A growing awareness about brain health and Alzheimer's disease in the general population is leading to an increasing number of cognitively unimpaired individuals, who are concerned that they have reduced cognitive function, to approach the medical system for help. The term subjective cognitive decline (SCD) was conceived in 2014 to describe this condition. Epidemiological data provide evidence that the risk for mild cognitive impairment and dementia is increased in individuals with SCD. However, the majority of individuals with SCD will not show progressive cognitive decline. An individually tailored diagnostic process might be reasonable to identify or exclude underlying medical conditions in an individual with SCD who actively seeks medical help. An increasing number of studies are investigating the link between SCD and the very early stages of Alzheimer's disease and other neurodegenerative diseases.

Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.

Evidence before this study Using PubMed and Google Scholar the authors reviewed prior work on longitudinal neuroimaging markers of Alzheimer pathology with a focus on autosomal dominant Alzheimer disease (ADAD). We searched for all articles prior to October 31 st , 2017 with no language restrictions for the keywords Alzheimer's, Alzheimer, longitudinal, positron emission tomography, PET, MRI, atrophy, FDG, hypometabolism, familial, and autosomal. Theories proposed initially in 2010 by Jack and colleagues and revised in 2013 posited temporal trajectories of Alzheimer biomarkers relative to each other and clinical decline. Work by Bateman and colleagues in 2012, Benzinger and colleagues in 2013, and Fleisher and colleagues in 2015 depict such temporal ordering of biomarkers in ADAD populations derived from cross-sectional analyses. There was also a small subset of longitudinal ADAD studies, but these had one or more limitation such as small populations (n<50), examination of only one biomarker, not accounting for regional differences or correlations in the brain, or had a short duration of longitudinal followup. Added value of this studyOur study presents the first known work examining both the longitudinal temporal trajectories and spatial patterns of Alzheimer pathology in ADAD cohorts using neuroimaging. This work also presents the largest known cohort to date of ADAD individuals studied longitudinally with multiple neuroimaging biomarkers. Longitudinal analyses can provide a more accurate and powerful way to model the temporal emergence of pathology in ADAD. We find that mutation carriers first display Aβ accumulation, followed by hypometabolism, and finally structural atrophy; this is consistent with theoretical models and cross-sectional estimates from ADAD. Most importantly we consider such temporal relationships not in one singular summary measure, but characterize these trajectories throughout the brain. We found that the accrual of pathology varied throughout the brain and by modality in terms of the time of initial emergence and the rates of longitudinal change. These findings suggest region specific vulnerabilities to β-amyloidosis, metabolic decline, and atrophy that change over the course of the disease. Implications of all the available evidenceOur results build upon existing evidence characterizing biomarkers in clinical and preclinical Alzheimer disease. Our findings suggest that imaging biomarkers follow a sequential pattern, with β-amyloidosis, hypometabolism, and structural atrophy emerging more than twenty, fifteen, and ten years respectively before the expected onset of dementia. Although there is a general hierarchical pattern, there was considerable regional heterogeneity. Most commonly, regions demonstrated an increase in β-amyloidosis and structural atrophy, but there was not evidence of metabolic declines. Further, rather than being homogenous, the same biomarker often demonstrates different longitudinal trajectories across brain regions. Characterizing the temporal and regional dynamics...