cognitive, biofluid biomarker and genetic data, and biofluid samples available to researchers, resulting in more than 3500 publications. This review covers studies from 2018 to 2020. METHODS We identified 1442 publications using ADNI data by conventional search methods and selected impactful studies for inclusion. RESULTS Disease progression studies supported pivotal roles for regional amyloid beta (Aβ) and tau deposition, and identified underlying genetic contributions to Alzheimer's disease (AD). Vascular disease, immune response, inflammation, resilience, and sex modulated disease course. Biologically coherent subgroups were identified at all clinical stages. Practical algorithms and methodological changes improved determination of Aβ status. Plasma Aβ, phosphorylated tau181, and neurofilament light were promising noninvasive biomarkers. Prognostic and diagnostic models were externally validated in ADNI but studies are limited by lack of ethnocultural cohort diversity. DISCUSSION ADNI has had a profound impact in improving clinical trials for AD.

Introduction Convenient, cost-effective tests for amyloid beta (Aβ) are needed to identify those at higher risk for developing Alzheimer's disease (AD). This systematic review evaluates recent models that predict dichotomous Aβ. (PROSPERO: CRD42020144734). Methods We searched Embase and identified 73 studies from 29,581 for review. We assessed study quality using established tools, extracted information, and reported results narratively. Results We identified few high-quality studies due to concerns about Aβ determination and analytical issues. The most promising convenient, inexpensive classifiers consist of age, apolipoprotein E genotype, cognitive measures, and/or plasma Aβ. Plasma Aβ may be sufficient if pre-analytical variables are standardized and scalable assays developed. Some models lowered costs associated with clinical trial recruitment or clinical screening. Discussion Conclusions about models are difficult due to study heterogeneity and quality. Promising prediction models used demographic, cognitive/neuropsychological, imaging, and plasma Aβ measures. Further studies using standardized Aβ determination, and improved model validation are required.

Introduction Mild-Alzheimer's disease (AD) subjects without significant Aβ pathology represent a confounding finding for clinical trials because they may not progress clinically on the expected trajectory, adding variance into analyses where slowing of progression is being measured. Methods A prediction model based on structural magnetic resonance imaging (MRI) in combination with baseline demographics and clinical measurements was used to impute Aβ status of a placebo-treated mild-AD sub-cohort (N = 385) of patients participating in global phase 3 trials. The clinical trajectories of this cohort were evaluated over 18 months duration of the trial, stratified by imputed Aβ status within a mixed-model repeated measures statistical framework. Results In the imputed Aβ-positive cohort, both cognitive (ADAS-Cog 14 and MMSE) and functional (ADCS-iADL) measures declined more rapidly than in the undifferentiated population. Discussion Our results demonstrate imputing Aβ status from MRI scans in mild-AD subjects may be a useful screening tool in global clinical trials if amyloid measurement is not available.

Background: According to the amyloid cascade hypothesis, b-amyloid (Ab) pathology is an early event in Alzheimer’s disease (AD), followed by structural, functional and finally cognitive changes. If Ab+ is essential for AD, Abcognitive decline is non-AD, whichmay involve changed structure and function compared to Abcognitively healthy persons (NL), but the changes should be different from those seen in Ab+ cognitive decline. In this study, we tested the specific hypothesis that there are differences in brain structure, metabolism, and white matter (WM) connectivity between AbNL and Abearly mild cognitive impairment (MCI). Furthermore, we assessed the relative importance of imaging modalities in classification of Abearly-MCI from AbNL in terms of effect size.Methods:Ab-negative status of NL and early-MCI subjects fromADNI-GO/2 studies was based on both their AV45-PETand CSF-Ab data, with cohort characteristics summarized in the table. Relative to NL, age-, sex-, and education-adjusted earlyMCI effect-size of regional cortical thickness, tissue volume,WM fractional anisotropy (FA), and regional metabolic PET uptake was estimate and corrected for multiple comparison at p1⁄40.05 significance level. Results: Compared to AbNL, Abearly-MCI had significant 1) cortical thinning in the left superior temporal (d1⁄4-0.49), right inferior temporal (d1⁄4-0.47), right posterior banks of the superior temporal sulcus (d1⁄4-0.46), and left caudal anterior cingulate (d1⁄4-0.46); 2) tissue volume loss in the left amygdala (d1⁄4-0.64), left hippocampus (d1⁄4-0.46), and increased third ventricle CSF (d1⁄40.55); 3) hypermetabolism in the bilateral paracentral (left: d1⁄41.05; right: d1⁄40.65); and 4) diffused WM integrity degradation including the left fornix (cres)/stria terminalis (d1⁄4-0.59), bilateral internal capsule (d1⁄40.36 -0.57), bilateral tapatum (d1⁄4-0.42 -0.54), right cerebral peduncle (d1⁄4-0.52), bilateral splenium and genu of corpus callosum (d1⁄4-0.38 -0.48), right external capsule (d1⁄4-0.42), and left posterior thalamic radiation (d1⁄4-0.37). Conclusions: Abcognitive decline at early-MCI stage involves both structural and functional brain changes. Althoughmetabolic and volumetric changes had greater effect size, impact on WM fiber integrity was more wide-spread. The involvement of hippocampal, amygdala, and temporal lobe atrophy, and WM degeneration at fornix/stria terminalis was surprising in these subjects without AD-related Ab pathology, suggesting a non-Ab-pathology-related cognitive decline mechanism.