Impact of Major Alzheimer's-Related Gene May Be Felt Years Before Any Symptoms Appear

The best-known genetic variant linked to Alzheimer's disease may be "at work" promoting deposits of plaque in the brain long before any symptoms of the disease can be measured on tests, according to a national research study led by Indiana University (IU) School of Medicine investigators.

In a research paper published in the journal Alzheimer's and Dementia, the scientists provide additional evidence for focusing research, and eventually treatment, on people at risk of Alzheimer's long before the disease is diagnosed.

The study focused on people with "significant memory concerns," defined as older adults who complained that they had mentally slipped in recent months or years, but when given standard cognition and memory tests they fell within normal ranges. People in this category have also been called the "subjective cognitive decline" group by Alzheimer's researchers.

The paper's authors, led by Shannon L. Risacher, PhD, an assistant professor of radiology and imaging sciences, and Andrew J. Saykin, PsyD, director of the Indiana Alzheimer Disease Center and IU Center for Neuroimaging, drew on data collected as part of the national Alzheimer's Disease Neuroimaging Initiative. The ADNI project is a global public-private collaborative initiative that is collecting and making available a broad range of long term Alzheimer's-related data from volunteers ranging from cognitively normal "controls" to patients with diagnosed Alzheimer's disease.

As it becomes more evident that effective treatments for Alzheimer's may need to be applied many years before serious symptoms appear, researchers are focusing more intently on at-risk patients with significant memory concerns, Risacher and Saykin say.

"These are the individuals who are the logical target for the next wave of clinical trials," says Saykin, who also leads the ADNI Genetics Core.

"There are many potential interventions, and not only on the pharmaceutical side," he says. "There are intensive studies now of exercise, diet modification, cognitive stimulation, sleep, and other lifestyle factors that could lead to an improvement."

The gene in question, APOE, has several variants, or "alleles." One of those variants, APOE ε4, has been linked to an increased risk of developing Alzheimer's disease in older adults—although not all Alzheimer's patients have APOE ε4 alleles, and not all those who do will develop Alzheimer's disease. APOE ε4 is common, found in about 25% of the population. Patients with Alzheimer's disease who also have APOE ε4 tend to have an earlier age of onset of symptoms.

Looking at data from nearly 600 ADNI participants, the researchers compared those with the APOE ε4 variant to those with other forms of the gene. In the "significant memory concerns" group the researchers found evidence of Alzheimer's-like pathologies from several biomarkers among the APOE ε4 carriers including the following:

• increased levels of amyloid plaque, the clumps of protein fragments commonly found in the brain tissue of Alzheimer's patients;
• in the cerebrospinal fluid, decreased levels of the protein precursor to the plaques, suggesting that the protein was being recruited to the brain as part of the plaque creation process; and
• in the cerebrospinal fluid, increased levels of tau, another protein associated with Alzheimer's disease.

However, the analysis did not find evidence of reduced levels of glucose metabolism nor atrophy of brain structures that are associated later stages of Alzheimer's progression.

The study provides the foundation for further focused research among patients at risk of Alzheimer's earlier than in much other research, Risacher says.

"ADNI provides access to a wide range of biomarkers, structural and functional neuroimaging with MRI, PET scans for amyloid and for glucose metabolism, CSF biomarkers for amyloid and tau, plus genetics, and clinical and cognitive tests. No other data set has all these state-of-the-art biomarkers available for analysis," she says.

Additional researchers contributing to the study were Sungeun Kim, Kwangsik Nho, Tatiana Foroud, and Li Shen of the IU School of Medicine; Ronald C. Petersen and Clifford R. Jack Jr. of the Mayo Clinic; Laurel A. Beckett of the University of California-Davis; Paul S. Aisen of the University of California-San Diego; Robert A. Koeppe of the University of Michigan; William J. Jagust of the University of California-Berkeley; Leslie M. Shaw and John Q. Trojanowski of the University of Pennsylvania; and Michael W. Weiner of the University of California-San Francisco.

Data collection and sharing for the Alzheimer's Disease Neuroimaging Initiative (ADNI) was provided by National Institutes on Aging U01 AG024904 as well as other public and private sector funding listed on the ADNI website. Additional support for the analyses in this report included NIH grants R01 AG19771, P30 AG10133, R01 LM011360, R00 LM011384, U24 AG21886, the Alzheimer's Association, and the Indiana University Health-Indiana University School of Medicine Strategic Research Initiative.

Source: Indiana University School of Medicine