Alzheimer’s disease (AD) is a neurodegenerative disease that currently accounts for around two-thirds of all dementia cases, but AD incidence is rapidly increasing, predicted to grow from approximately 47 million global sufferers in 2015 to 75 million by 2030.

It is characterised by a number of pathological features: presence of Amyloid beta (Aβ) plaques and neurofibrillary tangles formed by tau protein hyperphosphorylation that spread throughout the brain, as well as general neuronal cell loss and reduced synaptic capacity. These features are reported to start proliferating long before symptoms are visible, some suggesting at least 15 years.

Recently, DNA methylation has also been heavily implicated in AD and other neurodegenerative diseases, and changes in DNA methylation patterns in the brain have been identified as contributing to, or a marker of, AD progression.

They specifically investigated a high-ranked key driver gene (that had high contribution to AD risk) HTR2A, which is related to biological pathway signalling, showing that this particular gene is down-regulated in AD, and had low protein expression, consistent with a nearby DMR with high levels of methylation.

They demonstrated the pattern of associated DNA methylation with gene and protein expression in high-risk AD genes multiple times, suggesting that these genes could represent potential therapeutic targets.

The second most common methylation mark is 5-hydroxymethylcytosine (5hmC), which is present at far fewer positions in the human genome but is enriched 10-fold higher in brain than peripheral tissues, suggesting a unique function within neuronal systems.

They link this 5hmC reduction to a decrease in TET activity, the enzyme that catalyses the conversion of 5mC to 5hmC. Decreased TET activity has also been shown in the brains of humans who died with AD, and they suggest that this could be the cause for the reduction in 5hmC.

They further investigate the relationship between 5hmC, TET and AD by overexpressing human TET catalytic domains in the mouse AD models, which results in a significant attenuation of the neurodegenerative process with reduced Aβ accumulation and Tau protein hyperphosphorylation. These results reflect the crucial role of 5hmC and its deregulation in the events leading up to AD neurodegeneration.

According to study of the amyloid-β protein precursor (APP) in control groups and AD patients . APP was the only gene that was consistently hypermethylated in both the blood and the brain, suggesting that it might be the most effective diagnostic biomarker of blood for AD. Early study showed that a blood test is as good at identifying people in early stages of the disease as cerebrospinal fluid tests approved by the Food and Drug Administration (FDA) for Alzheimer’s diagnosis. In the future, a blood test soon may replace present expensive and invasive method by brain scans and spinal taps.

Appendix

1. Prince, Martin, et al. World Alzheimer report 2015. The global impact of dementia: an analysis of prevalence, incidence, cost and trends. Diss. Alzheimer’s disease international, 2015.
2. Wang, Erming et al. “Genome-wide methylomic regulation of multiscale gene networks in Alzheimer’s disease.” Alzheimer’s & dementia : the journal of the Alzheimer’s Association vol. 19,8 (2023): 3472-3495. doi:10.1002/alz.12969
3. Chen, Lei et al. “5-Hydroxymethylcytosine Signatures in Circulating Cell-Free DNA as Diagnostic Biomarkers for Late-Onset Alzheimer’s Disease.” Journal of Alzheimer’s disease : JAD vol. 85,2 (2022): 573-585. doi:10.3233/JAD-215217
4. Nicolas R. Barthélemy et al. "Highly accurate blood test for Alzheimer’s disease is similar or superior to clinical cerebrospinal fluid tests" Nature Medicine volume 30, pages 1085–1095 (2024).