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Alzheimer's disease (AD) is a neurodegenerative condition that progresses over decades. Early detection of individuals at high risk of future progression toward AD is likely to be of critical significance for the successful treatment and/or prevention of this devastating disease. In this paper, we present an empirical study to characterize how predictable an individual subjects' future AD trajectory is, several years in advance, based on rich multi-modal data, and using modern deep learning methods. Crucially, the machine learning strategy we propose can handle different future time horizons and can be trained with heterogeneous data that exhibit missingness and non-uniform follow-up visit times. Our experiments demonstrate that our strategy yields predictions that are more accurate than a model trained on a single time horizon (e.g. 3 years), which is common practice in prior literature. We also provide a comparison between linear and nonlinear models, verifying the well-established insight that the latter can offer a boost in performance. Our results also confirm that predicting future decline for cognitively normal (CN) individuals is more challenging than for individuals with mild cognitive impairment (MCI). Intriguingly, however, we discover that prediction accuracy decreases with increasing time horizon for CN subjects, but the trend is in the opposite direction for MCI subjects. Additionally, we quantify the contribution of different data types in prediction, which yields novel insights into the utility of different biomarkers. We find that molecular biomarkers are not as helpful for CN individuals as they are for MCI individuals, whereas magnetic resonance imaging biomarkers (hippocampus volume, specifically) offer a significant boost in prediction accuracy for CN individuals. Finally, we show how our model's prediction reveals the evolution of individual-level progression risk over a five-year time horizon. Our code is available at https://github.com/batuhankmkaraman/mlbasedad.

The health and function of tissue rely on its vasculature network to provide reliable blood perfusion. Volumetric imaging approaches, such as multiphoton microscopy, are able to generate detailed 3D images of blood vessels that could contribute to our understanding of the role of vascular structure in normal physiology and in disease mechanisms. The segmentation of vessels, a core image analysis problem, is a bottleneck that has prevented the systematic comparison of 3D vascular architecture across experimental populations. We explored the use of convolutional neural networks to segment 3D vessels within volumetric in vivo images acquired by multiphoton microscopy. We evaluated different network architectures and machine learning techniques in the context of this segmentation problem. We show that our optimized convolutional neural network architecture with a customized loss function, which we call DeepVess, yielded a segmentation accuracy that was better than state-of-the-art methods, while also being orders of magnitude faster than the manual annotation. To explore the effects of aging and Alzheimer's disease on capillaries, we applied DeepVess to 3D images of cortical blood vessels in young and old mouse models of Alzheimer's disease and wild type littermates. We found little difference in the distribution of capillary diameter or tortuosity between these groups, but did note a decrease in the number of longer capillary segments (>75μm) in aged animals as compared to young, in both wild type and Alzheimer's disease mouse models.

[This corrects the article DOI: 10.1371/journal.pgen.1006711.].

Heritability estimation provides important information about the relative contribution of genetic and environmental factors to phenotypic variation, and provides an upper bound for the utility of genetic risk prediction models. Recent technological and statistical advances have enabled the estimation of additive heritability attributable to common genetic variants (SNP heritability) across a broad phenotypic spectrum. Here, we present a computationally and memory efficient heritability estimation method that can handle large sample sizes, and report the SNP heritability for 551 complex traits derived from the interim data release (152,736 subjects) of the large-scale, population-based UK Biobank, comprising both quantitative phenotypes and disease codes. We demonstrate that common genetic variation contributes to a broad array of quantitative traits and human diseases in the UK population, and identify phenotypes whose heritability is moderated by age (e.g., a majority of physical measures including height and body mass index), sex (e.g., blood pressure related traits) and socioeconomic status (education). Our study represents the first comprehensive phenome-wide heritability analysis in the UK Biobank, and underscores the importance of considering population characteristics in interpreting heritability.

Alzheimer's disease (AD) and its transitional state mild cognitive impairment (MCI) are characterized by amyloid plaque and tau neurofibrillary tangle (NFT) deposition within the cerebral neocortex and neuronal loss within the hippocampal formation. However, the precise relationship between pathologic changes in neocortical regions and hippocampal atrophy is largely unknown.In this study, combining structural MRI scans and automated image analysis tools with reduced cerebrospinal fluid (CSF) Aβ levels, a surrogate for intra-cranial amyloid plaques and elevated CSF phosphorylated tau (p-tau) levels, a surrogate for neocortical NFTs, we examined the relationship between the presence of Alzheimer's pathology, gray matter thickness of select neocortical regions, and hippocampal volume in cognitively normal older participants and individuals with MCI and AD (n = 724). Amongst all 3 groups, only select heteromodal cortical regions significantly correlated with hippocampal volume. Amongst MCI and AD individuals, gray matter thickness of the entorhinal cortex and inferior temporal gyrus significantly predicted longitudinal hippocampal volume loss in both amyloid positive and p-tau positive individuals. Amongst cognitively normal older adults, thinning only within the medial portion of the orbital frontal cortex significantly differentiated amyloid positive from amyloid negative individuals whereas thinning only within the entorhinal cortex significantly discriminated p-tau positive from p-tau negative individuals.Cortical Aβ and tau pathology affects gray matter thinning within select neocortical regions and potentially contributes to downstream hippocampal degeneration. Neocortical Alzheimer's pathology is evident even amongst older asymptomatic individuals suggesting the existence of a preclinical phase of dementia.