Alzheimer's disease and the 'ABSENT' hypothesis: mechanism for amyloid beta endothelial and neuronal toxicity

Med Hypotheses. 2005;65(1):123-37. doi: 10.1016/j.mehy.2004.08.031.

Abstract

Alzheimer's disease [AD] is the most common cause of dementia among people age 65 and older. One of the biggest stumbling blocks in developing effective drug therapy for Alzheimer's disease has been the lack of a comprehensive hypothesis that explains the mechanism behind all of the histopathological changes seen in patients suffering from Alzheimer's disease. An overview of the currently popular 'amyloid' and 'vascular' hypotheses for AD demonstrates that neither hypothesis by itself can explain all the known histopathological and biochemical lesions seen in Alzheimer's disease. The paper presents a hypothesis that tries to explain the mechanism behind almost all the histopathological changes, and varying clinical manifestations seen in both diagnosed AD and Vascular Dementia [VaD]. The new hypothesis is based on the known dual toxicity of beta amyloid to both vascular and neuronal tissues, their synergy and the resultant net effect on the onset and progression of AD. The new hypothesis therefore will be known as the Amyloid Beta Synergistic Endothelial and Neuronal Toxicity [ABSENT] hypothesis. The ABSENT hypothesis will try to show the common chemical mechanism behind almost all of the pathological changes seen in AD. According to the ABSENT hypothesis, beta amyloid itself generates all the free radicals that cause both vascular dysfunction and the neuronal damage seen in AD. The chemical mechanism proposed is based on evidence from physical chemistry experiments, calculations as well as in vitro/in vivo experiments. The ABSENT hypothesis does not favor one mode of beta amyloid-induced brain damage over the other, rather it considers the net effects of the neuronal stress/damage caused by both the cerebrovascular dysfunction and direct neurotoxicity caused by beta amyloid. The hypothesis states that each patient has a different balance of predisposing factors that modulate the extent of neurotoxicity and cerebrovascular dysfunction caused by beta amyloid and thereby explains the wide range and mixed nature of damage and dysfunction seen in the studies done on patients diagnosed with AD, VaD or 'mixed dementias'. According to the hypothesis, beta amyloid peptides are necessary if not sufficient to cause AD, VaD and mixed senile dementias. The hypothesis, therefore, proposes the term Beta Amyloid Dementias [BAD] to describe the conditions currently covered by the diagnoses of 'AD', 'VaD' and 'Mixed [senile] Dementias'. Finally, the ABSENT hypothesis tries to put forth a direct chemical mechanism behind the apparent synergy and increased association between old age, pre- and coexisting vascular disease, diabetes and AD.

MeSH terms

  • Aged
  • Alzheimer Disease / diagnosis
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology*
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Peptides / toxicity*
  • Cerebrovascular Disorders / pathology
  • Cerebrovascular Disorders / physiopathology
  • Dementia, Vascular / diagnosis
  • Dementia, Vascular / metabolism
  • Dementia, Vascular / pathology
  • Diabetes Mellitus / pathology
  • Diabetes Mellitus / physiopathology
  • Endothelium, Vascular / drug effects*
  • Endothelium, Vascular / metabolism
  • Endothelium, Vascular / pathology
  • Humans
  • Models, Biological*
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neurons / pathology
  • Vascular Diseases / complications

Substances

  • Amyloid beta-Peptides