Clinical, radiological and immunohistological distinctions between limbic-predominant and typical Alzheimer’s disease: A systematic review

Background: Alzheimer’s disease (AD) is the leading cause of dementia worldwide, with prominent hippocampal and medial temporal lobe atrophy. Limbic-predominant (LP) AD has been proposed as a distinct subtype, but distinctions from typical AD remain unclear. This systematic review evaluates clinical, radiological, and immunohistological differences between LP and typical AD. Methods: Following PRISMA guidelines, PubMed, Embase, and Web of Science were searched. Data on baseline characteristics, clinical, radiological, and immunohistological features were extracted. Screening was performed with Rayyan.ai, and study quality was assessed using the Newcastle–Ottawa Scale. Results: From 211 articles, 21 studies were included, totaling 11,315 patients: 1,178 (15.7%) LP, 4,159 (36.7%) typical AD, and 5,378 (47.6%) other presentations. Weighted averages: education 24.31 years (LP) vs. 17.15 years (AD); age at onset 77.36 years (LP) vs. 72.33 years (AD); disease duration 8.43 years (LP) vs. 8.95 years (AD). Clinical presentations were similar, with cognitive impairment and memory deficits predominant. MRI and FDG-PET revealed lower hippocampal volume and higher metabolism in LP. Tau-PET showed lower R2 relaxation in parietal, cingulate, and cuneus regions and elevated hippocampal neurofibrillary tangles. Immunohistology revealed higher hippocampal tau burden and more TDP-43 inclusions in LP compared to typical AD. Conclusion: LP and typical AD exhibit notable radiological and immunohistological differences, though clinical presentations overlap. Current evidence cannot definitively classify LP as a distinct subtype or separate disease. Further studies are required to clarify these distinctions.