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Early diagnosis, prevention and treatment of Alzheimer Disease – where are we at now?

12th July 2019, Dr Chee L Khoo 

When we think about Alzheimer disease (AD) we think about the two classes of abnormal structures, extracellular amyloid plaques and intraneuronal neurofibrillary tangles. The soluble building blocks of these structures are amyloid-β (Aβ) peptides for plaques and tau for tangles. We have known about the association between Aβ and tau and AD for some time yet the only therapies available for patients with AD are the cholinesterase inhibitors and memantine which only target the symptoms of the disease. At best, they may slow the disease progression but even that is questionable now. How close are we to a breakthrough in early diagnosis, prevention and thence, treatment of this debilitating disease?

The chicken or the egg problem

AD is characterised by a slow accumulation of pathological amyloid beta (Aβ) species in the brain [1-3], which starts a decade or more before the symptoms occur. Data from studying genetically at-risk groups and otherwise cognitively unimpaired individuals suggests that there are progressive biomarker changes years before cognitive impairment. Treatment that interfere with the production, accumulation, or toxic sequelae of Aβ in the preclinical stages of the disease should be effective in preventing or slowing the progression of AD when initiated in the pre-clinical stages of the disease before irreversible neuronal loss. Unfortunately, anti-amyloid drugs that reduce Aβ [4–9], generally have not led to improvements in cognition in the early or mild AD stages.

Is the failure of these anti-amyloid agents the result of poor design of the trials or is it because even in the preclinical stage, the deposition of Aβ has already caused irreversible damage? So, perhaps, we need biomarkers that appear even before the presence of Aβ deposits. Designing a prevention trial of this nature, however, will need very large numbers of cognitively unimpaired persons studied over many years [10,11]. AD is a disease of slow progression with deterioration over many decades and not everyone with positive markers will develop Aβ deposits and not everyone with Aβ deposits will develop the disease.

Perhaps, we are looking at the wrong marker. Amyloid plaques are composed of extracellular amyloid beta (Aβ) and intracellular neurofibrillary tangles (NFTs) containing hyper‑phosphorylated tau (p‑tau). Tau may contribute to the pathogenic AD onset through Aβ‑dependent and Aβ‑independent mechanisms. AD is not the only degenerative disease caused by abnormal tau. Other tau-related neurodegenerative diseases, so-called taupathies, include fronto-temporal lobar degeneration (FTLD), Pick disease, progressive supranuclear palsy (PSP), and cortico-basal degeneration.

Although the role of p‑tau in AD pathology is thought to be secondary to Aβ accumulation in the brain, a growing body of evidence suggests that tau has unique roles in AD that are Aβ independent. Pathological changes in tau correlate more accurately with disease progression and cognitive changes [12]. Further, it is thought that Aβ could act as an initiator triggering tau pathology. The formation of Aβ in transgenic mice increases tau hyperphosphorylation.

Because targeting Aβ have not resulted in successful reversion or attenuation of AD symptoms, research seems to have shifted toward the role of tau in the pathogenesis of AD. A large number of anti-tau treatments ranging from blocking tau hyperphosphorylation (which causes the abnormal form of tau), inhibiting tau aggregation, blocking the inhibitors of tau degradation and tau immunisation are in progress. Most of these promising approaches are still in preclinical development whilst some have progressed to Phase I-III clinical trials.

Another direction in research is to select patients according to presence or absence of amyloid and tau on PET scan and see whether these correlate with future cognitive decline. The National Institute on Aging and Alzheimer’s Association working group proposed that patients be categorised based on the presence of amyloid and tau on a PET scan and atrophy as seen on an MRI scan. Patients can be categorised based on AT(N): A is for amyloid, t is for tau protein, and atrophy (neurodegeneration) would be (N), just like we categorise breast cancers according to receptor status.

In a recent study, 480 patients from the Mayo Clinic Study of Aging who did not have dementia were followed up for 4.9 years (13). The majority (92%) stayed cognitively unimpaired.  The 3 groups with the fastest rates of memory decline all had abnormal amyloid (A+T+[N]−, A+T−[N]+, and A+T+[N]+). This illustrated a dominant association of memory decline with amyloidosis but only when present in combination with tauopathy, neuro-degeneration, or both. However, biomarkers predicted not only which groups were likely to decline, but also which were not.

This study is very useful as it may help us select out a more homogeneous patient population to put into clinical trials. Perhaps, patients with a similar burden of disease may be more likely to show benefit from newer therapies.

References:

  1. Bonham LW, Geier EG, Fan CC, Leong JK, Besser L, Kukull WA,et al. Age-dependent effects of APOE epsilon4 in preclinical Alzheimer’s disease. Ann Clin Transl Neurol 2016;3:668–77.
  2. Jansen WJ, Ossenkoppele R, Knol DL, Tijms BM, Scheltens P, Verhey FR, et al. Prevalence of cerebral amyloid pathology in persons without dementia: A meta-analysis. JAMA 2015;313:1924–38.
  3. Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med 2016;8:595–608.
  4. Doody RS, Thomas RG, FarlowM, Iwatsubo T, Vellas B, Joffe S, et al. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med 2014;370:311–21.
  5. Holmes C, Boche D,Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, et al. Long-term effects of Abeta42 immunisation in Alzheimer’s disease: Follow-up of a randomised, placebo-controlled phase I trial. Lancet 2008;372:216–23.
  6. Salloway S, Sperling R, Gilman S, Fox NC, Blennow K, Raskind M, et al. A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology 2009; 73:2061–70.
  7. Sevigny J, Chiao P, Bussiere T, Weinreb PH, Williams L, Maier M, et al. The antibody aducanumab reduces Abeta plaques in Alzheimer’s disease. Nature 2016;537:50–6.
  8. Salloway S, Sperling R, Fox NC, Blennow K, Klunk W, Raskind M, et al. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N Engl J Med 2014;370:322–33.
  9. Egan MF, Kost J, Tariot PN, Aisen PS, Cummings JL, Vellas B, et al. Randomized Trial of Verubecestat for Mild-to-Moderate Alzheimer’s Disease. N Engl J Med 2018;378:1691–703.
  10. Reiman EM, Langbaum JB, Tariot PN. Alzheimer’s prevention initiative: A proposal to evaluate presymptomatic treatments as quickly as possible. Biomark Med 2010;4:3–14.
  11. Reiman EM, Langbaum JB, Fleisher AS, Caselli RJ, Chen K, Ayutyanont N, et al. Alzheimer’s Prevention Initiative:A plan to accelerate the evaluation of presymptomatic treatments. J Alzheimers Dis 2011;26:321–9.
  12. Agadjanyan MG, Zagorski K, Petrushina I, Davtyan H, Kazarian K, Antonenko M, et al. Humanized monoclonal antibody armanezumab specific to N‑terminus of pathological tau: Characterization and therapeutic potency. Mol Neurodegener 2017;12:33. doi: 10.1186/s13024‑017‑0172‑
  13. CR Jack, HJ Wiste, TM Therneau, et al. Associations of Amyloid, Tau, and Neurodegeneration Biomarker Profiles With Rates of Memory Decline Among Individuals Without Dementia. JAMA 2019 Jun 18;321(23)2316-2325

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