The exact cause of the majority of Alzheimer’s cases (sporadic) is still not fully known, however, around 5-10% of all cases are due to genetic differences, which are now well characterised.

Genetics

5-10% of all cases are what is termed familial Alzheimer’s disease, and are due to inherited genetic mutations to key genes. Less than 1% of all cases of Alzheimer’s are due to autosomal dominant inheritance and its associated early-onset Alzheimer’s before the age of 65 (rare).

There are three key deterministic genes (directly causative) associated with genetic forms of Alzheimer’s: APP, PSEN1 & PSEN2. These genes are all involved in amyloid processing and the production of beta-amyloid plaques, the main pathological hallmark of Alzheimer’s disease.

Therefore, having a family history of dementia may suggest that specific genetic mutations may exist in the gene pool of the family, and that you may have an increased risk of developing Alzheimer’s. Genetic screening and genetic counselling may be offered if this is the case.

There are several risk factor genes that have been associated with but not proven causative of Alzheimer’s. The most common of these genes is the APOE4 allele (form of APOE gene) that increases the risk of developing Alzheimer’s by 3-15 times depending on the inheritance of APOE4 alleles. It is estimated that around 60% of all people with Alzheimer’s have at least one APOE4 allele. Having APOE4 alleles in combination with other deterministic genes, or other risk factors (outlined below) may exacerbate disease severity and progression.

Other implicated genes include autosomal dominant mutations to ABCA7 and SORL1. Allelic variations of TREM2 (microglia implicated) are also thought to confer up to a 3 times higher risk of developing Alzheimer’s disease. There are many polymorphisms (subtle genetic changes; SNPs) in up to 20 other genes that are associated with an increased risk of developing Alzheimer’s.

Risk Factors (Protective & Destructive)

Aside from genetic causes of Alzheimer’s disease, the exact mechanism of how Alzheimer’s develops is still poorly understood, though there are several key risk factors involved.

Factors associated with increased Alzheimer’s risk:

• Advancing age – 1 in 6 people over the age of 80 have dementia, and the risk of developing Alzheimer’s doubles every 5 years after 65.
• Head injuries – There is an association with severe head injuries and the development of Alzheimer’s. Furthermore, having head injuries when dementia is present can actually worsen the symptoms and prognosis.
• Cardiovascular disease – Lifestyle factors that are associated with heart disease such as diabetes, high blood pressure, high blood cholesterol levels, smoking and obesity are also all associated with an increased risk of both vascular dementia (primarily) as well as Alzheimer’s.
• Down’s syndrome – The genetic basis for Down’s syndrome (trisomy 21) which has a 3rd copy of chromosome 21, also carries an extra copy of the APP gene which produces beta-amyloid. Having an extra copy of the APP gene leads to a 50% increase in amyloid is production over normal levels. Therefore, persons with Down’s syndrome are at higher risk of developing Alzheimer’s.
• Other common risk factors that may contribute to developing Alzheimer’s also include having a sedentary lifestyle, hearing loss, stress and untreated depression.
• A single study has also shown an association between calcium supplementation and Alzheimer’s disease, but only among older women who have a history of stroke.