Family History of Alzheimer's Linked to Preclinical Markers

Kate Johnson

Authors and Disclosures

October 17, 2011 — A family history of Alzheimer's disease (AD) is associated with preclinical abnormalities in biomarkers for the condition, regardless of the risk conferred by the apolipoprotein E (APOE) susceptibility gene, according to a study published in the October issue of the Archives of Neurology.

"The current results point to the likelihood of non-APOE susceptibility genes for AD," write lead author Chengjie Xiong, PhD, from Washington University School of Medicine, St. Louis, Missouri, and colleagues.
The biomarker changes "have the potential to capture the earliest possible antecedent events" of AD, the authors suggest.

"Our findings are important because they suggest AD biomarker changes occur long before people begin to have clinical symptoms (ie, in a mid- to old age cognitively normal cohort)," Dr. Xiong told Medscape Medical News. "However, the utility of these markers in the clinical setting has yet to be fully established," he added.

Antecedent Biomarkers

The study included 269 cognitively normal participants, aged 45 to 75 years, who were part of the Antecedent Biomarkers for AD: The Adult Children Study.

Individuals with and without a family history of AD were included in the study. A positive family history was defined as having at least 1 biological parent in whom the age of onset for dementia of the Alzheimer type (DAT) was younger than 80 years. A negative history was defined as both biological parents living to at least age 70 years without DAT.

Participants underwent baseline clinical and cognitive tests including magnetic resonance imaging to measure brain volumes; diffusion tensor imaging to measure white matter microstructure; positron emission tomography, using the [¹¹C] benzothiazole tracer Pittsburgh compound B; and lumbar puncture to measure cerebrospinal fluid biomarkers. Cognitive function was assessed with psychometric testing and attentional tasks.

The researchers found that participants with a positive family history of AD had a more pronounced age-related decrease in cerebrospinal fluid amyloid beta 42 levels than those with no such history, independent of the presence of an APOE4 allele.

"Age-adjusted cerebrospinal fluid [amyloid beta 42 levels were] decreased for individuals with APOE4 compared with the level for those without, and the decrease was larger for individuals with a positive [family history] compared with the decrease for those without," the authors write.

In addition, Pittsburgh compound B cortical binding potential (MCBP) was also influenced by family history, independent of APOE4. Participants with a positive family history who were positive for APOE4 had the largest age-related increase of MCBP (P < .001), the authors note.

"For individuals younger than 55, MCBP increased by age at a significantly faster pace for individuals with APOE4 compared with the pace for those without APOE4...eventually leading to a higher level of MCBP for those with APOE4 compared with the level for those without (P = .01)," they write. "For individuals older than 55, a trend (P = .09) was found to suggest a faster age-related increase of MCBP for individuals with APOE4 compared with the increase for those without APOE4."

Cognitive and clinical tests found no influence of family history in this cohort.

Together, the data "suggest that AD has a lengthy period during which cerebral lesions gradually accumulate in the absence of symptoms (ie, preclinical AD)," they write. "We expect that eventually these lesions cause sufficient synaptic and neuronal damage to result in symptomatic AD."

Clinical Utility?

Whether the observed biomarker changes will eventually lead to the development of AD in the study participants remains to be seen, Dr. Xiong told Medscape Medical News. Therefore, the clinical utility of the biomarker measurement is not yet established.

"Many biomarkers have been well studied and used in research settings," Dr. Xiong noted. "There is no doubt to me that they will be crucial in studying preclinical AD. I do think many biomarkers will eventually be used in [a] clinical setting, especially with more and more evidence on how these markers can help track early disease changes."

Although the clinical utility of the findings remains to be seen, "the importance of the paper lies in the continued exploration of biomarker levels in asymptomatic middle-aged people," David Knopman, MD, a neurologist in the Alzheimer's Disease Research Center at the Mayo Clinic in Rochester, Minnesota, told Medscape Medical News.

"The notion that family history is important is most certainly not new, but the fact that family history [is important] even after taking APOE genotype into account shows that even in asymptomatic younger people, there are genetic determinants...that are relevant and are not entirely accounted for by APOE genotype," he said. "For people like me who are interested in preclinical AD, it is a useful piece of information."

The study was supported by a grant from the National Institute on Aging, the American Roentgen Ray Scholar Award, and the Charles F. and Joanne Knight Alzheimer's Research Initiative of the Washington University Alzheimer's Disease Research Center. One study author receives research funding from Eli Lilly and Company, AstraZeneca, Pfizer, and C2N Diagnostics through Washington University; he is also a member of the scientific advisory board for En Vivo, Satori, and C2N Diagnostics and is a consultant for Innogenetics. Another study author is the chief medical officer for Avid Radiopharmaceuticals. Dr. Knopman has served on a safety monitoring board for a Lilly anti-Alzheimer's drug; is an investigator in clinical trials for Baxter, Forest, and Pfizer; and is the deputy editor of Neurology.
Arch Neurol. 2011;68:1311-1317. Abstract
Family History of Alzheimer's Linked to Preclinical Markers