Chapter 4: Mapping Connections: An understanding of neurological conditions in Canada – Risk factors

4. Risk factors for neurological conditions

Given the spectrum of impacts caused by neurological conditions on individuals (Chapter 1), the extent and costs of their care needs (Chapter 2), as well as the number of Canadians potentially affected by these conditions (Chapter 3), the prevention and early detection of neurological conditions are important strategies for alleviating their burden at the individual, community, and health care levels. Two projects of the Study were devoted to identifying and outlining the biological, lifestyle, socioeconomic, environmental, psychosocial, and genetic factors that are potentially associated with the development and progression of 14 neurological conditions [13][14]. The project teams reviewed several thousand articles, applied predetermined criteria to select systematic reviews, meta-analyses, and observational studies, and analyzed them using a process of qualitative synthesis.

Risk factors for disease progression were exceedingly difficult to identify [14], as it was often impossible to disentangle risk factors for onset from determinants of progression or rate of progression. To do so would require repeated observations over time, beginning with or before the earliest manifestations of the condition and continuing until its advanced stages, and for some conditions, even after the death of the individual.

4.1 Potential modifiable risk factors for the onset of neurological conditions are being identified

Associations identified by the Onset Risk Factors Project [13] that could be modified by available interventions were particularly relevant, as they offer the potential for the prevention or mitigation of neurological conditions. For example, the synthesis of the literature confirmed that some cardiovascular risk factors, such as smoking and diabetes, are not only associated with the development of stroke but also with Alzheimer’s disease and other dementias. Brain injury, a neurological condition in itself, was also identified as a risk factor for Alzheimer’s disease and other dementias in men, and for epilepsy in both sexes. In turn, addressing falls in the aging population would help reduce risks associated with the development of traumatic brain and spinal cord injuries. The synthesis of the literature performed by this project team also corroborated that environmental risk factors, such as vitamin D deficiency, were associated with multiple sclerosis and that exposure to pesticides was associated with Alzheimer’s disease and other dementias, ALS, brain tumours, and Parkinson’s disease. It was further noted that complications of pregnancy and delivery were associated with several neurological conditions in children.

Identifying potential factors in the prevention of neurological conditions is encouraging, but when reviewing these results, it is important to understand that the presence of a factor associated with a condition does not necessarily imply that it is the cause of the condition, and conversely, its absence would not guarantee that an individual would not develop the condition. Furthermore, some of the associations identified by this project may only occur in a small percentage of the cases of a specific neurological condition, or may only apply to specific populations. These findings may be useful to future researchers seeking to determine population attributable risks. The Onset Risk Factors Project [13] research team recognized the need to assess both the clinical and public health significance of these risk factors; that is, if a risk factor is only associated with a small proportion of cases of a rare neurological condition, the impact of an intervention would be smaller from a public health perspective than if the risk factor is associated with a large proportion of cases of a common neurological condition. The Onset Risk Factors Project [13] team is currently applying these considerations to their project.Footnote 48 

The existing information on risk factors will eventually be expanded by other projects of the Study. For instance, the Canadian Longitudinal Study on Aging: Neurological Conditions Initiative (CLSA–NCI) Project [5] aims to incorporate in its study a long-term assessment of risk and predictive lifestyle factors for epilepsy, dementia, Parkinson's disease, and brain injury. In addition, existing data sources, such as those of the EMR and interRAI Projects [6][8], could be developed further to yield additional insights into the lifestyle, socioeconomic, and environmental factors that constitute risks for specific neurological conditions. Eventual incorporation of risk factor dynamics into the seven microsimulation models would improve the precision of model projections and would allow for the evaluation of various outcomes obtained using different interventions [10]. Finally, expanding existing disease or patient registries, which was an objective of the Cerebral Palsy Registry Project [4], will improve study power in the identification of risk factors for low prevalence neurological conditions. This information may eventually assist Canadians in the reduction of their risk at the individual level, and may lead to strategies for the prevention and early detection of neurological conditions.

4.2 Genetic factors for the onset of neurological conditions are being identified

Certain neurological conditions targeted by the Study are caused by mutations of single genes that can be identified by highly predictive genetic tests. In conditions such as dystonia, Huntington's disease, and muscular dystrophy, the recognition of such genes as risk factors has considerable prognostic value. Certain autosomal dominant forms of Alzheimer's disease can be caused by mutations of the genes for amyloid precursor protein, presenilin 1 (PSEN1), or presenilin 2 (PSEN2). Moreover, approximately 10% of Parkinson’s disease cases are attributable to mutations of single genes, either dominant (SNCA, LRRK2) or autosomal recessive (Parkin, PINK1, DJ-1). Familial ALS makes up 5% of all ALS patients.Footnote 49  A mutation in SOD1 (Cu/Zn superoxide dismutase) was found in 20% of familial ALS cases; other mutations (e.g. FUS, TARDBP and C9ORF72) were also identified.Footnote 50 

Other neurological conditions result from the interplay of one or more susceptibility genes and toxic or environmental factors (that are often unidentified). Examples include sporadic Alzheimer's disease (APOE e4 allele and other genes), ALS (ATAXIN-2 and others), epilepsy (genes for voltage-gated or ligand-gated ion channels),Footnote 51 multiple sclerosis (HLA-DRB1*1501 allele and unidentified genes suspected on the basis of familial studies), and Parkinson's disease (at least 19 identified susceptibility genes).Footnote 52 Because of the lack of accuracy (due to inadequate sensitivity and/or specificity), susceptibility gene testing is currently not recommended in these cases to assess the risk of developing neurological conditions. However, susceptibility genes are of great interest because some may provide insights into the mechanisms that lead to these complex disorders.

4.3 Knowledge gaps

Clear and comprehensive evidence on risk factors for the onset and progression of neurological conditions are not yet available. In general, data on risk factors for neurological conditions are lacking or deficient regarding:

  • The clinical or public health relevance of statistically validated risk factors;
  • Risk factors for the progression of neurological conditions, with respect to the potential improvement or deterioration of the condition; and 
  • The relative and population-attributable risk of modifiable risk factors for the onset of neurological conditions, which would allow for the assessment of the potential effectiveness of prevention measures at the individual and population levels.

Steps have been taken to improve the availability of data and information on risk factors for neurological conditions in the future.

4.4 Key themes

Regarding this component of the Study, which provided preliminary findings on risk factors for certain neurological conditions, it was noted that:

  • The statistical analysis of risk factors for the onset of neurological conditions is a step in the process of identifying associations that are potentially amenable to prevention.
  • Risk factors for disease progression require detailed and expensive longitudinal studies of ‘at risk’ and affected individuals throughout the course of the conditions, from their earliest to most advanced stages.
  • There are substantial methodological challenges involved in the identification of risk factors related to disease causality. Such challenges include difficulty in demonstrating temporal relationships and in proving biological plausibility. In many instances, the appropriate studies have yet to be conducted.
  • There is a complex interplay among genetic, epigenetic, and environmental factors that needs to be recognized when assessing risks for individuals and their family members.

Report a problem or mistake on this page
Please select all that apply:

Thank you for your help!

You will not receive a reply. For enquiries, contact us.

Date modified: