A risk factor is something which may increase an individual’s chance of developing a particular disorder.
With Alzheimer’s disease, the major risk factor is age although there are others which may exert their influence in the determination of the disease and the age at which the onset of symptoms appear. For instance, an individual’s genetic make-up will substantially influence the likelihood of Alzheimer’s disease and the likely age at which the disease will appear.
Risk factors which are not so clearly defined are those of gender, with women being at a greater risk of suffering from Alzheimer’s disease than men. One explanation that has been suggested for this gender difference is the reduced level of oestrogen post-menopause.
Other risk factors which have been proposed are those of: head injury especially when accompanied with loss of consciousness; cultural differences; levels of educational achievement; environment; lifestyle; diet; and association with other diseases or viral infections.
There may be several different risk factors for Alzheimer’s disease, the main one being that of ageing. Of those people over the age of 65 years 5% will suffer from Alzheimer’s disease. This figure increases to 50% in the over 90 year old population. These figures are a conservative estimate from published studies.
As the brain ages it becomes less efficient at processing vital chemicals known as neurotransmitters and clearing unwanted residues from the brain. The formation of abnormal deposits in the brain of key proteins, referred to as ‘plaques’ and ‘tangles’, affect its proper functioning. ‘Plaques’ and ‘tangles’ occur insidiously with ageing but more rapidly when associated with Alzheimer’s disease. These neuropathological features of Alzheimer’s remain the major determination of the disease at post mortem. Research investigating the occurrence of 'plaques' and 'tangles’ and their correlation with the onset and severity of disease has failed to establish a significant relationship between the numbers of ‘plaques’ and ‘tangles’ and symptoms suffered.
Histological staining of brain tissue post mortem (right) reveals amyloid plaques (large deposits) and neurofibrillary tangles (small features) characteristic of Alzheimer’s disease.
Studies have shown that there is considerable variability within the human population of the occurrence of ‘plaques’ and ‘tangles’ and the age at which they begin to develop in the brain. However, Alzheimer’s disease is invariably associated with a greater number of ‘plaques’ and ‘tangles’ when compared at post mortem to an aged matched normal brain. These ‘hallmarks’ of the disease are associated with neuronal cell death which inevitably leads to the striking distinction in size and weight between the brains of Alzheimer’s patients and those of similarly aged people who enjoyed good mental health.
The brains of Alzheimer’s disease patients (left) lose their structure due to cell loss and increase in the size of internal cavities. The Alzheimer’s brain seen on the left is visibly lacking structure when compared to a healthy brain seen on the right.
Alzheimer’s disease has been linked to an inheritance of one of several genes known to carry mutations. To date, Alzheimer’s disease has been attributed to the inheritance of mutations in three genes – Amyloid Precursor Protein (APP); Presenilin 1 (PS1) and Presenilin 2 (PS2). In most cases these are causative of an ‘early age of onset’ form of the disease. Inheriting variants of other genes may also lead to a genetic predisposition for Alzheimer’s disease.
The genetic transmission of Alzheimer’s disease is described as ‘autosomal dominant’ which means that 50% of all family members within each generation will inherit the disease. Often the age of onset will be similar between family members as will be the symptoms suffered and the duration of the disease, thus giving the disease an element of predictability. Within these families there is no selection in favour of females over males.
It is difficult to state the percentage of Alzheimer’s disease which may be attributed to an inherited genetic disorder and that arising spontaneously. However, estimates have been reported to vary between 5 - 14% of Alzheimer’s disease being attributed to the inheritance of a known genetic pre-disposition. The more common occurrence of Alzheimer’s disease is therefore associated with a ‘spontaneous’ form which is mainly attributed to increasing age.
A protein known as ‘amyloid’ is pivotal to the disease irrespective of whether or not Alzheimer’s is ‘inherited’ or occurs ‘spontaneously’. Amyloid is implicated in the neuropathology of the disease being the key protein involved in neuropathological ‘plaque’ formation (see picture above illustrating the amyloid plaque deposit). It is further implicated by those individuals who have inherited a genetic mutation in their Amyloid Precursor Protein (APP) gene.
However, other individuals who are particularly at risk of suffering from Alzheimer’s disease as a result of disturbances in the amyloid gene are Down syndrome adults. In most cases, Down syndrome is caused by an individual inheriting three copies (trisomy), rather than the normal two copies of chromosome 21 i.e., one received from each parent. The APP gene is located on chromosome 21. Thus, people who inherit three copies of the APP gene, as in the case of most Down syndrome, have a strong genetic pre-disposition for Alzheimer’s disease.
Not all genes considered as risk factors are inherited as genetic mutations. Some genes naturally have different variants which may be passed from generation to generation. One such gene is the Apolipoprotein E gene (ApoE) which has three different ‘allelic’ forms. ApoE4 is the variant associated with poor cholesterol processing, and the inheritance of this variant of the gene increases the risk of Alzheimer’s disease. The ApoE gene has been established unequivocally as a susceptibility gene for Alzheimer’s disease. Research studies have shown that inheritance of the ApoE4 variant from one parent increases the risk of suffering from Alzheimer’s disease after the age of 90 years, whereas people who have inherited the ApoE4 variant from both parents are likely to show signs of the disease before the age of 70 years.
Published reports indicate that the ApoE4 risk factor only accounts for approximately 50% of ‘late onset’ cases. Therefore other factors must also exist, albeit that they remain to be identified.
Other factors which are not so obviously genetically driven may also contribute to an individual’s risk of developing Alzheimer’s disease. Acetylcholine, a chemical known to be important in processing memory, is destroyed by a naturally occurring enzyme in the brain called Acetylcholinesterase. Normally, the levels of chemical and enzyme are in balance, however, levels of Acetylcholine decrease within Alzheimer’s patients. Early pharmaceutical interventions have focused on inhibiting the action of the enzyme Acetylcholinesterase in order to preserve diminishing levels of Acetylcholine. Acetylcholinesterase inhibitors are a family of drugs which have been developed to counter this process.
Head trauma from accidents or sporting injuries and poor diet have also been investigated as causative of Alzheimer’s disease but the evidence is less clear cut. Results of studies have suggested that a person who has received a severe blow to the head is at increased risk of developing Alzheimer’s disease. This risk is higher if at the time of the injury the person is over 50, has a specific genetic risk factor, and lost consciousness just after the accident.