Co-aggregation of amyloidogenic proteins in age-related neurodegenerative diseases

Age-related neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and related dementias, are increasingly understood as multifactorial proteinopathies involving co-aggregation of amyloidogenic proteins such as Tubulin-associated unit protein (Tau), α-synuclein (α-syn), amyloid-β (Aβ), and TAR DNA-binding protein 43 (TDP-43). Rather than acting independently, these proteins often cross-seed, co-localize, and modulate each other’s aggregation dynamics and toxicity. This review critically examines the mechanistic and pathological underpinnings of heterotypic protein co-aggregation, integrating biophysical, cellular, animal, and human data. Further, this review proposes a conceptual framework that views neurodegeneration as a network of interacting misfolded proteins shaped by ageing-related changes in lipid membranes, redox balance, proteostasis, and genetic factors. Emphasis is placed on translational opportunities: co-aggregation-specific biomarkers in cerebrospinal fluid and extracellular vesicles, and emerging multi-targeted therapies including immunotherapy, proteostasis modulators, and autophagy-inducing chimeras. This review also discusses the clinical implications of co-pathology in mixed dementias and overlapping disorders. It is therefore time to move beyond the classical one protein–one disease paradigm and embrace models that explicitly incorporate heterotypic co-aggregation, mixed pathologies, and shared vulnerability pathways across ageing-related disorders. By reframing co-aggregation as a central pathogenic mechanism, this review highlights the need for diagnostics and therapeutics that address the interconnectivity of protein misfolding in ageing brains. The graphical abstract integrates key heterotypic interactions among Tau, α-syn, Aβ, and TDP-43 across molecular, cellular, and clinical levels. It highlights how age-related changes in lipid membranes, redox balance, proteostasis, and genetic risk factors converge to promote misfolding, cross-seeding, and prion-like propagation of these proteins, ultimately driving synaptic failure and neurodegeneration. The scheme also summarizes major translational implications, including the emergence of co-aggregation-specific biomarkers in cerebrospinal fluid and extracellular vesicles, and the need for multi-target therapeutic strategies that simultaneously modulate several interacting proteinopathies. Image created with www.biorender.com . • Heterotypic co-aggregation of Tau, α-syn, Aβ, and TDP-43 underlies shared pathology in Alzheimer’s, Parkinson’s, and related dementias. • Cross-seeding and physical interactions among misfolded proteins exacerbate toxicity and disease spread. • Age-related changes in lipid membranes, redox homeostasis, proteostasis, and genetics modulate co-aggregation dynamics. • A network-based framework reframes neurodegeneration as an interconnected misfolding landscape rather than isolated proteinopathies. • Co-aggregation-informed biomarkers and multi-targeted therapies offer new avenues for diagnosis and intervention in mixed neurodegenerative disorders.