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Genetics & Age-Related Cognitive Decline: Insights from TOMORROW Trial (2024 Study)

In a study utilizing data from the TOMMORROW trial, researchers have embarked on a novel exploration of genetic associations with cognitive change in older individuals.

Employing a genome-wide association study (GWAS) approach, they’ve identified specific genetic variants linked to cognitive dynamics, providing new insights into the genetic underpinnings of cognitive change with aging.


  • Novel Genetic Insights: Two genetic variants, rs534221751 and rs34743896, have been associated with changes in the attention domain of cognition in older adults.
  • Role of Education: A polygenic risk score (PRS) for education was found to be significantly linked to baseline cognition, particularly in the language domain.
  • Methodological Advancement: The study demonstrates the viability of using GWAS to analyze cognitive change over time, marking a significant methodological advancement.
  • Implications for Aging: These findings underscore the genetic complexity of cognitive change in aging populations and hint at potential new avenues for intervention and support.

Source: Translational Psychiatry (2024)

How Genetics Influence Cognition

Brain Development & Function

Brain Structure and Functionality: Genetic factors significantly influence the development and functioning of the brain. Variants in genes can affect the structure of brain regions involved in memory, attention, and processing speed.

Neurotransmitter Systems: Genes play a crucial role in the regulation of neurotransmitter systems like dopamine, serotonin, and acetylcholine, which are essential for various cognitive processes.

Synaptic Plasticity: Genetic variations can impact synaptic plasticity—the ability of synapses to strengthen or weaken over time. This plasticity is fundamental to learning and memory.

Cognitive Reserve: Some genetic factors contribute to an individual’s cognitive reserve, determining their resilience to neurological damage and their ability to maintain cognitive function in the face of aging or disease.

Neurodevelopmental Disorders: Genetics can predispose individuals to neurodevelopmental disorders like autism spectrum disorder or attention-deficit/hyperactivity disorder (ADHD), which significantly impact cognitive abilities.

Gene-Environment Interaction

Genetics does not work in isolation.

Cognitive abilities are also shaped by the interaction between genetic predispositions and environmental factors like education, socio-economic status, and lifestyle choices.

How Genetics Influence Cognitive Decline

Genetic Variants & Aging

  • Age-Related Genetic Changes: Certain genes, like APOE ε4, are known to be associated with an increased risk of Alzheimer’s disease and other forms of dementia, influencing the rate and nature of cognitive decline.
  • Neurodegenerative Diseases: Genetics can predispose individuals to neurodegenerative diseases, which are major contributors to cognitive decline. For example, mutations in genes like PSEN1 and PSEN2 are linked to early-onset Alzheimer’s disease.
  • Cellular Aging: Genes involved in cellular repair, maintenance, and aging processes like telomere shortening can impact how the brain ages, potentially influencing cognitive decline.

Magnitude of Genetic Impact

  • Varied Impact Across Individuals: The extent to which genetics influences cognitive decline varies widely among individuals. While genetics can predispose to certain conditions, its impact is modulated by a range of other factors, including lifestyle and environmental influences.
  • Polygenic Influence: Cognitive decline is typically not the result of a single gene, but rather the combined effect of multiple genes (polygenic influence), each contributing a small effect.
  • Predictive Challenges: Due to the complexity and multifactorial nature of cognitive decline, predicting it based solely on genetic information is challenging. While certain genetic profiles can indicate higher risk, they do not guarantee cognitive decline.

Genetics & Cognition Later in Life: TOMORROW Trial Data (2024 Study)

Mahedy et al. explored the genetic underpinnings of cognitive change in an aging population with data from the TOMORROW trial.

Specifically, the study sought to:

  • Identify Genetic Variants: To discover genetic variants associated with changes in different cognitive domains, particularly in cognitively normal older adults.
  • Understand the Role of Education: To assess the impact of a polygenic risk score (PRS) for education on baseline cognition in later life.
  • Demonstrate Methodological Feasibility: To prove the viability of using genome-wide association studies (GWAS) for analyzing trajectories of cognitive change.


  • Study Design: Utilizing data from the TOMMORROW trial, a multinational, phase 3, double-blind, placebo-controlled clinical trial.
  • Participants: The study included 2515 individuals aged 65–83, deemed cognitively normal at baseline.
  • Genetic Analysis: DNA samples were genotyped, and a GWAS was conducted using generalised estimating equation (GEE) modeling to study cognitive trajectories.
  • Cognitive Assessments: Tests encompassed domains like attention, executive functioning, episodic memory, language, and learning.
  • Statistical Approach: Multilevel models (MLM) and GEE were used to analyze the repeated cognitive measures data.


  • Identification of Genetic Variants: Two genetic variants, rs534221751 and rs34743896, were found to be associated with changes in the attention domain of cognition.
  • Education PRS: A significant association was observed between the education-related PRS and baseline cognition, highlighting the genetic component of educational attainment and its impact on later-life cognitive function.
  • Methodological Success: The study successfully demonstrated the feasibility of using GWAS to analyze cognitive change trajectories, a significant advancement in genetic studies.


  • Sample Size and Power: With 2515 participants, the study may have been underpowered for detecting more subtle genetic associations.
  • Generalizability: The findings primarily apply to cognitively normal older adults and may not be generalizable to younger populations or those with cognitive impairments.
  • Causal Inferences: The observational nature of the study limits the ability to make causal inferences between identified genetic variants and cognitive changes.
  • Specificity of Cognitive Domains: The study’s focus on specific cognitive domains, such as attention, may overlook other important aspects of cognition.
  • Need for Replication: Given the novel nature of the findings, there is a need for replication in independent cohorts to validate the results.

Details of Results: Specific Genes in Age-Related Cognitive Decline (2024)

  • rs534221751 & rs34743896 Variants: The study identified two significant genetic variants. Variant rs534221751, located in a gene desert on chromosome 21, and variant rs34743896, an intergenic SNP on chromosome 2, were both associated with changes in the attention domain scores.
  • NCAM2 Gene: Through chromatin interaction evidence, NCAM2 (Neural Cell Adhesion Molecule 2) emerged as a gene of interest, particularly in relation to variant rs534221751. NCAM2 plays a crucial role in nervous system development and synaptic plasticity.
  • CRIPT & ATP6V1E2 Genes: The study provided evidence suggesting that the rs34743896 variant is associated with the expression of two genes, ATP6V1E2 and CRIPT. ATP6V1E2 is involved in proton-transporting ATPase activity, and CRIPT is linked to synaptic function and learning.
  • Gene Expression Associations: Although the GWAS signal was associated with the expression of ATP6V1E2 and CRIPT in blood, colocalization analysis indicated that these associations were not strong in brain tissues, suggesting a more complex relationship.

Potential Implications of the Study: Genetics & Cognition in Aging Adults (2024)

  • Understanding Cognitive Aging: The identification of these genetic variants offers new insights into the biological mechanisms underlying cognitive changes in aging, especially in the attention domain.
  • Target for Interventions: The association of NCAM2, CRIPT, and ATP6V1E2 genes with cognitive change could lead to the development of targeted interventions, potentially slowing or modifying the trajectory of cognitive decline in older adults.
  • Genetic Screening: These findings might pave the way for genetic screening in older adults to identify those at higher risk of cognitive decline, allowing for earlier interventions.
  • Educational Strategies: The strong link between the education-related PRS and baseline cognitive function underscores the importance of educational attainment in cognitive health, highlighting the potential for educational strategies in cognitive decline prevention.

Future Directions in Genetics & Cognitive Function Research (2024)

  • Larger, Diverse Cohorts: Future studies should include larger and more diverse cohorts to improve the power to detect genetic associations and to ensure the generalizability of findings.
  • Longitudinal Studies: There is a need for more longitudinal studies to better understand how these genetic variants influence cognitive changes over time.
  • Integration of Multi-Omics Data: Combining genomic data with other omics data (like transcriptomics, proteomics, and metabolomics) could provide a more comprehensive understanding of the biological pathways involved in cognitive aging.
  • Exploring Gene-Environment Interactions: Investigating how genetic factors interact with environmental and lifestyle factors could offer a more nuanced understanding of cognitive aging and potential intervention points.
  • Focus on Other Cognitive Domains: While the TOMMORROW trial focused on attention, future research should explore genetic associations with other cognitive domains such as memory, executive function, and language.
  • Clinical Trials: The translation of these genetic findings into clinical trials to test targeted interventions based on an individual’s genetic makeup could be a promising avenue for preventing or delaying cognitive decline.

Potential Strategies to Counteract Age-Related Cognitive Decline

Below are some strategies that may help offset or counteract cognitive decline in older age.

  1. Cognitive Training and Mental Stimulation: Engaging in activities that challenge the brain, such as puzzles, memory games, learning new skills, or languages, can enhance cognitive reserve and may delay cognitive decline.
  2. Physical Exercise: Regular physical activity, especially aerobic exercises like walking, swimming, or cycling, has been shown to improve cognitive functions by enhancing blood flow to the brain and promoting neurogenesis.
  3. Healthy Diet: A diet rich in antioxidants, omega-3 fatty acids, and low in saturated fats, such as the Mediterranean diet, may support brain health and reduce the risk of cognitive decline.
  4. Social Engagement: Maintaining strong social connections and engaging in social activities can stimulate cognitive processes and may protect against cognitive decline.
  5. Adequate Sleep: Good sleep hygiene is crucial for cognitive health. Quality sleep aids in memory consolidation and clearing brain toxins.
  6. Stress Management: Chronic stress can negatively impact cognitive function. Techniques such as mindfulness, meditation, and yoga can help manage stress levels.
  7. Control of Cardiovascular Risk Factors: Managing blood pressure, cholesterol levels, and avoiding tobacco and excessive alcohol consumption can reduce the risk of cognitive decline.
  8. Lifelong Learning: Continual education and intellectual curiosity can stimulate the brain and may help maintain cognitive functions.

Takeaway: Genetics & Cognition in Older Age

The journey to unravel the complexities of age-related cognitive decline is ongoing, and the TOMMORROW trial marks a significant milestone in understanding the genetic dimensions of this challenge.

By identifying specific genetic variants linked to cognitive changes in older adults, this research opens new pathways for targeted interventions.

However, it’s not just about genetics; lifestyle factors like physical activity, diet, social engagement, and mental stimulation play crucial roles in maintaining cognitive health.

As we move forward, integrating genetic insights with lifestyle modifications presents a holistic approach to combating cognitive decline.

The future of cognitive health research is promising, blending advanced genetic studies with practical, everyday strategies to preserve and enhance cognitive function in aging populations.

This integrated approach is key to supporting an aging population and improving quality of life in the golden years.


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