Amyloid Cascade or Tau Dysfunction: The Cause for Alzheimer´s Disease

Abstract

Alzheimer´s Disease (AD) is an age-related neurodegenerative disorder which has yet to be fully understood. The amyloid cascade hypothesis (ACH) has played the prominent role in explaining the etiology and pathogenesis of AD. It proposes that the deposition of β-amyloid (Aβ) is the initial pathological event in AD leading to the formation of senile plaques (SPs) and then to neurofibrillary tangles (NFTs), neuronal cell death, and ultimately dementia. However, ACH has recently come under severe scrutiny as it has been claimed that SPs may be developed independently and might be the effect of the disease rather than the cause of AD. The present review indeed argues that the amyloid cascade is an effect of the disease and not the cause. We argue that excitotoxic processes caused by hyperphosphorylation of tau tangles at dendritic spines are the leading cause of the change in energy metabolism leading to apoptosis. We also propose that there are links among metabolism, the deposition of amyloid plaques, hyperphosphorylation of tau, and the decline of cognitive functions, following the increase of intraspinal cAMP that we claim is associated with decline of lactate.