Am J Geriatr Psychiatry 8:3, Summer 2000 257 Apolipoprotein-E and White-Matter Hyperintensities in Late-Life Depression Helen Lavretsky, M.D., Ira M. Lesser, M.D. Marcy Wohl, R.N., Bruce L. Miller, M.D. C. Marc Mehringer, M.D., Harry V. Vinters, M.D. The authors conducted a follow-up study of 16 patients with late-life depression ap- proximately 6 years after their initial assessment to evaluate the relationships be- tween apolipoprotein-E (APO-E) status and white-matter hyperintensities (WMH). Ten patients had WMH at baseline, and four patients demonstrated an increase in WMH size over time. Three of four patients with the APO-E e4 allele demonstrated an increase in WMH over time, and only 1 of 12 patients without an e4 allele had an increase in WMH. Three of four patients with APO-E e4 allele developed a chronic course of major depression at follow-up. Patients with APO-E e4 had a higher number of depressive episodes and lower age at onset. APO-E may be a risk factor for cerebrovasculardis- ease associated with late-life depression and may affect the clinical characteristics and disease course of depression. (Am J Geriatr Psychiatry 2000; 8:257–261) Received May 18, 1999; revised November 15, 1999; accepted November 23, 1999. From the UCLA School of Medicine, Department of Psychiatry. Address correspondence to Dr. Lavretsky, UCLA–NeuropsychiatricInstitute, Room 37-425, 760 Westwood Pl., Los Angeles CA 90024. Copyright  2000 American Association for Geriatric Psychiatry M ajor depression in elderly patients is frequently se- vere and associated with higher rates of morbidity and mortality. 1,2 The presence of medical comorbidity and chronic illnesses, such as cardio- and cerebrovas- cular diseases, is frequently a component of, as well as a risk factor for, late-life depression. 3–7 Strategies such as neuroimaging or genetic screening for underlying de- menting illnesses may be useful procedures to detect these age-associated pathogenic processes. 8 The evidence of cerebrovascular disease can be seen on magnetic resonance imaging (MRI) by identi- fying areas of signal hyperintensities on T 2 -weighted im- ages in white matter (WMH). Several cross-sectional studies demonstrated associations among WMH, corti- cal atrophy, and depression, particularly in late-onset depression (LOD). 9–18 Other reported clinical features of depression associated with WMH include cognitive impairment and psychotic features, 18–21 poor response to pharmacotherapy, 22–23 and increased risk of devel- oping Alzheimer’s disease when cognitive impairments present during a depressive episode. 13,14,18–20,24 Major identified risk factors for WMH include advanced age and hypertension. 13,14,18 WMH in the deep white mat- ter, periventricular WMH, and lesions of the basal gan- glia (e.g., caudate) are most frequently reported in as- sociation with LOD. 18,19 Apolipoprotein-E (APO-E) is known to play a role in lipid metabolism and cholesterol transport important in cardiovascular and cerebrovascular disease. 25,26 It is also known as a major susceptibility locus that accounts for approximately half the heritability of late-onset Alz- heimer’s disease (AD). 25 The presence of the APO-E e4 allele is associated with increased risk for AD and lower age at onset, 25 as well as increased risk for cardio- and