Alzheimer's Biomarkers Dip Later in Disease

Pauline Anderson

March 07, 2014

Researchers have uncovered a pattern of Alzheimer disease (AD) biomarker activity that differs from the accepted trajectory and could affect future clinical trials.

Led by Anne M. Fagan, PhD, research professor, neurology, Washington University School of Medicine, St. Louis, Missouri, the team of investigators found that levels of AD-related biomarkers in patients with an autosomal dominant AD (ADAD) mutation increase early in the disease, before symptoms developed, but then, in contrast to conventional thinking, decrease once symptoms appear.

This pattern suggests that Alzheimer's biomarkers change depending on the stage of the disease process.

The study results, said Dr. Fagan, emphasize the importance of studying biomarker changes "over time" in individuals at risk for dementia. She said she would "almost predict" that patients will eventually get a "baseline" AD biomarker picture at a certain age against which later levels can be compared to better monitor disease progress.

The research was published online March 5 in Science Translational Medicine.

The analysis included 146 carriers of an AD-related mutations (APP, PSEN1, or PSEN2) and 96 noncarriers involved in the Dominantly Inherited Alzheimer Network (DIAN). Carriers were grouped as asymptomatic or symptomatic. Almost 60% of the participants were female and about 25% carried at least one APOE 4 allele.

Investigators carried out imaging on the patients and collected plasma and cerebrospinal fluid (CSF) samples. The biomarkers of interest were amyloid-β (Aβ1-42), tau (a marker of neuronal cell loss), phosphorylated tau (ptau, a marker of neurofibrillary tangles), and visinin-like protein-1 (VILIP-1, a neuronal calcium sensor that is also a marker of cell death).

The study confirmed that in mutation carriers, AD pathology is laid down years before the onset of significant impairments in cognitive performance, as measured by the Mini-Mental State Examination and other scales.

The pattern of disease pathology in the asymptomatic period of ADAD included elevated concentrations of Aβ1-42 in the plasma and CSF very early in the presymptomatic phase in carriers. Aβ1-42 apparently accumulates in the brain until a critical threshold is reached, after which concentrations in the CSF decrease as Aβ1-42 is taken up in Aβ plaques.

"Aβ aggregates in the brain, and when it does, there is less of it going into the CSF, so that's why it's reduced," explained Dr. Fagan.

Concentrations of Aβ1-42 1-42 in the plasma remain high in carriers over the course of the disease, probably because of the sustained contribution of peripheral overexpression of Aβ1-42 1-42 in these individuals, said the authors.

Levels of the other biomarkers also increase as neurons become injured. It's believed that as AD assaults the brain, dying cells release these biomarkers, which accumulate in the spinal fluid.

Longitudinal Analysis

Researchers did a longitudinal analysis of a subset of 37 patients to evaluate changes in biomarker concentrations over time. That analysis found relatively small but consistent and statistically significant reductions in the 3 markers of neurodegeneration.

"When we look at the biomarkers in the smaller cohort over time, within an individual, we see reductions in (Aβ)42, which is what we expect, and we see elevations of tau early on in asymptomatic phases, but then the surprising thing was a decrease later," said Dr. Fagan.

It's surprising because it was assumed, on the basis of cross-sectional studies, that tau levels would continue to increase over time, said Dr. Fagan. "But what we see is the opposite; we see that it's starting to decrease."

There are several theories as to why tau levels start to decrease. One hypothesis, said Dr. Fagan, is that there is a more "robust" phase of cell death during the preclinical phase and that at some point, "there just aren't that many neurons left to die" and thus generate increased biomarker activity.

It's not clear at what point the levels of biomarkers start to decrease. "That's an interesting question," commented Dr. Fagan. "We hope that as the cohort gets bigger and we can follow patients as they progress from asymptomatic to the symptomatic phase that we will see where that shift is."

Does this pattern apply to late-onset AD? That's being investigated, said Dr. Fagan. One study is enrolling cognitively normal middle-aged children with and without a positive family history of AD (not mutation related). The hypothesis, said Dr. Fagan, is that biomarker evidence over time will reveal more prevalent changes in those with a family history of AD, and indeed, this is already being observed.

Dr. Fagan stressed that during the symptomatic period of AD, the brain continues to shrink.

Intense Focus

The long stage during which AD abnormalities develop in advance of cognitive symptoms is receiving intense focus right now, noted Dr. Fagan. "The Alzheimer's disease field has undergone what is considered a paradigm shift in the past 5 or 10 years with an appreciation of this preclinical phase" that biomarkers have determined lasts from 10 to 20 years before the onset of symptoms, she said.

As more clinical trials of biomarkers to assess the success or failure of Alzheimer's drugs get under way, it will become increasingly important to know how they behave and which ones to use. Ptau, said Dr. Fagan, may be a better biomarker than tau because tau levels increase in response to a traumatic brain injury or other brain insult, such as a stroke, and so is not specific for AD.

In addition, as tau-targeted treatments come down the pipeline, the VILIP-1 biomarker, while highly correlated with tau, may take on an increasingly important role, she said. "In clinical trials, it will be really important to have some sort of marker of cell death that is independent of tau; if you're going after a tau target, you can't use tau as an outcome."

Dr. Fagan consults for Roche and Eli Lilly.

Sci Translat Med. Published online March 5, 2014. Abstract

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