Diagnosis and treatment of dementia: 1. Risk assessment and primary prevention of Alzheimer disease

Abstract

Background: In addition to nonmodifiable genetic risk factors, potentially modifiable factors such as hypertension, hyperlipidemia and environmental exposures have been identified as risk factors for Alzheimer disease. In this article, we provide physicians with practical guidance on risk assessment and primary prevention of Alzheimer disease based on recommendations from the Third Canadian Consensus Conference on the Diagnosis and Treatment of Dementia, held in March 2006.

Methods: We developed evidence-based guidelines using systematic literature searches, with specific criteria for study selection and quality assessment, and a clear and transparent decision-making process. We selected studies published from January 1996 to December 2005 that met the following criteria: dementia (all-cause, Alzheimer disease or vascular dementia) as the outcome; longitudinal cohort study; study population broadly reflective of Canadian demographics; and genetic risk factors and general risk factors (e.g., hypertension, education, occupation and chemical exposure) identified. We graded the strength of evidence using the criteria of the Canadian Task Force on Preventive Health Care.

Results: Of 3424 articles on potentially modifiable risk factors for dementia, 1719 met our inclusion criteria; 60 were deemed to be of good or fair quality. Of 1721 articles on genetic risk factors, 62 that met our inclusion criteria were deemed to be of good or fair quality. On the basis of evidence from these articles, we made recommendations for the risk assessment and primary prevention of Alzheimer disease. For the primary prevention of Alzheimer's disease, there is good evidence for controlling vascular risk factors, especially hypertension (grade A), and weak or insufficient evidence for manipulation of lifestyle factors and prescribing of medications (grade C). There is good evidence to avoid estrogens and high-dose (> 400 IU/d) of vitamin E for this purpose (grade E). Genetic counselling and testing may be offered to at-risk individuals with an apparent autosomal dominant inheritance (grade B). Screening for the apolipoprotein E genotype in asymptomatic individuals in the general population is not recommended (grade E).

Interpretation: Despite the personal and societal burden of dementia, our understanding of genetic predisposition to dementias and the contribution of other risk factors remains limited. More importantly, there are few data to explain the overall risks and benefits of prevention strategies or their impact of risk modification.

Box 1

Figure 1: The amyloid precursor protein (APP) is a transmembrane protein that can undergo a series of proteolytic cleavage by secretase enzymes. When it is cleaved by α-secretase in the middle of the β-amyloid domain (Aβ), it is not amyloidogenic. However, when APP is cleaved by β- and γ-secretase enzymes, neurotoxic Aβ peptides are released, which can accumulate into oligomer aggregate. Mutations in the APP gene tend to inhibit cleavage by α-secretase and consequently enable preferential cleavage by β-secretase. Mutations in the presenilin-1 and presenilin-2 genes (PSEN1 and PSEN2), which are components of the γ-secretase complex, increase cleavage by γ-secretase at this site. In both situations, the result is excess Aβ peptide production. The current Aβ hypothesis suggests that the soluble oligomers can impair synaptic function between neurons. Simultaneously, the oligomers may aggregate into insoluble β-sheet amyloid fibrils, which can trigger a local inflammatory response. Over time, the subsequent oxidative stress and biochemical changes ultimately lead to neuronal death and the development of neuritic plaques typical of Alzheimer disease. Image by: Lianne Friesen and Nicholas Woolridge

Figure 2: Images of normal hippocampus (A) and hippocampus of a patient with Alzheimer disease (B) [Bielschowsky stain]. The numerous dark brown spots seen in the abnormal hippocampus are the neuritic plaques typical of Alzheimer disease. At higher magnification (C), these plaques (black arrows) and tangles (white arrows) seen in Alzheimer disease are clearly visible. Image by: Images courtesy of Dr. Ian R.A. MacKenzie, Department of Pathology, University of British Columbia

Box 2