Plasma Aß Levels and Cerebrovascular Disease in Nondemented Carriers of an E4 Allele

Abstract & Commentary

Source: Van Dijk EJ, et al. Plasma Amyloid ß Apolipoprotein E, lacunar infarcts, and white matter lesions. Ann Neurol. 2004;55:570-575.

Cerebral white matter lesions (WML) and lacunar infarcts frequently are observed on MRI scans in elderly subjects. They are considered to be caused by disease of small vessels, with hypertension, advanced age, and cerebral amyloid angiopathy (CAA) as the most important risk factors. In CAA, amyloid ß peptide (Aß) is deposited in small and medium-sized cerebral arteries. The Aß peptide consists of either 40 (Aß 1-40) or 42 (Aß 1-42) amino acids derived from the proteolytic processing of the amyloid precursor protein.

Van Dijk and colleagues investigated whether plasma Aß levels were associated with lacunar infarcts and WML in the general population, and whether the apolipoprotein E (APOE) genotype modified this association. They studied more than 1000 participants in the Rotterdam Scan Study1 who were 60 to 90 years of age and not demented. Cross-sectional associations were analyzed with adjustments for age, sex, creatine level, and hypertension.

In APOE E4 carriers, plasma Aß levels were positively associated with lacunar infarcts and WML. Plasma Aß 1-40 and Aß 1-42 levels increased with age and creatine levels (see Table below).

Characteristics of Participants


Aß 1-40 levels were higher in hypertensives and Aß 1-42 levels were lower in APOE E4 carriers. Gender, smoking, and diabetes were not associated with plasma Aß levels.

Van Dijk et al offer several speculative explanations for the association between higher plasma Aß levels and cerebral small vessel disease in APOE E4 carriers, but not in noncarriers. It may be that fibrillary deposits of Aß in the vessel wall lead to obliteration of the vessel lumen and subsequent lacunes and WML. Alternatively, soluble Aß may alter cerebral autoregulation by enhancing endothelium-dependent vasoconstriction. Another possibility is that higher Aß levels result from cerebral hypoperfusion and might, in turn, via vascular deposition of Aß, make hypoperfusion worse. The possible role of the APOE E4 allele in all 3 scenarios would be to facilitate transport of Aß from the CSF into vascular smooth muscle cells.


The observation that APOE E4 in combination with elevated plasma Aß levels is associated with cerebral small vessel disease is new but not surprising. APOE E4 has been linked to pathologic changes in several brain diseases from Alzheimer’s Disease to multiple sclerosis.2 The possible mechanisms whereby APOE E4 influences disease progression include, among others, impaired neuronal repair and plasticity, accelerated neuronal degeneration and direct tissue damage via oxidative inflammatory and neurotoxic mechanisms. Given the impact of APOE E4 on the course of several disease processes, it may be that in the near future, APOE testing will become a routine screening test. — John J. Caronna

Dr. Caronna, Vice-Chairman, Department of Neurology, Cornell University Medical Center, Professor of Clinical Neurology, New York Hospital, is Associate Editor of Neurology Alert.


1. Hofman A, et al. Eur J. Epidemiol. 1991;7:403-422.

2. Enzinger C, et al. Ann Neurol. 2004;55:563-569.