THE PATHOPHYSIOLOGY OF ALZHEIMER’S DISEASE

Research has shown that when amyloid beta is no longer properly cleared from the brain, it accumulates and can lead to neurodegeneration long before the first symptoms of Alzheimer’s disease (AD) start to become visible.1-6

This understanding of AD highlights the importance of early detection and diagnosis as a central component of future patient care.

Understanding the Pathophysiology of Alzheimer’s Disease

Transcript

Amyloid beta and the start of AD

It is believed that Alzheimer’s disease is based on the buildup of two proteins in the brain—amyloid beta and tau—thought to be caused by advanced age and/or genetic factors.1,7-9

One of the pathological hallmarks of Alzheimer’s disease is the abnormal accumulation of amyloid beta, due to an imbalance in production and inadequate clearance in the brain.1,7-9

Multiple Forms of Amyloid Beta Result From Abnormal Accumulation and Aggregation10

Amyloid beta protein that results from abnormal accumulation and aggregation of monomer, oligomer, fibril, and amyloid plaque

Amyloid beta monomers (single proteins) aggregate into soluble oligomers (small aggregates of proteins), which then combine to form insoluble fibrils (long aggregates of proteins) and plaques.1

Oligomers are soluble and may spread throughout the brain. Fibrils are larger aggregrates that are insoluble and assemble into amyloid beta plaques.10

How the amyloid beta cascade leads to neurological damage

It is unclear whether all or only some of these amyloid beta forms are damaging to the brain, but there is evidence to support that aggregated forms, such as oligomers and plaques, may be toxic to nerve cells.1

In people with Alzheimer’s disease, the presence of amyloid beta is believed to trigger a pathological cascade that may promote the abnormal phosphorylation of tau protein, which leads to the formation of neurofibrillary tangles within neurons.3,7

Together, abnormal accumulation of amyloid beta plaques and neurofibrillary tangles can impair neuronal function because of neuronal and synaptic loss (atrophy) in the brain, and may cause neurodegeneration.1,7

Pathological Changes Across Alzheimer’s Disease Stages11

AB (AMYLOID BETA ACCUMULATION)

It is believed that amyloid beta accumulation starts decades before the onset of clinical symptoms, setting off a cascade that leads to the formation of neurofibrillary tangles and the initiation of neurodegeneration in Alzheimer’s disease.11

SYNAPTIC DYSFUNCTION

When amyloid beta is no longer cleared from the brain properly, it accumulates and leads to synaptic dysfunction and neurodegeneration long before the first symptoms of Alzheimer's disease start to become visible.11

TAU-MEDIATED NEURONAL INJURY

The accumulation of amyloid beta is believed to promote the abnormal phosphorylation of tau protein, which leads to the formation of neurofibrillary tangles within the neurons.11

BRAIN STRUCTURE

Together, abnormal accumulation of amyloid beta plaques and neurofibrillary tangles may cause neurodegeneration through neuronal and synaptic loss (atrophy).11

COGNITION

MCI due to AD may show evidence of disease pathology along with impairment in 1 or more cognitive domains that does not interfere with daily functioning.12

CLINICAL FUNCTION

Initially, amyloid beta plaques accumulate in the centers of higher mental functions. Over time, plaques spread to related structures involved in learning and memory. Ultimately, plaques compromise areas that regulate attention, emotion, and various other activities, severely impacting daily life.13,14

*Mild cognitive impairment.
Adapted from Sperling, Copyright 2011, with permission from Elsevier. https://www.sciencedirect.com/journal/alzheimers-and-dementia

What’s Next? Addressing the Challenges of Alzheimer’s Disease>>

References

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  11. Sperling RA, Aisen PS, Beckett LA, et al. Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging–Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7(3):280-292.
  12. Morris JC, Blennow K, Froelich L, et al. Harmonized diagnostic criteria for Alzheimer’s disease: recommendations. J Intern Med. 2014;275(3):204-213.
  13. Serrano-Pozo A, Frosch MP, Masliah E, Hyman BT. Neuropathological alterations in Alzheimer disease. Cold Spring Harb Perspect Med. 2011;1(1):a006189. doi:10.1101/cshperspect.a006189.
  14. Alzheimer's Association. Alzheimer’s Association Report: 2019 Alzheimer’s disease facts and figures. Alzheimers Dement. 2019;15:321-387.

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