Groundbreaking research has led to new diagnostics and therapeutic targets and created new hope for slowing or stopping Alzheimer’s disease (AD) progression.
It’s well known that AD has a strong genetic component. Apolipoprotein E (APOE4) is expressed in 40% to 65% of all AD diagnoses and is considered one of the most important risk factors for developing the disease. A gene-editing technology known as CRISPR could make genetics a modifiable factor.
Gene Editing Rewrites the Risk
APOE4 appears to stimulate the pathology of Alzheimer’s disease by accelerating the spread of amyloid-beta, sticky protein fragments that clump into plaques that build up in the brain, and tau proteins that form toxic tangles and disrupt messages between the cells.
Dr. Philip Scheltens, a professor of cognitive neurology and director of the Alzheimer Center at the VU University Medical Center in Amsterdam, emphasizes that APOE4 is not a causal gene, explaining, “You may escape the disease…but you have a higher risk.”
Clustered regularly interspaced short palindromic repeats, better known as CRISPR, have emerged as a powerful gene-editing tool that has the potential to address the genetic root cause of AD and other diseases of the central nervous system.
CRISPR is being used to create more accurate disease models, identify therapeutic targets, and explore corrective interventions at the genetic level, which could correct genetic mutations and help curb the process that drives AD. Scheltens sees significant promise in gene editing.
“I would be in favor of … trying to reduce the risk [of Alzheimer’s disease] by removing one of these E4 alleles and turning them into an E3 or an E2,” he says. “That would immediately reduce the risk for Alzheimer’s disease with eight or 16 times less of a risk.”
From Genetics to Omics
Gene-focused strategies are just one piece of a much larger puzzle. There have also been significant developments in the field of omics in AD that have helped understand mechanisms, biomarkers, and potential therapeutic targets.
Analyses of transcriptomics, proteomics, and metabolomics of blood, brain, and cerebrospinal fluid samples have shed light on how factors such as inflammation, metabolic pathways, and B vitamins affect disease processes.
“When it comes to proteomics, metabolomics, lipidomics … there are these beautiful big datasets globally where you can also use more AI-based models … that can speed up the development industry,” explains Dr. Miia Kivipelto, a professor in clinical geriatrics at Karolinska Institutet Center for Alzheimer Research.
“The concept that genes may not be as non-modifiable as we have been thinking … is clearly something for the future.”
The Power of Lifestyle Interventions
Genes are not destiny. Worldwide, 45% of dementia cases are linked to modifiable risk factors.
The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) trial found that lifestyle changes can significantly reduce the risk of cognitive decline. It looked at five modifiable risk factors: healthy diet, regular physical activity, cognitive training, social activity, stress management, and cardiovascular risk management.
The results found a 25% improvement in cognition in the intervention group. Additional research also found that APOE4 carriers were more vulnerable to environmental factors and had the potential to benefit the most from lifestyle interventions.
“Our analysis indicates that APOE4 carriers are getting more clear benefit of the intervention,” Kivipelto says. “That is, of course, great news because you can’t change your genes.”
For a deeper dive into the science of Alzheimer’s disease, check out Pearson’s four-episode podcast series, “The Progress Profile: Alzheimer’s Research in Focus.”
