Background  Abnormal cerebrospinal fluid (CSF) biomarker levels predict development of Alzheimer disease with good accuracy and are thought to precede cognitive deterioration.

Objective  To investigate whether changes in CSF biomarker levels over time in healthy older adults are associated with a concurrent decline in cognitive performance.

Design  Retrospective analysis of longitudinal CSF biomarker levels and clinical data.

Setting  A combined academic dementia disorder research center and dementia clinic.

Participants  Thirty-seven cognitively healthy older volunteers (mean age, 73 years).

Main Outcome Measures  Longitudinal CSF total tau protein, hyperphosphorylated tau protein 181, and β-amyloid_1-42 protein levels and cognitive assessments at baseline and at follow-up 4 years later.

Results  Low levels of CSF β-amyloid_1-42 protein at follow-up were associated with decreased delayed word recall score on the Alzheimer Disease Assessment Scale–cognitive subscale (r_s = –0.437, P < .01) and with slower results on A Quick Test of Cognitive Speed (r_s = –0.540, P < .001). Individuals with a decrease during the 4-year study of 15% or more in CSF β-amyloid_1-42 protein level performed worse on the Alzheimer Disease Assessment Scale–cognitive subscale delayed word recall (z = –2.18, P < .05) and A Quick Test of Cognitive Speed (z = –2.35, P < .05) at follow-up. An increase over time of 20% or more in CSF hyperphosphorylated tau protein 181 level correlated with slower results on A Quick Test of Cognitive Speed at follow-up (z = –2.13, P < .05). Furthermore, the presence of the APOE-4 (OMIM 107741) allele was associated with a greater longitudinal decrease in CSF β-amyloid_1-42 protein level (² = 10.47, P < .05) and with a higher CSF total tau protein level at follow-up (² = 8.83, P < .05). No correlation existed between baseline CSF biomarker levels and baseline or follow-up cognitive scores.

Conclusions  In this group of healthy older adults, changes in CSF biomarker levels previously associated with Alzheimer disease correlated with a decline in cognitive functions. Changes in CSF biomarker levels may identify early neurodegenerative processes of Alzheimer disease.