Summarizing attributable factors and evaluating risk of bias of Mendelian randomization studies for Alzheimer's dementia and cognitive status: a systematic review and meta-analysis.

Abstract

Background: No effective treatment is available to delay or reverse the onset and progression of Alzheimer's dementia (AD). Mild cognitive impairment, a clinical state between normal aging and AD, may offer the proper window for AD intervention and treatment. This systematic review aimed to summarize evidence from Mendelian randomization (MR) studies exploring factors attributable to AD and related cognitive status and to assess its credibility.

Methods: We searched PubMed, Embase, MEDLINE, and the Cochrane Library to identify MR studies investigating the associations between any factor and AD and related cognitive status. The risk of bias in MR studies was evaluated using nine signaling questions tailored to identify potential biases based on the STROBE-MR guidelines.

Results: A total of 125 eligible publications were examined, including 106 AD-related MR studies reporting 674 records and 28 cognition-related MR studies reporting 141 records. We identified 185 unique causal risk factors for AD and 49 for cognitive status. More than half of the MR studies reporting AD or cognitive status outcomes exhibited poor methodological quality, with a high risk of bias observed in 59% of the AD-related studies and 64% of the cognitive-related studies.

Conclusions: This systematic review summarized modifiable factors and omics signatures, providing a database of MR studies on AD and related cognitive status. The evaluation of bias risk in MR studies serves to raise awareness and improve overall quality. A critical appraisal checklist for assessing the risk of bias may pave the way for the development of a standardized tool.

Systematic review registration: The review protocol was registered with the Prospective Register of Systematic Reviews (PROSPERO) under the registration number CRD42023213990.