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Persons inheriting fully penetrant autosomal dominant mutations causing familial Alzheimer disease (AD) provide the opportunity to characterize presymptomatic biomarker changes in a population where studies might be performed to efficiently identify preventative interventions. Decreased Aβ42 and increased total tau (t-tau) and phosphorylated tau (p-tau) in CSF are associated with incident1 and established AD.2 These markers have been increasingly incorporated as outcome measures for clinical trials, but further characterization of their natural course is necessary to interpret such studies. Though longitudinal changes in these markers are expected for individuals developing AD, such changes have yet to be thoroughly documented prospectively. Here we report changes in AD CSF biomarkers over time in a presymptomatic carrier of the V717I mutation in the amyloid precursor protein (APP) gene.3
Due to confidentiality issues, the gender and chronological age of this individual are not disclosed. As the age of disease onset can be consistent within families harboring this APP mutation,3 we report the individual's age relative to the median age of dementia diagnosis within their family. The subject was enrolled in a UCLA institutional review board– approved study of persons at risk for familial AD in which participants undergo in-depth clinical, genetic, and biochemical assessments. CSF was collected and stored in polypropylene tubes. Samples were centrifuged and the supernatant stored at −80°C. Initial and follow-up samples were later analyzed for t-tau, p-tau181, and Aβ42 levels using Innogenetics INNO-BIA AlzBio3 multiplex assays on standardized xMAP Luminex technology in duplicate in the same run. The interassay coefficient of variation reported by the manufacturer is 7.7%, which was verified in a storage stability study. The presence of the V717I substitution in APP was assessed with direct sequencing. Clinical assessment including comprehensive neuropsychological testing and the Clinical Dementia Rating (CDR) scale were performed blind to mutation status.
At the time of the initial lumbar puncture (LP), the participant was 22 years younger than the median age of dementia diagnosis within the family, performed within normal limits on neuropsychological testing, and scored 0 on the CDR. The second LP was performed 4.5 years later, at which time neuropsychological performance remained stable and CDR remained 0. Longitudinal CSF analyses indicated that Aβ42 levels decreased from 683.8 pg/mL to 575.6 pg/mL (−16%), t-tau levels increased from 88.3 pg/mL to 107.6 pg/mL (+22%), and p-tau181 levels increased from 30.8 pg/mL to 48.8 pg/mL (+58%). Corresponding values of Aβ42, t-tau, and p-tau181 in 5 nonmutation carrying family members enrolled in the same study from whom CSF was obtained and assays performed in an identical manner (mean adjusted age 6 years prior to dementia diagnosis) were 618.4 pg/mL (SEM = 44.8), 50.5 pg/mL (SEM = 4.2), and 24.6 pg/mL (SEM = 4.1). Therefore, in the 4.5-year interval between LPs, Aβ42 fell from the high to low range of normal. t-Tau was already elevated at baseline and at follow-up both t-tau and p-tau181 levels had increased to levels above those of persons not carrying familial AD mutations.
We previously demonstrated decreased Aβ42/Aβ40 ratios and increased t-tau and p-tau181 in CSF from presymptomatic familial AD mutation carriers4 with virtually no overlap between tau levels in mutation carriers and noncarriers. Cross-sectional differences in Aβ42, t-tau, and p-tau181 levels between controls and patients with AD are well-documented.2 However, longitudinal changes in these biomarkers have not been consistently reported in prior studies and recent work indicates these measures remain relatively stable over intervals of up to 2 years in mild cognitive impairment (MCI) and AD.5 A recent study in persons without dementia (mean age 73 years) found that though baseline CSF Aβ42, t-tau, and p-tau181 levels were not related to cognitive function, decreasing CSF Aβ42 and increasing p-tau181 levels over 4 years' time were associated with cognitive decline.6 Furthermore, the APOE ϵ4 allele was associated with greater decreases in Aβ42 and increases in t-tau. Another study found stability of CSF Aβ42 and t-tau levels among cognitively normal subjects, persons with MCI, and persons with AD over a 1-year period except for a modest increase in t-tau in elderly controls (mean age 75).7
Our findings indicate that CSF biomarker changes occur early during the presymptomatic state in familial AD and we found substantial changes between 22 and 17 years before the expected onset of dementia. Though persons carrying familial AD mutations allow one to sensitively identify the time course of biomarker changes during the presymptomatic period, the degree to which these findings can be generalized to late-onset AD is unclear. Verification of our results with larger numbers of subjects awaits larger studies such as those of the Dominantly Inherited Alzheimer Network (http://www.dian-info.org/).
Disclosure: Dr. Ringman receives research support from Pfizer Inc, Elan Corporation, the NIH, Easton Consortium for Alzheimer's Disease Drug Discovery and Biomarker Development, the Sidell Kagan Foundation, and the Shirley and Jack Goldberg Trust. K. Taylor reports no disclosures. Dr. Teng receives research support from the NIH/NIA, AFAR, the John A. Hartford Foundation, the Atlantic Philanthropies, the Starr Foundation, and John Douglas French Alzheimer's Foundation; and holds stock/stock options in Eli Lilly and Company, GE Healthcare, Cerner Corporation, and Bristol-Myers Squibb. Dr. Coppola receives research support from the NIH, the Consortium for Frontotemporal Dementia Research, the Adelson Medical Research Foundation, the Tau Consortium, and the Easton Consortium. Dr. Gylys receives research support from the NIH.