This review reframes age-related neurodegeneration as driven by heterotypic co-aggregation of amyloidogenic proteins (α-synuclein, tau, Aβ, TDP-43), synthesizing biophysical, cellular, animal, and human data on cross-seeding and shared vulnerability pathways and highlighting translational…

By centering α-synuclein's interactions with other amyloid proteins and implicating proteostasis, lysosomal/autophagy dysfunction, and membrane/redox changes, the paper points to actionable biomarker strategies and multi-target therapeutic approaches directly relevant to Parkinson's drug discovery…

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.