Late onset Alzheimer’s disease is the most common form of the disease, which affects over 35 million people around the world with crippling dementia. Recent evidence suggests that early intervention can help slow down the memory loss—one of Alzheimer’s hallmark symptoms. Earlier intervention can occur with earlier detection, and so researchers have been focusing on finding minimally invasive ways to diagnose the disease before the severe dementia fully kicks in.
A recent study to this effect was published in Clinical Genetics, which was the result of a collaboration between several major research institutions: University of Turku, Hospital District of Southwest Finland, University of Helsinki, Aalto University, Karolinska Institutet, Jönköping University, and University of Southern California.
The scientists from these institutions wanted to focus on how epigenetics can affect the development of Alzheimer’s—particularly in 23 pairs of Finnish twins where one sibling had late-onset Alzheimer’s, and one did not.
This level of collaboration allowed for larger sample sizes and the potential for more elaborate data analysis, which in turn meant that any potential correlations detected would have greater statistical—and therefore clinical—significance.
The researchers started off by preforming bisulfite sequencing on the blood samples that were gathered from the twins. They found there were differences in DNA between the twins in as many as 11 different genomic regions.
DNA methylation is an epigenetic mechanism that does not change the actual DNA sequence, but affects the DNA’s physical exposure and therefore its accessibility to the cellular machinery that transcribes and translates the sequence into action, allowing the control of gene expression.
Although these genes are associated with neuronal function and pathology, there were no differences in gene expression in the blood that correlated with disease. However, it is worth noting that the DNA methylation of the gene ADARB2 was shown to be differentially methylated in the hippocampus.
In order to further validate these correlations, the researchers looked at further twin studies. They compared DNA methylation of the ADARB2 gene in 62 Finnish and Swedish twin pairs who, again, had one twin with late-onset Alzheimer’s and one without. They also used this data set to see what else could affect DNA methylation at this site, and they identified factors like age, gender, smoking status, and APOE profile as contributing factors. APOE stands for apoliprotein E, which, when present in a certain form on chromosome 19, correlates with higher risk of late-onset Alzheimer’s.
Still further analysis of 120 additional discordant Swedish twin pairs showed that while this DNA mark does not predict Alzheimer’s, but becomes differentially methylated after the disease starts. This means that this methylation site can be helpful in diagnosing late-onset Azheimer’s.
While this study effectively opens the door on a potential tool for diagnosis, further validation is needed beyond just extending the sample sizes as well as the samples, to include patients beyond just Scandinavian twins. There were differences noted between the levels of methylation in the patients with Alzheimer’s, which should be further characterized in terms of clinical significance, particularly alongside other factors such as smoking status.
Additionally, further understanding the role of ADARB2 in the brain could be helpful. So far, studies in mice have shown that removing this region of DNA causes memory and learning issues that closely mirror those experienced in Alzheimer’s; this might be the result of blocking enzymatic activity.
Source: Konki, M. et al. (2019). Peripheral blood DNA methylation differences in twin pairs discordant for Alzheimer’s disease. Clin Epigenet 11,130
Reference: Univ. of Turku Press Release Changes Associated with Alzheimer’s Disease Detectable in Blood Samples Univ. of Turku. 11 Nov 2019. Web.