OBJECTIVE To examine whether plasma markers of amyloid precursor protein metabolism (amyloid beta-protein ending in Val-40 [Abeta40] and Ala-42 [Abeta42]), inflammation (high-sensitivity C-reactive protein), and folic acid metabolism (folic acid, vitamin B(12), and total homocysteine levels) are associated with the rate of cognitive and functional decline in persons with Alzheimer disease. DESIGN Longitudinal study across a mean (SD) of 4.2 (2.6) years with assessments at approximately 6- to 12-month intervals. SETTING Outpatient care. PATIENTS A cohort of 122 patients having a clinical diagnosis of probable Alzheimer disease, each with at least 2 assessments across time. MAIN OUTCOME MEASURES Scores on the cognitive Information-Memory-Concentration subscale of the Blessed Dementia Scale and the functional Weintraub Activities of Daily Living Scale. RESULTS Low plasma levels of Abeta40, Abeta42, and high-sensitivity C-reactive protein were associated with a significantly more rapid cognitive decline, as indexed using the Blessed Dementia Scale, than were high levels. Low levels of Abeta42 and high-sensitivity C-reactive protein were significantly associated with more rapid functional decline on the Weintraub Activities of Daily Living Scale than were high levels. These plasma markers contributed about 5% to 12% of the variance accounted for on the Blessed Dementia Scale and the Activities of Daily Living Scale by fixed-effects predictors. Measures of folic acid metabolism were not associated with changes on either the Blessed Dementia Scale or the Activities of Daily Living Scale. CONCLUSIONS Plasma markers of amyloid precursor protein metabolism and C-reactive protein may be associated with the rate of cognitive and functional decline in patients with Alzheimer disease.