Tag Archives: genetic

Genetic Evidence Suggests Iron is Linked to Alzheimer’s Disease

According to a recent study, people with a rare variant in the HFE gene are three times less likely to develop dementia than the general population.

You’ve probably heard that consuming enough iron is important for overall health. However, too much iron can also be a bad thing. In particular, people with Alzheimer’s disease often have abnormally high levels of iron in their brains. (See The Role of Metals in Alzheimer’s Disease). The question of whether iron is a cause or consequence in Alzheimer’s still remains unanswered.

In a paper published this week in PLoS One, a group of Italian researchers investigated whether the genes that control levels of iron in the body could be related to the risk of dementia. They recruited 765 subjects who had Alzheimer’s disease, vascular dementia, or mild cognitive impairment, as well as 1,086 healthy controls of a similar age. Then they took DNA samples from the subjects and looked at four different genes that are involved in iron metabolism.

They found that one gene called High Ferrum (HFE), which is responsible for controlling absorption of iron from the blood, was protective against dementia. Specifically, subjects who had a particular variant of the HFE gene were one-third as likely to develop Alzheimer’s disease or vascular dementia compared to subjects who didn’t have the protective variant. The effect was even stronger for mild cognitive impairment, which the HFE variant reduced the risk to only one-fifth.

The researchers then looked at another gene called APOE, which has previously been shown to be involved in Alzheimer’s disease. People with the APOE4 variant of this gene were more than four times as likely to have Alzheimer’s. However, in subjects who also possessed the protective HFE variant, the impact of APOE4 was completely attenuated, and their risk of Alzheimer’s was normal.

How could the HFE gene protect people from dementia? One possibility, known as the metal hypothesis of Alzheimer’s disease, suggests that iron makes amyloid-beta plaques more toxic. Amyloid-beta, a protein that accumulates in Alzheimer’s patients’ brains, can interact with various metal ions to become extra toxic. Normally metals are blocked from entering the brain by the blood-brain barrier, but this barrier tends to become leaky in older people. Thus the hypothesis suggests that influx of iron and other metals into the brain may cause amyloid-beta to aggregate and become more toxic, thus contributing to the development of Alzheimer’s.


The metal hypothesis suggests that the toxicity of beta-amyloid could be increased when it binds to metal ions. Image Source

However, the metal hypothesis can’t entirely explain these recent findings. For one thing, the variants in iron-controlling genes were also protective against vascular dementia, which does not involve amyloid-beta. In addition, the researchers did not observe any differences in blood iron levels based on these genetic variants, so it’s unclear exactly how these genes may be affecting iron metabolism. Future studies are needed to clarify if and how iron could be involved in Alzheimer’s and other types of dementia.


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A New Approach to Predicting Risk of Alzheimer’s Disease


An individual’s risk for Alzheimer’s disease is affected by a variety of genetic and environmental factors. While the causes of early-onset Alzheimer’s are well understood, the genetic factors underlying late-onset Alzheimer’s disease (LOAD), which makes up 95% of total cases, are less clear. The APOE4 allele is considered the major risk factor for this form of Alzheimer’s, as it can increase your risk by 2-3 times if you have one copy of the allele or up to 15 times if you have two copies. APOE4 does not guarantee that an individual will develop LOAD, and researchers have been searching for other genes that may be involved. (For more background see The Genetics of Alzheimer’s Disease).

Genome-wide association studies, which systematically analyze the 0.1% of DNA sequence that varies between individuals, have linked at least 21 other genes to an increased risk of LOAD. Individually, each of these genes has only a small influence in comparison to APOE4, often increasing one’s risk by only a few percentage points. However, when many of these small genetic risk factors are combined, they can greatly affect an individual’s chances of developing LOAD.

Overall, studies suggest that approximately 33% of an individual’s risk for developing LOAD is attributable to genetics, with the rest being due to lifestyle choices and environmental factors. Of this, APOE and the 21 already-identified genes account for less than 25% of the genetic risk, suggesting that the majority of genetic risk factors for Alzheimer’s disease remain unknown.

New Results

In a recent study published in the journal Neurology, a group of researchers from the Alzheimer’s Disease Neuroimaging Initiative searched for other genes, outside of the 21 already identified, that could also act as slight risk factors for Alzheimer’s. They used data collected from the International Genomics of Alzheimer’s Project to compute polygenetic risk scores, or PGRS, for both young and elderly adults who did not have dementia. Each person’s PGRS was calculated using his or her unique combination of small genetic risk factors (including many that were not statistically significant in genome-wide association studies) in order to estimate the genetic risk for LOAD. The researchers then analyzed whether PGRS were associated with biological markers of preclinical Alzheimer’s disease.

In elderly subjects who did not have dementia, high PGRS was associated with poorer memory, smaller volume of the hippocampus (the part of the brain that helps us form new memories), and increased levels of toxic beta-amyloid in the brain. High PGRS in these individuals also correlated with an increased rate of cognitive decline and a greater probability of later being diagnosed with Alzheimer’s disease. The researchers also computed PGRS for younger subjects under the age of 35. They found that a high PGRS was associated with reduced hippocampal volume, similarly to the older subjects.

Together, these results suggest that more genes besides the currently-identified 21 may need to be considered when evaluating an individual’s risk for LOAD. The researchers plan to repeat this study using a larger sample size to verify the results. Future studies also will track younger subjects to see if PGRS can predict their risk for Alzheimer’s as they age, and compare these results to less comprehensive systems of genetic prediction. The hope is that by refining PGRS, we may one day be able to develop better genetic tests for young people that yield more accurate predictions of future Alzheimer’s risk.


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