PMID 19433664

Cerebrospinal Fluid Biomarkers and Rate of Cognitive Decline in Very Mild Dementia of the Alzheimer Type

Barbara J. Snider et al. Washington U. May 2009

Background

Amyloid Beta: formed after cleavage of the transmembrane amyloid precursor protein (APP) by a β-seceratase followed by a cleave by γ-secretase. Depending on location of cleavage by the γ-secretase, various isoforms, including Aβ40 and Aβ42 are formed. The Aβ42 is associated with plaques found in patients with AD. Tau: microtubule-associate protein (MAP). Interact with tubulin to stabilize microtubules. Phosphorylated tau (ptau) is the major component of neurofibrillary tangles found in patients with AD.

Introduction

Goal: “Determine whether Aβ42, tau, and ptau predict the rate of cogntive change in individuals with very mild dementia of the Alzheimer type (DAT)”. Patients with mild cognitive impairments and a raised level of Aβ42 are 17.7 times more likely to be diagnosed with DAT in the next 5 years. Healthy individuals with increased CSF Aβ42:tau and Aβ42:ptau ratios are 4 to 5 times more likely to be diagnosed with DAT in the next 3 or 4 years.

Methods

Participants: 49; at least 60 years old, healthy Diagnosed with DAT with a clinical dementia rating (CDR) of 0.5. 5 point scale to characterize 6 cognitive and functional domains (memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care) obtained through an interview with the patient and a reliable informant. Genotyped for APOε Annual assessment CDR Psychometric test: episodic memory, semantic memory and language, and executive function. LP: tau, ptau, Aβ42, Aβ40

• Low score on CDR-SB and high score on psychometric test = high cognitive functioning

Results:� Baseline assessment

No significant correlation between the biomarkers and age, years of education, the CDR-SB score, or the psychometric test score at the time of initial LP. Patients with at least one APOε4 allele had lower levels of Aβ42. Patients diagnosed with mood disorders (including depression) had higher levels of Aβ42. “Deposition of the Aβ42 peptide in plaques is considered the underlying basis for the approximately 50% decrease in CSF Aβ42 levels seen in AD. Although not totally undisputed, this theory is supported by the strong correlation between low CSF Aβ42 levels and high numbers of plaques in the neocortex and hippocampus....” Mattsson, 2009.

Results:� Correlation of baseline CSF Aβ42 levels with changes in CDR-SB scores

CDR-SB scores across time in 10 individuals with lowest vs. 10 individuals with highest CSF Aβ42 levels. Individuals with lowest CSF Aβ42 levels had a faster rate of cognitive decline.

Results:� Correlation of baseline biomarker levels with rate of change of CDR-SB scores

Divided participants into tertiles (low, medium, and high levels of biomarkers at initial LP). Calculated difference in the slopes of scores between tertiles for Aβ42, Aβ40, tau, ptau, and tau:Aβ42 and ptau:Aβ42 ratios.

Results:� Correlation of biomarker measures with changes in psychometric scores

Conclusion Individuals with:

lower CSF Aβ42 
higher CSF tau
higher CSF ptau 
higher CSF tau:Aβ42 
higher CSF ptau:Aβ42

exhibited a more rapid increase in cognitive impairment. Hence, baseline values of these biomarkers can be used to predict the rate of cognitive decline in individuals with mild dementia.

Discussion

CSF Aβ42 levels decrease before symptoms of cognitive impairment develop and then remain stable as AD progresses. Progression may not be linear throughout the course of the disease; slower at milder stages. CSF biomarker levels may be used as criteria for enrolling patients with mild cognitive impairments into therapy and drug trials. May help reduce the number of subjects needed.