A novel score to help identify people at most risk of Alzheimer's disease has been developed after the discovery of multiple, hitherto unknown genetic risk factors implicating novel biological pathways in early development of the disease, according to the largest study of its kind.
One notable new genetic region and associated pathway confirms as causative the role of tumour necrosis factor-alpha (TNF-α) in disease pathogenesis. This could have significant implications for therapy with many anti-TNFα agents already available.
Published in Nature Genetics, the study involved researchers from Europe, the US, Australia, and the UK (Oxford Population Health) formed part of the international collaboration with Cornelia van Duijn, PhD, professor of Epidemiology at Oxford Population Health, University of Oxford, UK, leading the Oxford arm.
The newly discovered genetic risk factors and associated risk score should aid clinical predictions and trials into early-stage therapies. It helps identify the risk of future Alzheimer's disease/dementia or progression from mild cognitive impairment to Alzheimer’s disease/dementia, with an improvement in Alzheimer’s risk prediction of 1.6- to 1.9-fold.
"We now have a risk score which is based on genes that has potential for use in the clinical setting, by predicting people at risk of getting Alzheimer's disease," Prof van Duijn told Medscape UK.
Regarding the discovery around the role of TNF-α, she highlighted that: "This opens a lot of new opportunities because TNF-α has been a research target in cancer and cardiovascular disease, and this finding provides opportunity for repurposing these medications potentially for Alzheimer's disease."
Prior to this study, there were hints of TNF-α involvement in Alzheimer's disease, but the work by the study's authors provides the first identification of a genetic region associated with TNF-α helping to elucidate its role.
"We didn't know if TNF-α was a cause or a consequence of Alzheimer's, because there is a lot of information in a dying brain. Now, it seems that the TNF-α pathway needs to be considered a cause of Alzheimer's pathways," she pointed out.
Clinical Implications of the Study
Susan Kohlhaas, PhD, Director of Research at Alzheimer’s Research UK commented on the study, referring to it as a "seminal study also gives us hope that research will win".
"Researchers were able to uncover more evidence that the immune system plays a pivotal role in the development of Alzheimer’s, which gives us clues about the pathways that might be most important to look at in our search for new treatments. The research also, however, tells us just how complex Alzheimer's is, with several different mechanisms implicated in the development of the disease."
What is exciting from a clinical perspective is that combining the effects of different genes predicts Alzheimer's in those with mild cognitive impairment. Currently, many patients with a suggestion of cognitive decline or memory loss are assessed for the APOE e4 gene. The presence of one e4 variant puts someone at twice the risk, with two variants, they are at 10 times higher risk of Alzheimer's. This gene also determines the age of onset. It is estimated that between 40% and 65% of people diagnosed with Alzheimer's have one or two copies of the APOE-e4 gene.
However, Prof van Duijn pointed out that the APOE e4 gene is often not informative enough. "The new risk score can help provide greater certainty the risk of developing Alzheimer's. This is a major leap forward."
"If we can delay the disease with all the known factors that we are able to target, such as in the liver and the gut, this could postpone the disease," she said. "I’m sure anyone over 70 will sign up."
Genome-Wide Association Study – Strength in Numbers
Prof Van Duijn has worked on the genetics of Alzheimer's disease for 30 years and more recently has been exploring the proteomics, metabolomics, and microbiome that underpin the disease.
In this study, the researchers performed a genome-wide association study (GWAS), an approach which analyses the entire genome of thousands or tens of thousands of people, whether healthy or sick, to identify genetic risk factors associated with specific aspects of the disease. The study used samples in the European Alzheimer & Dementia Biobank, which includes 20,464 clinically diagnosed cases of Alzheimer’s disease and 22,244 controls from 15 European countries, as well as data from the UK Biobank, which were analysed by the Oxford Population Health team.
A total of 75 regions (loci) of the genome associated with Alzheimer's were identified, 42 of which had never previously been associated with the disease. These regions were further characterised to explore the cellular mechanisms and pathological processes for the disease.
"We are starting to find pathways, some of which were expected but not strongly identified in the past," explained Prof van Duijn.
Many of the novel genes were found to be implicated in amyloid peptide production and Tau protein function, known to be central to Alzheimer's pathogenesis.
"There were questions around whether amyloid was only present in some families or was responsible for the bulk of patients. It was also questioned whether amyloid was a cause of the disease or a consequence of the disease.
"Our research is showing that amyloid and tau are important and that all the work on antibodies to these proteins is worthwhile. We see that the genes driving disease are also involved in the amyloid and Tau pathway," she added.
One anti-amyloid antibody, aducanumab, was already approved by the US Food and Drug Administration (FDA) in June 2021.
Heterogeneity of Alzheimer's Disease
Alzheimer's disease is starting to be understood as a disease of greater heterogeneity than previously thought.
"We see an increasing number of genes and thus protein pathways emerging that overlap across diseases, and this raises the question of whether there is a single therapy that can cure or prevent the disease," said Prof van Duijn.
She suggests that the genetic complexity makes it more likely that there is a combination of pathologies that increase the risk of Alzheimer's, as is the case in cardiovascular disease, which is a risk factor for dementia. "If that is the case, we probably will need a combination of interventions."
Van Duijn also found that genes involved in Parkinson’s disease (IDUA and CTSB), frontotemporal dementia (GRN and TMEM106B), and amyotrophic lateral sclerosis (TNIP1) were identified in their sample of Alzheimer's patients.
"This introduces a new level of complexity that raises the question of whether there is more overlap between the different forms of dementia than previously thought," she said, adding that, "although we cannot exclude misdiagnosis of disease in some cases, the findings are very consistent across studies".
However, Prof van Duijn pointed out that there may also be people with distinct pathology, for instance familial early-onset patients, who may benefit from a single intervention. "But in the majority of patients, the disease appears to be the result of a large number of failing genes and protein pathways, which are all important and their effects need to be disentangled in future research."
In addition, the study sheds light on the type of body cells involved in the disease. Alzheimer's disease is characterised by neuronal degeneration, explained Prof van Duijn. "But a large number Alzheimer genes are not expressed in neurons, for example APOE e4 is highly expressed in microglia and astrocytes [a sub-type of glial cell] and has only low expression in neurons."
Next steps: Link Genomic Findings to Other -omics and Other Ethnicities
Next, Prof van Duijn and her colleagues want to link the study findings of the Alzheimer's genes to proteomic (a set of proteins produced by the genes) changes. This is important in developing therapies because proteins are the major target for therapy.
Proteomic changes may not be limited to the brain. A major recent breakthrough is the ability to read out the major Alzheimer protein pathology - amyloid and phosphorylated Tau- and neurodegeneration via neurofilaments [breakdown proteins] in the blood. This may be relevant for diagnostic and therapeutic research, Prof van Duijn remarked.
"To improve chances of success of therapy we need to acknowledge it is not only changes in the brain that matter but also metabolomic and proteomic changes in the blood that matter too," she stressed. "The body must respond to the brain in some way."
It is also important to widen research to include other ethnicities. To date, only the Caucasian genomics have been studied and this is a limitation of the study, added Prof van Duijn. "This is true of genetics across the board. There are some African-American studies ongoing, and even in the UK Biobank study there is a limited number of Asian and African populations. For these populations it is likely that the risk score will work less well."
COI: Professor van Duijn has no relevant conflicts of interest.
Image 1 Credit: Oxford Population Health