Alzheimer's disease and related disorders in patients with bipolar disorders and other mental disorders: Actual neurodegenerative processes or phenocopies?

Abstract

Dear Editor,

We read with great interest the study by Liu et al.¹, which leverages a robust methodological framework in a large sample of nearly 500,000 participants to investigate the association between chronic psychiatric disorders and the risk of late-life neurocognitive diseases.

The study highlights an increased risk of neurocognitive disorders in patients with mood disorders and especially bipolar disorder (BD), with particular emphasis on Alzheimer's disease (AD). This conclusion is supported by the use of Mendelian randomization, which suggests a causal link between BD and AD. However, the study also uncovers an elevated risk for other types of dementia, including vascular dementia (VD) and frontotemporal dementia (FTD), with hazard ratios exceeding those for AD (AD 2.37 [1.43–3.94], VD 3.82 [2.16–6.75], FTD 5.80 [1.86–18.13]).¹ This broader finding is important, as it points to the possibility of multiple underlying mechanisms contributing to late cognitive impairment in BD.

These observations lead us to commend Liu et al. for their important contribution while also highlighting the complexity of interpreting their findings. The increased risk of neurocognitive disorders in BD, as demonstrated by their study, may include AD but also other dementias, each with distinct pathophysiological underpinnings. This aligns with prior research suggesting an elevated risk of other neurodegenerative conditions, such as Parkinson's disease, among patients with BD.⁸

To advance in the field, it will be essential to determine whether patients with BD and cognitive decline exhibit the characteristic pathological hallmarks of these neurodegenerative diseases or whether the observed associations reflect phenocopies. Such an effort requires the integration of biomarkers and neuropathological data into future studies, as well as the establishment of dedicated cohorts to explore these questions.

Altogether, these findings resonate with the historical concept of “vesanic dementia” a term that encapsulates the complex interplay between psychiatric disorders and late-life cognitive decline.⁹ This also underscores the importance of distinguishing late-life cognitive impairment in patients with BD from the cognitive impairments observed in younger patients, which likely arise from different mechanisms.

The authors declare no conflicts of interest. Author disclosures are available in the Supporting Information.