Clock hand and inner workings

What Time Hides

In Alzheimer’s disease, changes in the brain can begin years before symptoms appear1,2

Up to 20 years before the clinical symptoms of Alzheimer's disease (AD) emerge, pathophysiological changes are thought to take place—including the abnormal buildup of amyloid and tau.2,3

AD has been defined by two neuropathological hallmarks, including amyloid plaques that are composed of aggregated forms of amyloid beta and neurofibrillary tangles that form within neurons and are composed of abnormally phosphorylated tau (or hyperphosphorylated tau).2,3

AMYLOID: UP TO 20 YEARS BEFORE CLINICAL SYMPTOMS EMERGE3

Many experts believe one of the first pathophysiological changes of AD is the abnormal accumulation of amyloid beta in the form of amyloid plaques in the brain.2-6

TAU: UP TO 10 TO 15 YEARS BEFORE CLINICAL SYMPTOMS EMERGE6

The accumulation of amyloid is followed by the accumulation of hyperphosphorylated tau as many as 10 to 15 years before clinical symptoms emerge. This abnormal form of tau loses its ability to bind with microtubules, leading to the formation of neurofibrillary tangles. This progressive spread of tau precedes neurodegeneration and ultimately accompanies cognitive decline.2,7,8

SIGNIFICANT NEURODEGENERATION: BY THE TIME CLINICAL SYMPTOMS EMERGE

Abnormal accumulation of amyloid and tau are thought to contribute to synaptic loss and neuronal death, and are hypothesized to lead to clinical symptoms of cognitive impairment and eventually dementia.2,4,5,9

Hypothetical Model of the Sequences of Key Biomarker Changes in AD6

Time is of the essence

DISCOVER WHY

Aβ=amyloid beta; MCI=mild cognitive impairment.

References:

  1. Mattson-Carlgren N, Andersson E, Janelidze S, et al. Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease. Sci Adv. 2020;6(16):1-13.
  2. Aisen PS, Cummings J, Jack CR Jr, et al. On the path to 2025: understanding the Alzheimer’s disease continuum. Alzheimers Res Ther. 2017;9(1):1-10. https://alzres.biomedcentral.com/track/pdf/10.1186/s13195-017-0283-5.pdf . Accessed August 13, 2021.
  3. McDade E, Bednar M, Brashear HR, et al. The pathway to secondary prevention of Alzheimer’s disease. Alzheimers Dement (N Y). 2020;6(1):1-9.
  4. Chen GF, Xu TH, Yan Y, et al. Amyloid beta: structure, biology and structure-based therapeutic development. Acta Pharmacol Sin. 2017;38(9):1205-1235.
  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. Tracking pathophysiological processes in Alzheimer’s disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol. 2013;12(2):207-216.
  7. Porsteinsson AP, Isaacson RS, Knox S, Sabbagh MN, Rubino I. Diagnosis of early Alzheimer’s disease: clinical practice in 2021. J Prev Alzheimers Dis. 2021;8(3):371-386.
  8. Bateman RJ, Xiong C, Benzinger TL, et al; Dominantly Inherited Alzheimer Network. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med. 2012;367(9):795-804.
  9. Jack CR Jr, Bennett DA, Blennow K, et al. NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018;14(4):535-562.