Blood‐based multivariate methylation risk score for cognitive impairment and dementia

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Abstract INTRODUCTION The established link between DNA methylation and pathophysiology of dementia, along with its potential role as a molecular mediator of lifestyle and environmental influences, positions blood‐derived DNA methylation as a promising tool for early dementia risk detection. METHODS In conjunction with an extensive array of machine learning techniques, we employed whole blood genome‐wide DNA methylation data as a surrogate for 14 modifiable and non‐modifiable factors in the assessment of dementia risk in independent dementia cohorts. RESULTS We established a multivariate methylation risk score (MMRS) for identifying mild cognitive impairment cross‐sectionally, independent of age and sex (P = 2.0 × 10−3). This score significantly predicted the prospective development of cognitive impairments in independent studies of Alzheimer's disease (hazard ratio for Rey's Auditory Verbal Learning Test (RAVLT)‐Learning = 2.47) and Parkinson's disease (hazard ratio for MCI/dementia = 2.59). DISCUSSION Our work shows the potential of employing blood‐derived DNA methylation data in the assessment of dementia risk. Highlights We used whole blood DNA methylation as a surrogate for 14 dementia risk factors. Created a multivariate methylation risk score for predicting cognitive impairment. Emphasized the role of machine learning and omics data in predicting dementia. The score predicts cognitive impairment development at the population level.

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