Epidemiology & Biostatistics PhD student Himiede Wilson-Sesay presenting.
Klothogene and its association with APOE4 and Alzheimer’s Disease
Alzheimer’s disease (AD), the most common neurodegenerative disease, has genetic risk factors that play a pivotal role in its onset and progression. The APOE ε4 allele is the strongest genetic determinant of late-onset AD, yet its effect size varies across populations and individuals, suggesting that additional genetic modifiers influence susceptibility. One such modifier is Klotho (KL-VS variant), a gene associated with longevity, cognitive resilience, and neuroprotection. The KL-VS heterozygous genotype (KL-VS Het+) increases circulating Klotho levels, which have been linked to enhanced synaptic function and reduced neurodegeneration. This could make Klotho a biologically plausible target for modifying APOE4-related risk,particularly in midlife. The study investigated whether Klotho modifies APOE4-related AD risk.
Combined data from 22 AD case-control cohorts of non-Hispanic individuals of European ancestry aged ≥60years were used to assess whether Klotho-VS heterozygosity (KL-VS HET+) modifies APOE4-related AD risk. Genotyping was performed across cohorts using high-density arrays, followed by standard quality control, imputation, andremoval of related individuals. Participants were further stratified by APOE ε4status and age group (60–80 years vs.≥80 years). Alzheimer’s riskwas assessed using logistic regression, while the risk of conversion from normal cognition to MCI/AD was assessed using competing-risk regression, and CSF/PET Aβ levels were assessed using linear and mixed-effects models.
The study found that Klotho KL-VS heterozygosity (KL-VS Het+) significantly reduced AD risk among APOE ε4carriers aged 60–80, but not inthose aged 80 or older. Across more than 20 cohorts, APOE ε4 carriers with KL-VS Het+ had lower odds of AD, slower progression from normal cognition to MCI/AD,and showed reduced amyloid pathology, including higher CSF Aβ42 and lower amyloid PET burden. These protective effects were specific to APOE ε4 carriers—non-carriersdid not benefit from KL-VS heterozygosity. Overall, the findings demonstrate that KL-VS Het+ acts as a genetic resilience factor, modifying APOE ε4-relatedrisk by improving cognition and reducing amyloid deposition during a critical midlife window. Its effects are age-dependent and APOE-specific, underscoring the importance of integrating Klotho genotype into AD risk models. Building on these findings, we aim to extend analyses genome-wide to identify additional variants that may interact with APOE and Klotho to shape AD risk across diverse populations. To deepen our understanding of genetic resilience and inform precision medicine strategies for AD.
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