AMYLOID BETA CASCADE HYPOTHESIS

Alzheimer’s disease (AD) is thought to be caused by a sequence of events triggered by the accumulation of amyloid beta.1

How the amyloid beta cascade may lead to neurological damage

In people with AD, 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.1,2

Together, abnormal accumulation of amyloid beta plaques and neurofibrillary tangles can impair neuronal function and may cause neurodegeneration (atrophy).1,3

These pathological changes of Alzheimer’s disease are thought to begin decades before any clinical symptoms appear.²

Pathological Changes Across Alzheimer's Disease Stages4

To learn more about a specific disease stage, use the tappableclickable symbols.

Legend of a hypothetical model that represents the pathological changes across Alzheimer's disease stages
Red line representing amyloid beta (Aβ) in a hypothetical model
Green line representing synaptic dysfunction in a hypothetical model
Tan line representing tau in a hypothetical model
Turquoise line representing brain structure in a hypothetical model
Brown line representing cognition in a hypothetical model
Blue line representing clinical function in a hypothetical model
Aβ letters in a red circle, representing amyloid beta in a hypothetical model Aβ letters in a tan circle, representing amyloid beta in a hypothetical model SD letters in a tan circle, representing synaptic dysfunction in a hypothetical model SD letters in a green circle, representing synaptic dysfunction in a hypothetical model Tau abbreviation in a tan circle, representing synaptic dysfunction in a hypothetical model Tau abbreviation in a gray circle, representing synaptic dysfunction in a hypothetical model Brain structure abbreviation in a gray circle, representing synaptic dysfunction in a hypothetical modelFPO Progression Chart - Brain Structure icon Brain structure abbreviation in a turquoise circle, representing synaptic dysfunction in a hypothetical model Cognition abbreviation in a tan circle, representing synaptic dysfunction in a hypothetical model Cognition abbreviation in a black circle, representing synaptic dysfunction in a hypothetical modelFPO Progression Chart - Cognition active icon Clinical function abbreviation in a tan circle, representing synaptic dysfunction in a hypothetical model Clinical function abbreviation in a blue circle, representing synaptic dysfunction in a hypothetical model

AIcon of the Greek letter β, representing amyloid beta (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.4

Synaptic Dysfunction

When amyloid beta is no longer cleared from the brain properly, it accumulates and is widely believed to lead to synaptic dysfunction and neurodegeneration long before the first symptoms of Alzheimer’s disease start to become visible.4

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 neurons.4

Brain Structure

Together, abnormal accumulation of amyloid beta plaques and neurofibrillary tangles may cause neurodegeneration through neuronal and synaptic loss (atrophy).4

Cognition

The MCI stage of AD may show evidence of disease pathology along with impairment in 1 or more cognitive domains that do not interfere with daily functioning.7

Clinical Function

Initially, amyloid beta plaques accumulate in the centers of higher mental function and those related to learning and memory. Ultimately, plaques compromise areas that regulate attention, emotion, and various other activities, severely impacting daily life.8,9

*Mild cognitive impairment.

Adapted from Jack CR Jr, Knopman DS, Jagust WJ, et al. Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol. 2010;9(1):119-128, with permission from Elsevier. https://www.sciencedirect.com/journal/the-lancet-neurology.

An opportunity to diagnose

According to the cascade hypothesis, amyloid beta accumulation is the earliest marker of Alzheimer's disease pathology, occurring upstream of synaptic dysfunction and tau-mediated neuronal injury.5

This makes biomarker confirmation via amyloid positron emission tomography (PET) scan or cerebrospinal fluid (CSF) test all the more important. The diagnostic value of AD as the cause of MCI provides the clinician an opportunity to take action before greater neuronal damage occurs and more cognition and function are lost.6
SEE HOW BIOMARKER TESTING CAN SUPPORT A DIAGNOSIS OF AD

Support a diagnosis of AD in the MCI stage with biomarkers.

WHAT'S NEXT?

The role of amyloid beta

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References

1.
Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science. 2002;297(5580):353-356.
2.
Oboudiyat C, Glazer H, Seifan A, Greer C, Isaacson RS. Alzheimer’s disease. Semin Neurol. 2013;33(4):313-329.
3.
Querfurth HW, LaFerla FM. Alzheimer’s disease. N Engl J Med. 2010;362(4):329-344.
4.
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.
5.
Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med. 2016;8(6):595-608.
6.
Jack CR Jr, Knopman DS, Jagust WJ, et al. Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol. 2010;9(1):119-128.
7.
Morris JC, Blennow K, Froelich L, et al. Harmonized diagnostic criteria for Alzheimer’s disease: recommendations. J Intern Med. 2014;275(3):204-213.
8.
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.
9.
Alzheimer's Association. Alzheimer's Association Report: 2019 Alzheimer's disease facts and figures. Alzheimers Dement. 2019;15:321-387.

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