Vascular risk factors and Alzheimer's disease: are these risk factors for plaques and tangles or for concomitant vascular pathology that increases the likelihood of dementia? An evidence-based review

Abstract

Recent epidemiologic studies have noted that risk factors for atherosclerosis (for example, diabetes mellitus, hypertension, and hyperlipidemia) are associated with increased risk of incident Alzheimer's disease (AD). In this evidence-based review, we frame the proposition as a question: are vascular risk factors also risk factors for plaques and tangles or just for concomitant vascular pathology that increases the likelihood of dementia? To date, no representative, prospective studies with autopsy (evidence level A) show significant positive associations between diabetes mellitus, hypertension, or intracranial atherosclerosis and plaques or tangles. Some prospective, representative, epidemiologic studies (evidence level B) show associations between diabetes, hypertension, hyperlipidemia, and aggregated risk factors with clinically diagnosed incident AD. However, the strength of association diminishes in the following order: vascular dementia (VaD) > AD + VaD > AD. This pattern is arguably more consistent with the hypothesis that atherosclerosis promotes subclinical vascular brain injury, thereby increasing the likelihood of dementia and in some cases making symptoms present earlier. Several autopsy studies from AD brain banks (evidence level C) have observed positive associations between intracranial atherosclerosis and severity of plaques and tangles. However, these studies may reflect selection bias; these associations are not confirmed when cases are drawn from non-dementia settings. We conclude that, at the present time, there is no consistent body of evidence to show that vascular risk factors increase AD pathology.

Figure 1

Graph showing two alternative explanations. Do vascular risk factors (VRF) increase the probability of dementia by increasing plaques and tangles (arrows) or through subclinical infarcts (INF) (red line)? AD, Alzheimer's disease.

Figure 2

Sampling frame for convenience sample of Alzheimer's disease subjects and normal controls. Green shows two samples of normal controls (CN): CN1 is highly selected and CN2 is randomly sampled. In a cohort of Alzheimer's disease subjects (AD) and CN1, an association will be found between arteriosclerosis and Alzheimer's disease. In a cohort of AD and CN2, no such association will be found.

Figure 3

Sampling frame for a longitudinal aging cohort. An aging cohort study includes normal controls and subjects with Alzheimer's disease (AD) and stroke. The severity of arteriosclerosis and vascular risk factors are randomly sampled and representative for each group.

Figure 4

Sampling frame for a longitudinal aging cohort. At baseline examination, prevalent cases of stroke and Alzheimer's disease (AD) are identified and excluded from longitudinal follow-up.

Figure 5

Sampling frame for a longitudinal aging cohort. Prospective longitudinal follow-up allows estimation of new incident cases of stroke and Alzheimer's disease (AD). In ideal circumstances, it also allows the collection of a representative autopsy sample.