Molecular Crossroads: Shared and Divergent Molecular Signatures in Alzheimer’s Disease and Dementia with Lewy Bodies

Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) are the two most common forms of dementia due to neurodegeneration. AD is characterized by extracellular amyloid-β (Aβ) plaques and intracellular tau neurofibrillary tangles, whereas DLB is defined by α-synuclein (α-Syn)-containing Lewy bodies. Although AD and DLB exhibit divergent core features, the disorders frequently co-occur and converge on shared endpoints. Co-pathology is common and linked to more severe cognitive decline, faster progression, and clinicopathological heterogeneity. Here, we discuss the current understanding of shared and unique clinical and neuropathological features of AD and DLB. We compare genetic risk and pathological drivers (Aβ and tau in AD; α-Syn in DLB) and their overlapping co-pathology, and review downstream mechanisms—mitochondrial dysfunction, oxidative stress, neuroinflammation, and cerebrovascular contributions, including cerebral amyloid angiopathy. We highlight recent findings from state-of-the-art multi-omics (transcriptomic, proteomic, metabolomic, and single-cell/spatial studies) that reveal convergent and disease-specific molecular signatures of AD and DLB. We outline a framework for emerging next-generation biomarkers—from blood-based and cerebrospinal fluid assays to imaging and digital measures—for diagnosis and stratification, and discuss potential translational implications. Together, these advances help to disentangle shared from disease-specific mechanisms, which is essential for improved diagnosis and the development of precise, disease-modifying therapies.