There are two clinical types of Alzheimer’s disease (AD): early and late onset of the disease. Both have a genetic component which is different for each type:
Early form of AD
The early form of AD is clearly hereditary, but it accounts for only a very small percentage of all AD cases. In those affected the disease starts very early, between the ages of 30 and 65. Three genes are known to be responsible for this form: amyloid precursor protein (APP) on chromosome 21, presenilin 1 (PSEN1) on chromosome 14 and presenilin 2 (PSEN2) on chromosome 1. Most cases are caused by dominantly inherited mutations in one of these three genes. i.e. if one parent is affected, there is a 50% probability that the children will also be affected.
Late form of AD
In about 99% of all cases, AD occurs later in life. In this late-onset form of AD, symptoms do not appear until the age of 65. No specific gene has been found that is directly responsible for the late form, but apolipoprotein E (ApoE) gene on chromosome 19 is directly related to the risk of the disease. ApoE encodes an important lipid carrier protein in the brain, which is present in three different variants (so-called alleles): ApoE2, ApoE3 and ApoE4. As with almost all genes, humans carry two copies of ApoE, which can either be the same variants (e.g. ApoE4/ApoE4) or different variants (e.g. ApoE3/ApoE4). The respective variant of ApoE determines a person’s individual risk of disease:
- ApoE2 is relatively rare and can offer some protection against the disease, since AD usually occurs later in life in people carrying the ApoE2 allele than in a those carrying ApoE4.
- ApoE3 is the most common variant and occurs in about 64% of the population and is called the normal or ‘wild type’ variant. It will neither reduce nor increase the risk of the disease.
- ApoE4 – compared to the most common ApoE3 variant – significantly increases the risk of ADs: it is 4-fold higher in people with one copy of ApoE4 and up to 15-fold higher in people with two copies of this variant. AD patients who carry ApoE4 are more likely to develop symptoms of the disease earlier than carriers of other ApoE variants. For a long time it was thought that the ApoE4 gene variant favours the deposition of amyloid β plaques and tau protein accumulation, thereby contributing to the faster onset of Alzheimer’s disease. However, recent studies show that ApoE4 can accelerate the course of the disease by breaking down the blood-brain barrier via inflammatory processes. This damage to the brain capillaries occurs even before cognition starts to decline.
Mechanism of BBB damage: The pericytes secrete the ApoE4 protein, which activates the protein cyclophilin A (CypA). This triggers a downstream signaling pathway that involves the activation of the inflammatory protein matrix metalloproteinase-9 (MMP9) in pericytes and possibly also in endothelial cells. This leads (via inflammatory processes) to an interruption of the transitions between adjacent endothelial cells, which ultimately results in the opening of the BBB in the hippocampus. In the following picture the mechanism of pericyte damage is illustrated (modified according to Ishii & Iadecola 2020)
However, even the presence of ApoE4 does not necessarily lead to a BBB breakout. ApoE4 is considered just a risk factor gene. Inheritance of an ApoE4 allele does not mean that a person will definitely develop Alzheimer’s. Some people with an ApoE4 allele never get the disease, and others who develop Alzheimer’s do not have an ApoE4 allele. But because damage to the blood capillaries precedes cognitive loss, an early diagnosis in people with the ApoE4 gene could possibly be made by examining the brain’s blood vessels, which would allow an early therapy start.
Thus, the majority of Alzheimer’s diseases can be classified as late forms. The causes include not only the genetic component (variant of the ApoE gene) but also environmental and lifestyle factors. In contrast, the early form of Alzheimer’s disease is causally characterised by genetic causes. The following table shows a comparison of the two forms of the disease:
| Early type of AD | Late type of AD | |
| Frequency | Rare incidence (approx. 1% of all cases) | High incidence (approx. 99% of all cases) |
| Age at disease | Between 30 and 65 years | At age 65 years and older |
| Responsible genes | Causal mutation in 3 genes: Amyloid Precursor Protein APP Presenilin-1 PSEN1 Presenilin-2 PSEN2 | Polymorphic apolipoprotein E: Variant ApoE4 and number of its alleles increase the risk of the disease |
| Risk of Disease | Onset of the disease inevitably by autosomal dominant heritage | Increased risk in those affected, but no necessary onset of the disease |
Conclusion:
Only a small part of Alzheimer’s disease is causally genetic and triggers the early hereditary form of the disease. The majority of cases can be assigned to the late form of the disease, in which the genetic risk factor is determined by the gene variant of apolipoprotein E (ApoE), but many other environmental and lifestyle factors also play a role. The genetic variant ApoE4 carries the highest risk of disease. ApoE4 triggers accelerated damage to the blood-brain barrier via an inflammatory pathway, even before tissue loss occurs in the hippocampus and cognition slows down. These new findings may offer the chance of early diagnosis in ApoE4-risk patients via the brain vessels, which would allow early therapy initiation and represent a promising approach in the fight against premature cognitive decline.
References:
1. Campion, D. et al (1999) Early-Onset Autosomal Dominant Alzheimer Disease: Prevalence, Genetic Heterogeneity, and Mutation Spectrum. The American Journal of Human Genetics. 65/3, 664-670
2. Corder, E.H., Saunders, A.M., Strittmatter, W.J. Schmechel, D.E., Gaskell, P.C., Small, G.W., Roses, A.D., Haines, J.L., Pericak-Vance, M.A.: Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261/ 5123, 921-923
3. Yamazaki, Y., Zhao, N., Caulfield, T. R., Liu, C.-C. & Bu, G. (2019): Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. Nature Rev. Neurol. 15, 501–518
4. Montagne, A. et al. (2020): ApoE4 leads to blood–brain barrier dysfunction predicting cognitive decline. Nature 581, 71–76
