Acta Neuropathologica

, Volume 109, Issue 1, pp 25–31

Metabolic/signal transduction hypothesis of Alzheimer’s disease and other tauopathies


DOI: 10.1007/s00401-004-0951-y

Cite this article as:
Iqbal, K. & Grundke-Iqbal, I. Acta Neuropathol (2005) 109: 25. doi:10.1007/s00401-004-0951-y


Alzheimer’s disease (AD), the major cause of dementia in middle- to old-aged individuals, is multifactorial. Independent of the etiology, whether genetic or non-genetic, this disease is characterized by extracellular β-amyloid plaques and intraneuronal neurofibrillary tangles of abnormally hyperphosphorylated tau. However, the molecular mechanisms of neither AD nor other tauopathies are completely understood. To date, the most popular hypothesis of AD is the “Amyloid cascade hypothesis”, according to which β-amyloid, the cleavage product of β-amyloid precursor protein (APP), is neurotoxic and causes neurodegeneration and dementia. However, this hypothesis is inconsistent with the presence in normal aged human brain of the β-amyloid plaque burden similar to that in AD, and the absence of neurofibrillary pathology and neurodegeneration in mutated APP, presenilin-1 and presenilin-2 transgenic mice that show extensive β-amyloid plaque pathology. Here we propose an alternate hypothesis, the “Metabolic/signal transduction hypothesis”, which is consistent both with the pathology seen in AD and other tauopathies and as well as all experimental animal conditions. In this hypothesis, with increasing age, the fluidity of neuronal membranes is progressively reduced, which makes it less resistant to environmental/metabolic insults affecting one or more signal transduction pathways, which lead to a protein phosphorylation/dephosphorylation imbalance and abnormal hyperphosphorylation of tau. The hyperphosphorylated tau sequesters normal tau, MAP1 and MAP2, which results in breakdown of the microtubule network and, consequently, a progressive retrograde degeneration of the affected neurons and, ultimately, dementia.


Alzheimer’s diseaseTauopathiesMicrotubule-associated protein tauNeurofibrillary degenerationSignal transduction

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© Springer-Verlag 2005

Authors and Affiliations

  1. 1.Department of NeurochemistryNew York State Institute for Basic Research In Developmental DisabilitiesStaten IslandUSA