OBJECTIVE: To analyze a putative relationship between white matter lesions (WMLs), risk factors for WMLs, and Alzheimer disease (AD) as measured with the surrogate marker CSF Abeta42. METHODS: The authors analyzed effects of acquired risk factors for cerebrovascular disease and WMLs on AD as measured with an intermediate marker, CSF Abeta42. A total of 127 consecutive patients with subjective memory impairment (mean age 66 years; 57 women) investigated at a university-based memory clinic had brain MRI scans. WMLs were rated on a 12-point scale with a semiquantitative procedure. They used path analysis with established and possible risk factors for WMLs and for reduced CSF Abeta42 (age, hypertension, hyperhomocysteinemia, hypercholesterolemia, APOE-epsilon4) as variables. RESULTS: The WML score was 1.5 points higher (p < 0.05) in hypertensive than in nonhypertensive patients and 1.9 points higher (p < 0.05) in patients with hyperhomocysteinemia than in those with normal homocysteine levels. Hypercholesterolemia increased the probability of low CSF Abeta42 levels by 0.2 (p < 0.05). For each point increase in WML score, the probability of low CSF Abeta42 levels increased by 0.03 (p < 0.05). APOE-epsilon4 was associated with reduced CSF Abeta42 (p < 0.01). CONCLUSION: Both hypercholesterolemia and white matter lesions may contribute to low CSF Abeta42 by independent mechanisms.