Study suggests progression of Alzheimer’s may slow once symptoms emerge, following decades of early brain damage
New research into an inherited, autosomal-dominant form of Alzheimer’s disease indicates that the most rapid neuronal damage occurs long before clinical symptoms appear — but that the pace of neurodegeneration may actually slow once symptoms begin. The findings, reported by Professor Colin Masters of the Florey Institute of Neuroscience and Mental Health and the University of Melbourne with collaborators in the UK and US, were published in Science Translational Medicine.
Using longitudinal biomarker measurements and imaging in families who carry autosomal-dominant Alzheimer’s mutations, the researchers found evidence that brain changes accelerate a decade or more prior to symptom onset. “Our data show that rapid neuronal damage starts 10 to 20 years before symptoms appear,” Professor Masters said. “Importantly, we observed additional changes in the brain that coincide with the emergence of symptoms and indicate a relative slowing of neurodegeneration at that stage.”
Autosomal-dominant Alzheimer’s is a rare hereditary form of the disease arising from specific genetic mutations that almost always lead to early-onset dementia. Although it represents only roughly one percent of all Alzheimer’s cases, studying these families is especially valuable because at-risk individuals can be identified long before cognitive decline begins. That early identification allows researchers to map the timeline of biological changes — from cerebrospinal fluid (CSF) biomarkers to structural and molecular brain imaging — and to test interventions at defined stages of the disease process.
The research team combined advanced imaging methods (including MRI and PET) with repeated analyses of blood and CSF biomarkers to track disease progression over time. These biomarkers measure processes such as amyloid accumulation, tau pathology and markers of neuronal injury and inflammation. By following participants across years, the investigators were able to characterize how biomarker trajectories change as individuals move from a presymptomatic phase into symptomatic disease.
Building on these observations, the next phase is a clinical trial that will assess the safety, tolerability and biological effects of experimental therapies when administered well before symptoms appear. “As part of an international study, family members are invited to take part in a trial in which two experimental drugs are offered many years before clinical symptoms manifest,” Professor Masters explained. “It will be very informative to see how early clinical intervention alters biomarker trajectories and clinical outcomes in this uniquely informative group.”
The trial will use multimodal imaging and fluid biomarkers to monitor how the brain responds to treatment and to detect potential side effects. Results from this trial are expected to inform treatment strategies not only for familial, autosomal-dominant Alzheimer’s but also for more common, late-onset forms of the disease, because the biological pathways involved overlap and because intervention timing is likely to be critical for therapeutic success.
Participation and further information
The Florey Institute is recruiting additional participants for the Dominantly Inherited Alzheimer Network (DIAN) study. Individuals who know they carry a genetic mutation that causes autosomal-dominant Alzheimer’s, or those who are uncertain of their genetic status but have a parent or sibling with a known mutation, are encouraged to contact the study team by email at [email protected] for more information about eligibility and participation.
Press contact: Anne Rahilly – University of Melbourne
Source: University of Melbourne press release (summarized)
Image source: Image adapted from the University of Melbourne press release
Original research: Fagan AM, Xiong C, Jasielec MS, Bateman RJ, Goate AM, Benzinger TLS, Ghetti B, Martins RN, Masters CL, Mayeux R, Ringman JM, Rossor MN, Salloway S, Schofield PR, Sperling RA, Marcus D, Cairns NJ, Buckles VD, Ladenson JH, Morris JC, Holtzman DM, and The Dominantly Inherited Alzheimer Network. “Longitudinal Change in CSF Biomarkers in Autosomal-Dominant Alzheimer’s Disease.” Science Translational Medicine. Published online March 5, 2014. doi:10.1126/scitranslmed.3007901