Studying brain scans and cerebrospinal fluid of healthy adults, scientists have shown that changes in key biomarkers of Alzheimer’s disease during midlife may help identify those who will develop dementia years later, according to new research.
The study, at Washington University School of Medicine in St. Louis, is published July 6 in JAMA Neurology.
“It’s too early to use these biomarkers to definitively predict whether individual patients will develop Alzheimer’s disease, but we’re working toward that goal,” said senior author Anne Fagan, PhD, a professor of neurology. “One day, we hope to use such measures to identify and treat people years before memory loss and other cognitive problems become apparent.”
The study focused on data gathered over 10 years and involved 169 cognitively normal research participants ages 45 to 75 when they entered the study. Each participant received a complete clinical, cognitive imaging and cerebrospinal fluid biomarker analysis every three years, with a minimum of two evaluations.
At the participants’ initial assessments, researchers divided them into three age groups: early-middle age (45-54); mid-middle age (55- 64); and late-middle age (65-74).
Among the biomarkers evaluated in the new study were:
- Amyloid beta 42, a protein that is the principal ingredient of Alzheimer’s plaques;
- Tau, a structural component of brain cells that increases in the cerebrospinal fluid as Alzheimer’s disease damages brain cells;
- YKL-40, a newly recognized protein that is indicative of inflammation and is produced by brain cells;
- The presence of amyloid plaques in the brain, as seen via amyloid PET scans.
The scientists found that drops in amyloid beta 42 levels in the cerebrospinal fluid among cognitively normal participants ages 45-54 are linked to the appearance of plaques in brain scans years later. The researchers also found that tau and other biomarkers of brain-cell injury increase sharply in some individuals as they reach their mid-50s to mid-70s, and YKL-40 rises throughout the age groups focused on in the study.
Previous research has shown that all of these biomarkers may be affected by Alzheimer’s disease, but this is the first large data set to show that the biomarkers change over time in middle-aged individuals.
All of these changes were more pronounced in participants who carried a form of a gene that significantly increases the risk of Alzheimer’s disease. The gene is known as APOE, and scientists have known that people with two copies of a particular version of this gene have up to 10 times the risk of developing Alzheimer’s as those with other versions of the gene.
The data came from the ongoing Adult-Children Study at the university’s Charles F. and Joanne Knight Alzheimer’s Disease Research Center. Scientists have been following participants with and without a family history of the disease, with the aim of identifying Alzheimer’s biomarkers most closely associated with the development of full-blown disease years later.
“Alzheimer’s is a long-term process, and that means we have to observe people for a long time to catch glimpses of it in action,” Fagan said.
Funding: This research was supported by the National Institutes of Health (NIH), grants PO1AGO26276 and 5P30 NS048056; The Foundation for Barnes-Jewish Hospital; the Fred Simmons and Olga Mohan Fund; and Eli Lilly and Co.
Source: Michael C. Purdy – Washington University School of Medicine
Image Credit: Image is in the public domain
Original Research: Abstract for “Longitudinal cerebrospinal fluid biomarker changes in preclinical Alzheimer’s disease during middle age” by Courtney L. Sutphen, BS; Mateusz S. Jasielec, MS; Aarti R. Shah, MS; Elizabeth M. Macy, BA; Chengjie Xiong, PhD; Andrei G. Vlassenko, MD, PhD; Tammie L. S. Benzinger, MD, PhD; Erik E. J. Stoops, Eng; Hugo M. J. Vanderstichele, PhD; Britta Brix, PhD; Heather D. Darby, MSc; Manu L. J. Vandijck, MSc; Jack H. Ladenson, PhD; John C. Morris, MD; David M. Holtzman, MD; and Anne M. Fagan, PhD in JAMA Neurology. Published online July 6 2015 doi:10.1001/jamaneurol.2015.1285
Abstract
Longitudinal cerebrospinal fluid biomarker changes in preclinical Alzheimer’s disease during middle age
Importance Individuals in the presymptomatic stage of Alzheimer disease (AD) are increasingly being targeted for AD secondary prevention trials. How early during the normal life span underlying AD pathologies begin to develop, their patterns of change over time, and their relationship with future cognitive decline remain to be determined.
Objective To characterize the within-person trajectories of cerebrospinal fluid (CSF) biomarkers of AD over time and their association with changes in brain amyloid deposition and cognitive decline in cognitively normal middle-aged individuals.
Design, Setting, and Participants As part of a cohort study, cognitively normal (Clinical Dementia Rating [CDR] of 0) middle-aged research volunteers (n = 169) enrolled in the Adult Children Study at Washington University, St Louis, Missouri, had undergone serial CSF collection and longitudinal clinical assessment (mean, 6 years; range, 0.91-11.3 years) at 3-year intervals at the time of analysis, between January 2003 and November 2013. A subset (n = 74) had also undergone longitudinal amyloid positron emission tomographic imaging with Pittsburgh compound B (PiB) in the same period. Serial CSF samples were analyzed for β-amyloid 40 (Aβ40), Aβ42, total tau, tau phosphorylated at threonine 181 (P-tau181), visinin-like protein 1 (VILIP-1), and chitinase-3-like protein 1 (YKL-40). Within-person measures were plotted according to age and AD risk defined by APOE genotype (ε4 carriers vs noncarriers). Linear mixed models were used to compare estimated biomarker slopes among middle-age bins at baseline (early, 45-54 years; mid, 55-64 years; late, 65-74 years) and between risk groups. Within-person changes in CSF biomarkers were also compared with changes in cortical PiB binding and progression to a CDR higher than 0 at follow-up.
Main Outcomes and Measures Changes in Aβ40, Aβ42, total tau, P-tau181, VILIP-1, and YKL-40 and, in a subset of participants, changes in cortical PiB binding.
Results While there were no consistent longitudinal patterns in Aβ40 (P = .001-.97), longitudinal reductions in Aβ42 were observed in some individuals as early as early middle age (P ≤ .05) and low Aβ42 levels were associated with the development of cortical PiB-positive amyloid plaques (area under receiver operating characteristic curve = 0.9352; 95% CI, 0.8895-0.9808), especially in mid middle age (P < .001). Markers of neuronal injury (total tau, P-tau181, and VILIP-1) dramatically increased in some individuals in mid and late middle age (P ≤ .02), whereas the neuroinflammation marker YKL-40 increased consistently throughout middle age (P ≤ .003). These patterns were more apparent in at-risk ε4 carriers (Aβ42 in an allele dose-dependent manner) and appeared to be associated with future cognitive deficits as determined by CDR. Conclusions and Relevance Longitudinal CSF biomarker patterns consistent with AD are first detectable during early middle age and are associated with later amyloid positivity and cognitive decline. Such measures may be useful for targeting middle-aged, asymptomatic individuals for therapeutic trials designed to prevent cognitive decline.
“Longitudinal cerebrospinal fluid biomarker changes in preclinical Alzheimer’s disease during middle age” by Courtney L. Sutphen, BS; Mateusz S. Jasielec, MS; Aarti R. Shah, MS; Elizabeth M. Macy, BA; Chengjie Xiong, PhD; Andrei G. Vlassenko, MD, PhD; Tammie L. S. Benzinger, MD, PhD; Erik E. J. Stoops, Eng; Hugo M. J. Vanderstichele, PhD; Britta Brix, PhD; Heather D. Darby, MSc; Manu L. J. Vandijck, MSc; Jack H. Ladenson, PhD; John C. Morris, MD; David M. Holtzman, MD; and Anne M. Fagan, PhD in JAMA Neurology. Published online July 6 2015 doi:10.1001/jamaneurol.2015.1285
