Identifying Pre-Symptomatic Alzheimer’s Brain Changes to Facilitate Early Treatment

Guy McKhann, M.D.

Johns Hopkins University, Baltimore, MD

Grant Program:

Clinical Neuroscience Research

Funded in:

April 2016, for 1 years

Funding Amount:


Lay Summary

Identifying pre-symptomatic Alzheimer’s brain changes to facilitate early treatment

For the first time, researchers may be able to define the interrelated functional and structural brain changes that evolve over time in cognitively healthy adults who eventually develop Alzheimer’s disease (AD). Identifying the earliest brain signs of AD would enable clinical testing of experimental interventions to prevent or arrest degeneration of brain cells and their synapses (connections) that leads to AD before this damage becomes irreversible.

More than a decade before adults with memory problems are diagnosed with “mild cognitive impairment” (MCI), which often progresses to AD, the brain is building up abnormal “amyloid” and “tau” proteins. Symptoms only emerge when enough amyloid has accumulated between brain cells to begin damaging synapses so that cells cannot communicate, and when enough tau has accumulated within brain cells to lead to the cells’ death. By then, it is already too late to reverse or treat this interactive neurodegeneration. Since a significant proportion of those with MCI will eventually develop AD, it is essential to intervene prior to MCI onset by determining when and where amyloid and tau changes first occur and how their actions interrelate.

The investigators began investigating these questions in a population of cognitively healthy adults who have been followed now for two decades. The study was based on evidence indicating that certain measures in cerebral spinal fluid (CSF) reflect brain amyloid and tau accumulation even prior to the onset of MCI. They have been correlating changes in participants’ CSF with changes in the brain as assessed by MRI and changes in participants’ cognitive functioning.

Newly added to this study are two more recently developed imaging techniques to provide more direct measures of amyloid and tau accumulation and their effects in the brain. One is PET-PiB imaging that directly measure amyloid levels. While methods to directly image tau are being developed, investigators are using “resting state fMRI” (rs-fMRI) in participants who are not undertaking a specific task to measure changes in functional network connections.

With the groundbreaking development of a multi-modal brain atlas that has taken years to develop, the researchers now will be able to examine not only PET and MRI imaging changes individually but also their inter-related measures of changes in the same brain areas. They will correlate these measures with changes that occurred in participants’ CSF samples over time, to address a range of questions concerning the pre-symptomatic phase of AD.

Among these are: 1) Do the same brain areas that show high amyloid accumulation also show reduced volume (cell death), reduced neural connections, and reduced activity in functionally connected networks when no task is being performed? 2) Are certain brain regions that show reductions in volume (cell death), connections and functionally connected networks more strongly correlated with increased CSF levels of tau, while other regions are more strongly correlated with increased CSF levels of amyloid? 3) Is the combined measure of cell death and reduced neural connectivity associated with CSF measures of tau? If so, can this combined measure serve as a proxy for the amount of tau accumulation in the brain?

Researchers expect that the analyses addressing these and related questions will provide additional insights into the interrelated damage to specific brain areas related to varying levels of tau and amyloid accumulation that are seen before any memory problems occur. They anticipate that this information can be predictive of which healthy adults are likely to develop clinical symptoms of MCI and AD in the coming years. With this predictive capacity, clinical researchers could test experimental therapies in pre-symptomatic adults at the earliest stage when treatments have the greatest likelihood of arresting disease progression. Moreover, grouping pre-symptomatic clinical trials participants according to degree of preclinical disease would strengthen outcome assessments of experimental therapies.

Significance: The study may for the first time provide the integrated information necessary to characterize pre-clinical AD and facilitate clinical trials in at-risk cognitively healthy adults early enough for the interventions to arrest progression to AD.

Investigator Biographies

Guy McKhann, M.D.

Guy M. McKhann, M.D. is Professor of Neurology at the Johns Hopkins University (JHU) School of Medicine, with a joint appointment in the School’s Department of Neuroscience. He was the founding chairman of the School’s Neurology Department and also was the founding director of the University’s Zanvyl Krieger Mind/Brain Institute. Dr. McKhann has authored more than 200 publications. His clinical research has included studies of the Guillain-Barre Syndrome, which included research programs in the United States as well as in China. His most recent research has focused on the role of vascular factors in cognitive decline. He was co-editor for many years of the neurology textbook, Diseases of the Nervous System: Clinical Neurobiology. He and his colleague (and wife) Dr. Marilyn Albert published a book about aging and the brain for the general public entitled Keep Your Brain Young. Dr. McKhann has been involved with a number of scientific organizations, including as president of the American Neurological Association. Dr. McKhann attended Harvard University and received his MD degree from the Yale University School of Medicine.