Abstract
The Dominantly Inherited Alzheimer Network (DIAN) unites researchers aiming to understand autosomal dominant Alzheimer’s disease (ADAD). By longitudinally monitoring families worldwide, the DIAN Observational Study maintains an unprecedented resource of deeply phenotyped, freely available neuroimaging data on individuals with ADAD and their healthy relatives.
EXPERT OPINION
“This is a very important study of autosomal dominant Alzheimer’s disease (ADAD) across 21 centers worldwide, collecting a rich dataset from over 500 individuals with ADAD and controls, including genetics, MRI scans, PET scans, longitudinal data, cerebrospinal fluid biomarkers, and clinical measures. This unique study will enable researchers to understand the brain and cognitive changes in vivo and at preclinical stages at an unprecedented scale and with a richness of biomarkers.” Christos Davatzikos, University of Pennsylvania, Philadelphia, PA, USA
FROM THE EDITOR
“The massive scope of the types of data collected from each individual makes this study a truly impressive resource that should offer considerable advances in research on Alzheimer’s disease.” Jean Mary Zarate, Senior Editor, Nature Neuroscience
The mission
Globally, aging populations have resulted in an increased prevalence of Alzheimer’s disease (AD), a leading cause of death in older adults. AD is associated with abnormal accumulation of amyloid-β and tau proteins in the brain, as well as structural and functional decline, which lead to cognitive impairment. Clinical diagnosis of AD typically occurs late in the disease, which makes it difficult to study early pathology. Genetic risk for late-onset AD is most commonly identified with recessive inheritance of the APOE4 genotype1. Early-onset AD, which accounts for 1–6% of all cases, is most commonly associated with autosomal dominant AD (ADAD), which is caused by mutations in three genes: APP (encoding amyloid-β precursor protein), PSEN1 and PSEN2 (encoding presenilin 1 and presenilin 2, respectively)1. The near-perfect penetrance of ADAD mutations, along with highly consistent presentation and earlier onset of symptoms than in sporadic AD, make ADAD cohorts ideal for research into aging and dementia. The rarity of ADAD, combined with a desire to minimize participant burden and the potential to inform our understanding of AD, prompted the creation of the Dominantly Inherited Alzheimer Network; the DIAN Observational Study (DIAN-OBS) provides a globally available data resource.
The discovery
The DIAN-OBS is an ongoing longitudinal study that combines PET and MRI data from 21 sites around the world. Imaging data have been collected from 533 individuals from 206 families with known ADAD mutations (Fig. 1). Individuals from these families have a 50% chance of inheriting their familial mutation, and both carriers and non-carriers (who serve as well-matched study controls) are studied. The necessary standardization of acquisition protocols across disparate research centres offered the opportunity to curate a repository of richly phenotyped neuroimaging data. This data resource on ADAD enables researchers to test hypotheses about the early, pre-symptomatic stages of AD. Further, the neuroimaging data collected for the non-carrier controls represent a large resource of exceptionally high-quality data that is well suited for studies of healthy adults.
Fig. 1 |. Summary of the DIAN-OBS neuroimaging data.
a, Map of the global network of centres collecting DIAN data. DIAN-TU, DIAN-Trials Unit. b, Stacked area plot displaying the evolution of the DIAN-OBS and the contributions that have been collected from each site. FLENI, Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; UPMC, University of Pittsburgh Medical Center. © 2023, McKay, N. S. et al., CCBY 4.0.
PET and MRI data acquired during the DIAN-OBS were crucially important for establishing the temporal order of pathological changes that begin as early as two decades prior to the onset of cognitive symptoms in ADAD2. ADAD mutations are known to increase amyloid-β accumulation, which causes amyloidosis and subsequent tauopathy, structural atrophy, hypometabolism and cognitive decline. This order of pathological change onset is proposed to be identical in sporadic AD, although the mechanisms that trigger this cascade are unknown. DIAN neuroimaging data also illustrated that brain regions vary in their vulnerability to pathological onslaught. Multimodal longitudinal analyses revealed that the precuneus is the earliest region to manifest increased amyloid-β deposition, reduced thickness and hypometabolism in ADAD3.
The implications
The DIAN has curated a large, richly phenotyped and freely available resource of longitudinal neuroimaging data. These data have been fundamental for establishing the temporal order and spatial distribution of key AD pathologies and have provided the scientific framework behind clinical trials that assess the efficacy of protein-targeting drugs that may prevent, delay or reverse neuro-pathological damage.
Although it is proposed that sporadic AD and ADAD share a common hierarchy of pathophysiology, the origin of sporadic AD is multifaceted — probably the result of combined lifestyle, genetic and environmental factors. Thus, although ADAD may provide an informative model of broader AD, theories generated using ADAD data should be directly tested in sporadic AD cohorts.
DIAN-OBS data from the non-carrier population could be highly informative for research probing a wide range of biological processes across adulthood. Non-carrier individuals (as well as individuals carrying ADAD mutations) are characterized with genetic, clinical and cognitive data and with biofluid samples that are temporally linked to the neuroimaging data. These additional variables vastly increase the scope of questions that could addressed using DIAN-OBS data. Data from DIAN-OBS non-carriers were included in younger and older adult control groups to form a more representative lifespan cohort4. Such datasets are useful for examining differences in healthy ageing and may also be crucial for training machine learning models.
BEHIND THE PAPER.
The DIAN is often described as a global network of patients, families, researchers, and clinicians who collectively aim to advance the understanding of ADAD, and potentially other forms of AD. Without the dedication and commitment of these families, the DIAN would not exist today. Families often travel large distances to participate in week-long study visits, giving up vacations to participate. Behind the scenes, the DIAN is composed of many highly skilled and extremely dedicated teams of study coordinators, research assistants, medical imaging technologists, neuroimaging engineers, and data specialists, without whom this neuroimaging data repository would not exist. We sincerely thank these participants, families, and teams around the world for their efforts in the fight against AD. T.L.S.B.
REFERENCES
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