OBJECTIVE:

To elucidate the relationship between the 2 hallmark proteins of Alzheimer disease (AD), amyloid-(Aβ) and tau, and clinical decline over time among cognitively normal older individuals.

DESIGN:

A longitudinal cohort of clinically and cognitively normal older individuals assessed with baseline lumbar puncture and longitudinal clinical assessments.

SETTING:

Research centers across the United States and Canada.

PATIENTS:

We examined 107 participants with a Clinical Dementia Rating (CDR) of 0 at baseline examination.

MAIN OUTCOME MEASURES:

Using linear mixed effects models, we investigated the relationship between cerebrospinal fluid (CSF) phospho-tau 181 (p-tau(181p)),CSF Aβ(1-42), and clinical decline as assessed using longitudinal change in global CDR, CDR-Sum of Boxes, and the Alzheimer Disease Assessment Scale-cognitive subscale.

RESULTS:

We found a significant relationship between decreased CSF Aβ(1-42) and longitudinal change in global CDR,CDR-Sum of Boxes, and Alzheimer Disease Assessment Scale-cognitive subscale in individuals with elevated CSFp-tau(181p). In the absence of CSF p-tau(181p), the effect of CSF Aβ(1-42) on longitudinal clinical decline was not significantly different from 0.

CONCLUSIONS:

In cognitively normal older individuals,A-associated clinical decline during a mean of 3 years may occur only in the presence of ongoing downstream neurodegeneration.