Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common human neurodegenerative diseases. AD is primarily a dementing disease, and PD is a movement disorder. Together, they affect around 50 million people worldwide, with the vast majority of disease cases being sporadic. Their incidence increases with age. Like most neurodegenerative diseases, AD and PD are caused by the aggregation of a small number of proteins, with filament assemblies constituting the end-point of protein aggregation. AD is characterized by the presence of abundant extracellular plaques made of amyloid assemblies of Aβ peptides and intraneuronal inclusions made of assembled tau protein. Some dominantly inherited cases of AD are caused by mutations in the gene encoding the amyloid precursor protein (APP), the cleavage of which gives rise to Aβ. In these cases, dysfunction of APP precedes dysfunction of tau. In contrast, mutations in MAPT, the tau gene, give rise to dominantly inherited frontotemporal dementia and parkinsonism, with abundant tau inclusions in the absence of Aβ plaques. Extrapolation to the much more common sporadic cases of AD has given rise to the amyloid cascade hypothesis, which postulates that Aβ aggregation causes the formation of tau inclusions, synaptic dysfunction, nerve cell death, and brain shrinkage. However, tau inclusions correlate better with cognitive impairment, and Aβ may exert its effects through tau. Strategies targeting the formation of Aβ and tau assemblies are valuable for the development of mechanism-based therapies. Unlike AD, in which two distinct amyloid assemblies are present, PD is characterized by intracellular deposits, Lewy bodies and neurites, both composed of the protein α-synuclein. Dominantly inherited forms of PD are caused by mutations in SNCA, the α-synuclein gene. More than 95% of those diagnosed with PD have Lewy inclusions.

For many years, the mechanisms underlying AD and PD were widely believed to be cell-autonomous. This implies that the same molecular events, such as the formation of tau and α-synuclein assemblies, occur independently in a large number of cells in an otherwise healthy brain. Recent findings have suggested instead that non–cell-autonomous processes play an important part in AD and PD. Inclusions are thought to form in a small number of cells and—given enough time and, perhaps, a genetic predisposition—spread in a deterministic manner to distant brain regions. The formation of the first Aβ, tau, and α-synuclein inclusions is probably stochastic, with most seeds being degraded. Distinct molecular conformers of aggregated proteins (or strains) may underlie clinically different diseases. This is reminiscent of human prion diseases, such as Creutzfeldt-Jakob disease (CJD). However, there is reluctance to use the term prion for the inclusions of AD and PD. The main reasons are that in contrast to Kuru and CJD, transmission of AD and PD has not been demonstrated between individuals, and most experimental studies have used transgenic animals that overexpress disease proteins.

The prion concept appears to apply to all human neurodegenerative diseases with abnormal protein assemblies, including AD and PD. This has brought unity to the field and changed the way we think about these diseases. It has been known for some time that a seed can template aggregation of the homologous protein. However, the ability of protein aggregates to spread through the nervous system had previously been underappreciated. At a practical level, the new findings are helping to elucidate the mechanisms …