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

Two neuropathological hallmarks define AD—amyloid plaques (composed of aggregated forms of amyloid beta) and neurofibrillary tangles (formed within neurons and 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

An imbalance between the production and clearance of amyloid beta is thought to cause its accumulation in AD. This imbalance and subsequent accumulation forms amyloid plaques, which can be an initiating factor in the disease.5,7,8

TAU: UP TO 10 TO 15 YEARS BEFORE CLINICAL SYMPTOMS EMERGE9

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, which are a biomarker of AD thought to be correlated with cognition. This progressive spread of tau precedes neurodegeneration and ultimately accompanies cognitive decline.2,9-11

SIGNIFICANT NEURODEGENERATION: BY THE TIME CLINICAL SYMPTOMS EMERGE

Synaptic loss and neuronal death may result from the abnormal accumulation of amyloid and tau, ultimately leading to clinical symptoms of cognitive impairment and eventually dementia.2,4,5,12

Hypothetical Model of the Sequences of Key Biomarker Changes in AD6

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DISCOVER WHY

Aβ=amyloid beta; MCI=mild cognitive impairment.

References:

  1. Mattsson-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):60.
  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. Mawuenyega KG, Sigurdson W, Ovod V, et al. Decreased clearance of CNS beta-amyloid in Alzheimer's disease. Science. 2010;330(6012):1774.
  8. Querfurth HW, LaFerla FM. Alzheimer's disease. N Engl J Med. 2010;362(4):329-344.
  9. 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;3(8):371-386.
  10. 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.
  11. Tosun D, Landau S, Aisen PS, et al. Association between tau deposition and antecedent amyloid-β accumulation rates in normal and early symptomatic individuals. Brain. 2017;140(5):1499-1512.
  12. 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.