Fig. 5 |. Proposed relationships between pathological protein accumulation, neurodegeneration and drivers of the Alzheimer disease process.

The initial stages of Alzheimer disease (AD) development reflect relationships between cortical amyloid-β (Aβ; red) and tau (blue) in the medial temporal lobe (MTL) (1). This process appears to begin with Aβ deposition in the cortex but could have a bidirectional nature as accumulation of MTL tau, which may or may not reflect AD, usually precedes cortical Aβ in cognitively healthy older people. The relationship between these two proteins is associated with spread of tau out of the MTL into the medial parietal, lateral parietal and temporal cortices (2). This tau spread is associated with neurodegeneration (dark blue) in a similar topography to tau deposition (3), which in turn is related to cognitive decline and, eventually , dementia (4). Drivers of Aβ include various processes and factors. Disturbed or diminished sleep, increased neural activity , reduced physical and cognitive activity , cerebrovascular disease, old age, the apolipoprotein E gene ε4 allele (APOE4) and other proteinopathies have been linked to Aβ deposition. Some of these associations have not been described for tau pathology , but this could reflect the relative novelty of in vivo tau imaging. Old age, APOE4 and other proteinopathies appear to be associated with tau deposition in the MTL. Neurodegeneration is also associated with these factors and with cerebrovascular disease. Increased age, APOE4, other proteinopathies and cerebrovascular disease may also affect neurodegeneration independent of their effects on tau or Aβ. TDP43, TAR DNA-binding protein 43.