Cerebrospinal Fluid Levels ofβ-Amyloid 1-42, but Not of Tau, Are Fully Changed Already 5 to 10 Years Before the Onset of Alzheimer Dementia

TLDR

Early detection of prodromal Alzheimer disease is crucial because disease‑modifying therapies are most likely to be effective when initiated during the early stages of disease. The study aimed to evaluate whether CSF biomarkers total tau, phosphorylated tau, and β‑amyloid 1‑42 could predict future development of AD dementia within 9.2 years in patients with mild cognitive impairment and to compare biomarker levels between early and late converters. The authors conducted a clinical study of 137 MCI patients at a memory disorder clinic, performing baseline lumbar puncture to measure CSF biomarkers and following them for a median of 9.2 years to assess conversion to AD dementia. In a 9.2‑year follow‑up of 137 MCI patients, baseline CSF Aβ42 was markedly reduced in those who later developed AD, while T‑tau and P‑tau were elevated; the Aβ42:P‑tau ratio predicted AD with 88% sensitivity and 90% specificity, and about 90% of patients with abnormal CSF biomarkers progressed to AD within 9–10 years, indicating that Aβ42 changes precede tau pathology.

Abstract

<h3>Context</h3>Early detection of prodromal Alzheimer disease (AD) is important because new disease-modifying therapies are most likely to be effective when initiated during the early stages of disease.<h3>Objectives</h3>To assess the ability of the cerebrospinal fluid (CSF) biomarkers total tau (T-tau), phosphorylated tau (P-tau), andβ-amyloid 1-42 (Aβ42) to predict future development of AD dementia within 9.2 years in patients with mild cognitive impairment (MCI) and to compare CSF biomarkers between early and late converters to AD.<h3>Design</h3>A clinical study with a median follow-up of 9.2 years (range, 4.1-11.8 years). <h3>Setting</h3>Memory disorder clinic.<h3>Patients</h3>A total of 137 patients with MCI who underwent lumbar puncture at baseline.<h3>Main Outcome Measure</h3>Conversion to AD dementia. <h3>Results</h3>During follow-up, 72 patients (53.7%) developed AD and 21 (15.7%) progressed to other forms of dementia. At baseline, CSF Aβ42 levels were reduced and T-tau and P-tau levels were elevated in patients who converted to AD during follow-up compared with nonconverters (P &lt; .001). Baseline CSF Aβ42 levels were equally reduced in patients with MCI who converted to AD within 0 to 5 years (early converters) compared with those who converted between 5 and 10 years (late converters). However, CSF T-tau and P-tau levels were significantly higher in early converters vs late converters. A baseline Aβ42:P-tau ratio predicted the development of AD within 9.2 years with a sensitivity of 88%, specificity of 90%, positive predictive value of 91%, and negative predictive value of 86%.<h3>Conclusions</h3>Approximately 90% of patients with MCI and pathologic CSF biomarker levels at baseline develop AD within 9 to 10 years. Levels of Aβ42 are already fully decreased at least 5 to 10 years before conversion to AD dementia, whereas T-tau and P-tau seem to be later markers. These results provide direct support in humans for the hypothesis that altered Aβ metabolism precedes tau-related pathology and neuronal degeneration.