What Time Hides
In Alzheimer’s disease (AD), changes in the brain can begin years before symptoms appear1,2
Up to 20 years before the clinical symptoms of Alzheimer’s disease emerge, pathophysiological changes are thought to take place—including the abnormal buildup of amyloid plaques and hyperphosphorylated tau.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).2,4
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.2,4-7
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.6,8,9
00:03
[Main Title Screen]
Caption: Amyloid in Alzheimer’s Disease
[Lilly promotional code line and logo at bottom]
Caption: PP-AD-US-0292 3/2022 © Lilly USA, LLC 2022. All rights reserved.
00:06
[Animation of abnormal accumulation of a-beta - Focus on development of plaque]
Caption: Plaque Formation
Narrator: The accumulation of A-beta in Alzheimer’s disease is thought to be due to an imbalance between the production of A-beta and its elimination or clearance. This imbalance and resultant accumulation yields an excess of A-beta which is deposited into the plaques, likely leading to the initiation of the disease state.1,2
00:25
[Background visual – animated drawing of a-beta peptides Foreground – translucent slide with text listing abnormalities started by oligomers]
Caption: Abnormalities
- Tau pathology
- Inflammation
- Oxidative stress
- Mitochondrial dysfunction
- Synaptic dysfunction
- Neuronal death
00:45
[Animation showing development of diffuse plaques and neuritic plaques]
Caption: Diffuse Plaque
Caption: Neuritic Plaque
Narrator: A-beta may also accumulate within the extracellular space as two different kinds of plaques; diffuse plaques and neuritic plaques.9
00:52
[Animation – traveling through the core of a diffuse plaques]
Caption: Diffuse Plaque
Narrator: Diffuse plaques, consisting of amorphous, primarily non-fibrillar A-beta aggregates, are present in individuals with Alzheimer’s disease and to some degree in non-cognitively impaired aged individuals. These early diffuse deposits do not appear to manifest local toxicity.7,9
01:10
[Animation – traveling through the core of a diffuse plaques]
Caption: Neuritic Plaque
Narrator: In contrast, neuritic plaques are a hallmark of Alzheimer’s disease and are comprised of fibrillar A-beta arranged in a beta-pleated conformation.10
01:20
[Animation – close-up of a diffuse plaque, with labeling of dystrophic neuritis and NFTs]
Caption: Dystrophic Neurites
Narrator: These neuritic amyloid plaques are surrounded by swollen, degenerating axons and dendrites called “dystrophic neurites” and intracellular accumulations of neurofibrillary tangles.10
Caption:
References
- Mawuenyega KG, Sigurdson W, Ovod V, Munsell L, Kasten T, Morris, JC, et al. (2010). Decreased Clearance of CNS-Amyloid in Alzheimer's Disease. Science. 330(6012):1774.
- Querfurth HW and LaFerla FM. (2010). Alzheimer’s disease. New England Journal of Medicine. 362:329-44.
- Serrano-Pozo A, Frosch MP, Masliah E, and Hyman BT. Neuropathological Alterations in Alzheimer Disease. In: Selkoe DJ, Mandelkow E, and Holtzman DM, ed. The Biology of Alzheimer Disease. New York: Cold Spring Harbor Laboratory Press; 2012:1-23.
- LaFerla FM, Green KN, and Oddo S. (2007). Intracellular amyloid-β in Alzheimer's disease. Nature Reviews Neuroscience. 8(7):499-509.
- Pryor NE, Moss MA, and Hestekin CN. (2012). Unraveling the Early Events of Amyloid-β Protein (Aβ) Aggregation: Techniques for the Determination of Aβ Aggregate Size. International Journal of Molecular Sciences. 13(12):3038-3072.
- Allen S. Alzheimer's disease: a hundred years of investigation. In: Dawbarn D and Allen SJ, ed. Neurobiology of Alzheimer's Disease (Molecular and Cellular Neurobiology). 3rd ed. Oxford, UK: Oxford University Press; 2007:1-35.
- Selkoe DJ. (2011) Alzheimer Disease. Cold Spring Harbor Perspectives Biology. 3(7):1-17.
- Weller RO, Subash M, Preston SD, Mazanti I, and Carare RO. (2008). SYMPOSIUM: Clearance of Aβ from the Brain in Alzheimer’s Disease: Perivascular Drainage of Amyloid-β Peptides from the Brain and Its Failure in Cerebral Amyloid Angiopathy and Alzheimer’s Disease. Brain Pathology. 18(2):253-266.
- 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.
- Holtzman DM, Morris JC, and Goate AM. (2011). Alzheimer's Disease: The Challenge of the Second Century. Science Translational Medicine. 3(77):77sr1
TAU: UP TO 10 TO 15 YEARS BEFORE CLINICAL SYMPTOMS EMERGE3
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.2,3,10,11
00:03
[Main Title Screen]
Caption: Tau in Alzheimer’s Disease
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Caption: PP-AD-US-0293 3/2022 © Lilly USA, LLC 2022. All rights reserved..
00:05
[Animated, medium shot of pyramidal cell with NFTs.]
Narrator: Another hallmark of Alzheimer’s disease is the presence of neurofibrillary tangles, which are intra-neuronal bundles of aggregated forms of tau protein.1
00:14
[Animation of vesicle traveling down a neuron, with microtubule/axon/dendrite networks]
Caption: Microtubule
Narrator: The neuron, with its long axons and dendrites, depends on its microtubule network for vesicular transport and other functions.2
00:21
[Animation of vesicle traveling down a neuron. Inclusion of normal tau protein]
Narrator: Tau protein controls the assembly, disassembly, and stability of these microtubules within the neurons.3
00:29
[Animation of vesicle traveling down a neuron - Inclusion of normal tau protein and breaking up of network]
Narrator: Alzheimer’s disease is associated with abnormal forms of tau protein, including hyperphosphorylated tau, that have less affinity for the microtubules.3,4
00:38
[Animation of disintegration of a microtubule]
Caption: Vesicles
Narrator: The altered affinity disrupts microtubule function, impairs axonal transport, and ultimately injures the neurons.3
00:45
[Animation of helical filaments of tau proteins; with phosphorus bound to it]
Caption: Tau Proteins
Narrator: While tau is normally soluble, abnormal tau forms paired helical filaments that aggregate within the neurons. These insoluble forms of tau are apparent microscopically as neurofibrillary tangles.5,6
00:58
[Animated drawing of the brain – with spreading of tau/NFTs indicated by blue coloring indicate progression from
- medial temporal lobe to
- posterior temporal,
- parietal,
- occipital (except OCC POLE) to
- frontal last]
01:17
[Animated drawing of NFT, inside/ outside of neurons and plaques]
Narrator: The neurofibrillary tangles are not limited to the cell bodies of the neurons, but also occur in many of the dystrophic neurites present within and outside of the amyloid plaques.6
01:27
[Animated drawing of NFT, with growing number of damaged and dying neurons.]
Narrator: The abundance of neurofibrillary tangles and their regional spread appear to increase with the severity of, dementia.3,5,10-12
Caption:
References
- Weller RO, Subash M, Preston SD, Mazanti I, and Carare RO (2008). SYMPOSIUM: Clearance of Aβ from the Brain in Alzheimer’s Disease: Perivascular Drainage of Amyloid-β Peptides from the Brain and Its Failure in Cerebral Amyloid Angiopathy and Alzheimer’s Disease. Brain Pathology, 18(2):253–266.
- Stokin GB, Goldstein LS. Axonal transport and Alzheimer's disease. Annu Rev Biochem. 2006;75:607-627.
- Iqbal K, Alonso A, Chohan MO, El-Akkad E, Gong CX, Khatoon S, Liu F, and Grundke-Iqbal I. Molecular basis of tau protein pathology: role of abnormal hyperphosphorylation. In: Dawbarn D and Allen SJ, ed. Neurobiology of Alzheimer's Disease (Molecular and Cellular Neurobiology). 3rd ed. Oxford, UK: Oxford University Press; 2007:111-131.
- Allen S. Alzheimer's disease: a hundred years of investigation. In: Dawbarn D and Allen SJ, ed. Neurobiology of Alzheimer's Disease (Molecular and Cellular Neurobiology). 3rd ed. Oxford, UK: Oxford University Press; 2007:1-35.
- Serrano-Pozo A, Frosch MP, Masliah E, and Hyman BT. Neuropathological Alterations in Alzheimer Disease. In: Selkoe DJ, Mandelkow E, and Holtzman DM, ed. The Biology of Alzheimer Disease. New York: Cold Spring Harbor Laboratory Press; 2012:1-23.
- Selkoe DJ. (2011) Alzheimer Disease. Cold Spring Harbor Perspectives Biology. 3(7):1-17.
- Karran E, Mercken M, and De Strooper B. The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics. Nature Reviews Drug Discovery. 2011;(10):698-712.
- Frost B, Jacks RL, and Diamond MI. (2009). Propagation of Tau Misfolding from the Outside to the Inside of a Cell. Journal of Biological Chemistry. 284(19):12845–12852.
- Guo JL and Lee VMY. (2011). Seeding of Normal Tau by Pathological Tau Conformers Drives Pathogenesis of Alzheimer-like Tangles. Journal of Biological Chemistry. 286(17):15317–15331.
- Querfurth HW and LaFerla FM. (2010). Alzheimer’s disease. New England Journal of Medicine. 362:329-44.
- Holtzman DM, Morris JC., & Goate AM. (2011). Alzheimer's Disease: The Challenge of the Second Century. Science Translational Medicine. 3(77):77sr1.
- Nelson PT, Alafuzoff I, et al. Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol. 2012;71:362-81
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.2,5,6,12
00:03
[Main Title Screen]
Caption: Hallmark Biomarkers of Alzheimer’s Disease
[Lilly promotional code line and logo at bottom]
Caption: PP-AD-US-0294 3/2022 © Lilly USA, LLC 2022. All rights reserved.
00:07
[Begin with outline of person, highlight brain and bring rotating brain to the foreground.]
Narrator: Alzheimer’s disease is a progressive brain disorder that causes a gradual and irreversible loss of higher brain functions, leading to dementia and eventually death due to the debility associated with this disease.1,2
00:18
[Window-out key images – Titled visuals of: amyloid plaque, neurofibrillary tangles, and neuronal death.]
Caption: Amyloid Plaque
Caption: Neurofibrillary Tangles
Caption: Neuronal Death
Narrator: Pathologic hallmarks of Alzheimer’s disease include amyloid plaques, neurofibrillary tangles, and degeneration and loss of neurons and their synapses.1,3,4
00:33
Narrator: The development of biomarkers has helped to clarify the likely sequence of events that occurs in people with Alzheimer’s disease.5,6
00:41
[Animated visuals of different a-beta peptide formations, tau, and NFTs]
Narrator: While there are many unanswered questions, the prevailing theory suggests that abnormal production and clearance of the peptide in the brain called amyloid beta, or A-beta, initiates a complex series of pathological and toxic events.5,6
00:58
[Cliff Jack Figure – first visual includes only the a-beta line on graph along with axes labeling]
Caption
Clinical disease stage
Biomarker magnitude
Abnormal
Normal
Cognitively normal
MCI
Dementia
Narrator: A series of pathological events occur at different stages of the disease, as shown here in this prominent model of Alzheimer’s disease.7
This sequence of events is expressed as a hypothetical model of Alzheimer’s disease that describes a decades-long process beginning with the accumulation of A-beta in the brain,7
01:17
[Cliff Jack Figure – includes both a-beta and tau lines]
Narrator: …followed by the development of tau pathology,7
01:20
[Cliff Jack Figure – includes the 1) a-beta, 2) tau, 3) brain structure lines on graph]
Narrator: … synaptic dysfunction and neuronal death.7
01:24
[Cliff Jack Figure – includes the 1) a-beta, 2) tau, and 3) brain structure,4) memory and 5) clinical function lines on graph
- Animated entry of oblong circle appears around Med/Clin Fxn lines
- Next – a-beta line is circled]
Narrator: By the time that even subtle signs of dementia are apparent clinically, it is relatively late in the disease process and neuronal destruction has already begun.3,7
Based upon this model, the earliest pathological event is the abnormal accumulation of forms of A-beta.6,7,8
Caption:
References
- Mayeux R and Stern Y. Epidemiology of Alzheimer Disease. In: Selkoe DJ, Mandelkow E, and Holtzman DM, ed. The Biology of Alzheimer Disease. New York: Cold Spring Harbor Laboratory Press; 2012:1-19.
- Alzheimer’s Disease Education & Referral (ADEAR) Center. Alzheimer's Disease: Fact Sheet. NIH Publication No. 11-6423 12 July 2021. Available at http://www.nia.nih.gov/alzheimers/publication/alzheimers-disease-fact-sheet. Accessed October 21, 2021.
- Serrano-Pozo A, Frosch MP, Masliah E, and Hyman BT. Neuropathological Alterations in Alzheimer Disease. In: Selkoe DJ, Mandelkow E, and Holtzman DM, ed. The Biology of Alzheimer Disease. New York: Cold Spring Harbor Laboratory Press; 2012:1-23.
- 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.
- Blennow K, Zetterberg H, Fagan AM. Fluid Biomarkers in Alzheimer Disease. In: Selkoe DJ, Mandelkow E, and Holtzman DM, ed. The Biology of Alzheimer Disease. New York: Cold Spring Harbor Laboratory Press; 2012:1-23.
- Selkoe DJ and Hardy J. The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO Mol Med (2016)8:595-608.
- Jack CR Jr, Knopman DS, Jagust WJ, Shaw LM, Aisen PS, Weiner MW, Petersen RC, Trojanowski JQ. (2010) Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade. Lancet Neurology. 9(1):119-28.
- Selkoe DJ. (2011) Alzheimer Disease. Cold Spring Harbor Perspectives Biology. 3(7):1-17.
Hypothetical Model of the Sequences of Key Biomarker Changes in AD7
Data from 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.
Hypothetical model of dynamic biomarkers of the AD pathological cascade, beginning with the abnormal accumulation of amyloid and the subsequent accumulation of tau, which leads to MCI and eventually dementia.7
“I was forgetting words. My daughter wanted me to see the doctor.”
Time is of the essence
DISCOVER WHYAβ=amyloid beta; MCI=mild cognitive impairment.
References:
- 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.
- 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.
- Porsteinsson AP, Isaacson RS, Knox S, et al. Diagnosis of early Alzheimer’s disease: clinical practice in 2021. J Prev Alzheimers Dis. 2021;3(8):371-386.
- 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.
- 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.
- Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med. 2016;8(6):595-608.
- 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.
- Mawuenyega KG, Sigurdson W, Ovod V, et al. Decreased clearance of CNS beta-amyloid in Alzheimer's disease. Science. 2010;330(6012):1774.
- Querfurth HW, LaFerla FM. Alzheimer's disease. N Engl J Med. 2010;362(4):329-344.
- 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.
- 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.
- 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.