Early Brain Alterations May Occur Decades Before Onset of First Symptoms, Researchers Say

Scientists have found a series of brain alterations associated with Alzheimer’s disease that occur decades before the onset of the first symptoms. Identifying these biological and anatomical brain alterations in people at high-risk for the disease may help them receive earlier therapeutic interventions, the researchers said.

The study, “Identifying Changepoints in Biomarkers During the Preclinical Phase of Alzheimer’s Disease,” was published in Frontiers in Aging Neuroscience.

Alzheimer’s is a progressive neurodegenerative disorder marked by a continued decline in cognitive abilities. Recent studies have suggested the first signs of the disorder setting in may actually be shown decades before patients experience the first Alzheimer’s symptoms.

“This has led to an increasing interest in understanding the order and magnitude of biomarker changes during this ‘preclinical’ phase of AD,” the investigators said.

Researchers at the Johns Hopkins University reviewed the medical records of 290 cognitively normal individuals, ages 40 and older, at high risk of developing Alzheimer’s. Approximately 75% had a first-degree relative — a parent or a sibling — with the disease. All data was extracted from the BIOCARD study, a project launched by the National Institutes of Health (NIH) in 1995 with the aim of finding predictors of cognitive decline in individuals before the onset of Alzheimer’s.

Medical records included brain imaging data assessed by magnetic resonance imaging (MRI), and nine different cerebrospinal fluid (CSF) disease biomarkers gathered every two years, between 1995 and 2005. (CSF is the liquid that circulates around the brain and spinal cord). Participants also were given cognitive tests — including memory, learning, reading, and attention assessments —  once per year between 1995 and 2013.

Among the 290 participants, 209 remained cognitively normal at their last study visit, while 81 developed mild cognitive impairment or dementia associated with Alzheimer’s.

All nine CSF biomarkers showed significant changes over time — all of which occurred before the first symptoms of the disorder set in — in the 81 subjects who ended up developing Alzheimer’s. However, their timing was extremely variable.

Remarkably, the test assessing the levels of t-tau protein in the CSF — one of the classic biomarkers of Alzheimer’s — showed significant alterations at an average of 34 years before the onset of the first disease symptoms. The remaining CSF biomarkers and cognitive tests all showed subtle changes between 10 to 15 years before the onset of Alzheimer’s.

MRI scans also revealed a slight reduction in the size of the median temporal lobe, a brain region responsible for memory, among subjects who developed cognitive impairments. These reductions were seen three years before the onset of symptoms for the left side of the lobe, and nine years for the right side.

Using mathematical algorithms, the team tracked these alterations in brain morphology over time in all study participants, and found they were correlated with cognitive impairments.

“Several biochemical and anatomic measures can be seen changing up to a decade or more before the onset of clinical symptoms,” Michael Miller, PhD, director of the department of biomedical engineering at the Johns Hopkins University and the study’s author, said in a press release. “The goal is to find the right combination of markers that indicate increased risk for cognitive impairment, and to use that tool to guide eventual interventions to help stave it off.”