Can we blame the increase in Alzheimer’s on our genes?

As we have noted in previous blogs, the prevalence of Alzheimer’s disease is increasing and by 2050 it is predicted it will affect 160 million people globally. Over 200 genes so far have been identified that influence the risk of Alzheimer’s – so is this disease a consequence of our genetics or a mismatch of our genes with our environment?

Historically Alzheimer’s genetics has been divided into 2 categories – early onset (familial) Alzheimer’s (EOFAD) and Late Onset Alzheimer’s Disease (LOAD).

The amyloid hypothesis is central to both forms. This is the hypothesis that gives a central role to a protein called beta-amyloid which builds up between cells forming plaques that clump together resulting in destruction of brain cells. A certain amount of beta-amyloid is found in the brains of healthy individuals and there are processes that can clear beta-amyloid and prevent excessive accumulation and oligomerisation.

However, pathology occurs when build-up of beta-amyloid exceeds clearance capacity. This, and other pathological mechanisms relevant to Alzheimer’s, can be affected by an individual’s genetics.

Early Onset Familial Alzheimer’ Disease (EOFAD) – This form, with Mendelian-type inheritance, usually occurs before the age of 60 (ie in people in their 40’s and 50’s). The rare genes associated with this form have 100% penetrance (penetrance refers to how many people will get the disease, so if a particular mutation has 95% penetrance then 95% of those with the mutation will develop the disease while 5% will not). Fortunately, this form is rare and accounts for less than 5% of cases with Alzheimer’s. The genes involved are:

APP (amyloid precursor protein) – there are about 50 mutations which increase beta-amyloid production.

PSEN1 and 2 (presenilin 1 and 2) – these genes code for proteins that regulate amyloid precursor protein processing.  So mutations in these genes alter the processing of APP.

Mutations in all these genes increase the production of beta-amyloid and they produce a more toxic form of beta-amyloid – a longer and stickier form.

Amyloid Precursor Protein

APP is a gene that provides instructions for a protein called amyloid precursor protein; a trans-membrane protein with intracellular and extracellular sites. APP can be processed via 2 pathways – the trophic pathway and the anti-trophic pathway. It is the latter that results in beta-amyloid generation.

Trophic pathway: On the cell surface APP can be proteolysed by secretase enzymes; a-secretase and then g-secretase – a process that does not generate beta-amyloid. This process generates soluble amyloid precursor protein alpha (sAPPa) and alpha Carboxy Terminal Fragments (aCTF). These are products that support synaptic maintenance and can inhibit the toxic beta pathway. Thus this pathway is protective.

Anti-trophic pathway: This pathway involves different enzymes – beta-secretase (BACE1) cleaves APP on the cell surface a process that generates soluble APPb and b The bCTF fragment can then undergo gamma-secretase cleavage generating beta-amyloid of various lengths. Thus this pathway results in the production of beta-amyloid.

Not all mutations in the APP gene result in Early Onset Alzheimer’s – some are relevant to Late Onset and there is also at least one protective mutation which results in a 40% reduction in the formation of beta-amyloid.

Mutations in APP, PSEN1 and PSEN2 have been useful for identifying the biological pathways involved in Alzheimer’s and studies of these genes in cell lines and animal models have led strong support for the amyloid hypothesis.

Prevalence of Early Onset Alzheimer’s genes

According to the Alzheimer’s Society:

“the prevalence of the defective versions of these genes is as follows:

• More than 80 known families worldwide have a mutation in the APP gene on chromosome 21 which affects production of the protein amyloid.
• Nearly 4000 known families worldwide carry a mutation in the PSEN1 gene on chromosome 14. This causes up to half of all early onset familial Alzheimer’s disease with first symptoms from as early as 30 years of age.
• Only a few dozen known families (mainly resident in the US) have a mutation in PSEN 2 on chromosome 1 causing early onset familial Alzheimer’s disease that starts slightly later than for PSEN1.”

However, about one third of inherited Alzheimer’s cases are not related to APP or PSEN gene mutations implying the existence of further genes.

Late Onset Alzheimer’s Disease

Late onset Alzheimer’s disease is more common and accounts for around 95% of cases, it occurs after the age of 60 and the single most important genetic risk factor is ApoE4 (apolipoprotein). But its inheritance follows a more complex pattern. The chances of developing it depend on a number of risk factors and risk genes and over 200 genes have been identified.

APOE4

The gene variant with the greatest known influence on the risk of developing Late Onset Alzheimer’s is called ApoE4 (Apolipoprotein E4). This is the gene that James Watson, the co-discoverer of DNA, did not want to learn when having his genome sequenced.

It is a gene that is beneficial in the correct environment, so it is a good example of antagonistic pleiotropy. Antagonistic pleiotropy is when one gene controls for more than one trait where at least one of these traits is beneficial to the organism’s fitness and at least one is detrimental to the organism’s fitness. So one of the beneficial aspects of ApoE is that it allowed the development of a highly active immune system.

Apolipoprotein codes for a lipid binding protein and is found in various forms – ApoE2, ApoE3, ApoE4. ApoE2 is protective of Alzheimer’s; ApoE3 has average risk. ApoE4 is associated with Alzheimer’s and other chronic diseases including atherosclerotic cardiovascular disease, Lewy body dementia and inflammation.

About one quarter of the general population has one copy of the ApoE E4 variant. This increases their lifetime risk of developing Alzheimer’s by up to 4x.

About 2 per cent of the population has two copies of ApoE E4, ie one from each parent. This increases the risk of developing Alzheimer’s by about 10x or more (but even then they are not certain to develop it)

However, “ApoE4 is neither necessary nor sufficient for developing Alzheimer’s disease, which means that a person with the high risk variant may never get the illness, and conversely, one lacking the liability may still come down with the disease” Alzforum 2009.

What is the mechanism by which ApoE4 is involved in Alzheimer’s?

As explained, ApoE4 has been established to be the most significant single risk factor but the mechanisms were not well understood until recently. In March this year a landmark paper was published by Professor Bredesen’s team.

They found that ApoE4 functions as a transcription factor. A transcription factor is a protein that binds to specific DNA sequences controlling the rate of transcription of genetic information from DNA to messenger RNA. The paper states:

“ApoE4 undergoes nuclear translocation …… and functions as a transcription factor …… the ApoE4 binding sites include ~1700 gene promoter regions. The genes associated with these promoters provide new insight into the mechanism by which Alzheimer’s risk is conferred by ApoE4 because they include genes associated with trophic support, programmed cell death, microtubule disassembly, synaptic function, sirtuins and aging and insulin resistance, all processes that have been implicated in Alzheimer’s disease pathogenesis.” Theendakara et al 2016.

Of these 1700 genes, 76 have been found to have a role in Alzheimer’s pathology. For example – SIRT1 is an anti-aging gene that is thought to reduce the accumulation of beta-amyloid through activation of another protein. ApoE4 downregulates SIRT1. ApoE4 also downregulates anti-inflammatory genes and upregulates inflammation. It reduces glucose transportation to the brain and hence can result in hypoglycaemia.

ApoE4 carriers may have their risk of developing Alzheimer’s disease modified by mutations elsewhere in their genomes. Research is ongoing to find further risk and protective genes and teams from Europe and the US have joined forces to create the International Genomics of Alzheimer’s Project.

Among the other genes that have been found to be relevant in increasing risk are genes that affect beta-amyloid clearance; cholesterol and lipid metabolism; neurogenesis; inflammation; blood coagulation; thyroid health; gluten tolerance and methylation.

However, Alzheimer’s cannot simply be a matter of genetics – 100 years ago it wasn’t a significant problem and our genes have not changed since then. In the US there were about 200,000 people with Alzheimer’s in 1910, equivalent to about 0.2% of the population; in 2015 it was around 7 million which is 2.2% of the population.

Conclusion

By 2050 it is estimated that there will be 160 million globally suffering from the disease. Whilst early onset familial Alzheimer’s is strongly linked to genetics; the more prevalent late onset form involves multiple risk factors and risk genes but it is a new disease of our diet and lifestyle and the way these factors interact with our genes. This suggests that it is preventable and may be even be reversible by working with our genome, as we were doing when living a more traditional lifestyle.

That the disease can be reversed has been demonstrated in the work of Professor Bredesen which we have discussed in a previous blog. Cytoplan and our charitable foundation owners, The AIM Foundation, is bringing the work of Professor Bredesen to the UK and we will soon have education materials and a new range of supplements available to support practitioners who are working with clients looking to prevent this disease.

For more information on the nutritional therapy practitioner training and licensing scheme we will be offering please follow this link.

If you have any questions regarding the topics that have been raised, or any other health matters please do contact me (Amanda) by phone or email at any time.

amanda@cytoplan.co.uk, 01684 310099

Amanda Williams and the Cytoplan Editorial Team: Joseph Forsyth, Emma Williams, Simon Holdcroft, Clare Daley and Helen Drake

Related Cytoplan blogs

Alzheimer’s disease, Sleep and Melatonin

Elevated Homocysteine – A Risk Factor for Alzheimer’s Disease?

The Bredesen Protocol™ – Is nutrition the key to Alzheimer’s?

References

Alzheimer’s Society (2012) – Genetics of Alzheimers factsheet. https://www.alzheimers.org.uk/site/scripts/documents_info.php?documentID=168

Alzforum (2009) – Early ApoE4 memory effects, but do you really want to know? http://www.alzforum.org/news/research-news/early-apoe4-memory-effects-do-you-really-want-know

Theendakara V et al (2016) – Direct Transcriptional Effects of Apolipoprotein E. The Journal of Neuroscience, January 2016 DOI: 10.1523/JNEUROSCI. 3562-15.2016

Last updated on 20th July 2016 by cytoffice