CSF biomarker changes precede Alzheimer disease by decades

By Will Boggs MD

NEW YORK (Reuters Health) - Cerebrospinal fluid (CSF) levels of beta-amyloid 42 and other biomarkers of Alzheimer disease (AD) show significant changes decades before symptoms appear, according to findings from the Adult Children Study.

"We expected to see biomarker patterns consistent with the development of underlying AD pathology in cognitively normal middle-aged individuals but were surprised to see how young some of them were (with amyloid profiles observed in some who were in their late 40s)," Dr. Anne M. Fagan, from Washington University School of Medicine, St. Louis, Missouri, told Reuters Health by email.

Three CSF biomarkers reflect the core neuropathology of AD: beta-amyloid 42 (Abeta42; the primary constituent of amyloid plaques), total tau (a marker of neuronal injury and death), and hyperphosphorylated tau (P-tau, which forms intraneuronal neurofibrillary tangles).

Dr. Fagan and colleagues investigated longitudinal changes in these markers as a function of risk conferred by APOE genotype in 169 participants in the Adult Children Study, including 108 without APOE risk alleles and 61 with at least one APOE epsilon-4 allele.

Levels of CSF Abeta42 decreased over time in some cognitively normal individuals, starting as early as ages 45-54. In middle age (55-64 years), these reductions were associated with the development of amyloid plaques.

By mid and late middle age (65-74 years), some individuals showed dramatic increases in the neuronal injury markers and in visilin-like protein 1 (VILIP-1, a marker of neuronal death), according to the July 6 JAMA Neurology online report.

These biomarker changes were observed in both APOE risk groups, but they were more evident in epsilon-4 carriers.

Moreover, these changes were not clinically benign. Those who developed cognitive decline had low Abeta42 as well as high total tau levels earlier in life.

"CSF biomarkers have both diagnostic (identifying who has underlying AD pathology) and prognostic (when and how fast will cognitive symptoms develop and progress) utility in middle-aged individuals," Dr. Fagan said in her email. "Evaluation for biomarker use for individual patient care will require assay validation (current assays are for research use only) and longer biomarker and clinical follow-up in cognitively normal middle-aged cohorts as they progress along the disease continuum from normal to asymptomatic/preclinical AD to symptomatic AD."

"Evaluating biomarker change over time within individuals will likely be more informative for disease diagnosis and tracking compared to evaluation at a single time point," Dr. Fagan said. "I feel that it is very possible that in the future, baseline CSF collection (via lumbar puncture, which is very safe when performed by trained neurologists) will be routinely performed in middle age much like colonoscopies at age 50 are performed today."

"Once disease modifying therapies are developed, biomarkers can be used to identify individuals in this preclinical stage for initiating treatment and evaluating therapeutic efficacy," Dr. Fagan concluded.

SOURCE: https://bit.ly/1eJ7ClT

JAMA Neurol 2015.