Immune-Mediated Neurologic Conditions As An Independent Risk Factor For Dementia And Its Subtypes: A Meta-analysis Of The Evidence

Author Block: 

Mohamed I. Mohamed, Rana Sameh, Dana Farghaly, Basmalla Ashraf, Nadeen Hossam Mahmoud, Bishoy Kamel.
Alexandria University, Faculty of Medicine, Alexandria, Egypt.

Abstract:
Background:

Evidence regarding the independent risk of dementia associated with immune-mediated neurological conditions (IMNCs) is inconsistent. In light of ongoing debate over Alzheimer’s disease pathogenesis and the proposed autoimmune-autoinflammatory hypothesis, this study aims to provide disease-specific insights into the associations between IMNCs and distinct dementia subtypes.

Methods:

We performed a PRISMA-compliant meta-analysis with prospective PROSPERO registration (CRD420251031380). PubMed, Scopus, and Web of Science were searched from inception to December 18, 2025, using MeSH terms with expert librarian support. Most fully adjusted risk ratios (RRs) for ICD-coded dementia outcomes were pooled, with odds and hazard ratios converted to RRs using established methods when required. Random-effects meta-analyses using restricted maximum likelihood estimation with Hartung-Knapp adjustment were applied.

Results:

Twenty-five studies were included (4.2 million individuals with any immune-mediated condition and 29.6 million controls) from 23,129 references. IMNCs were associated with a 40% increased risk of all-cause dementia after outlier removal (aRR 1.40, 95% CI 1.22-1.60). Alzheimer’s disease risk was modestly increased, whereas vascular dementia was not. Multiple sclerosis showed a substantial increase in all-cause dementia risk - particularly among females - without corresponding increases in Alzheimer’s or vascular dementia. Neuromyelitis optica was consistently associated with higher dementia risk, while myasthenia gravis, Guillain-Barré syndrome, and myositis showed no significant associations. Mendelian randomization and neuropathological evidence did not support a genetically driven or β-amyloid-mediated mechanism.

Conclusion:

The association between IMNCs and dementia risk is heterogeneous and disease-dependent. Although an increased risk of all-cause dementia was observed, associations with specific dementia subtypes varied across conditions, and genetic and neuropathological evidence did not support a causal autoimmune or β-amyloid-driven mechanism. These findings highlight the importance of cautious interpretation and emphasize the need for condition-specific investigations.