Resolving Controversies on thePath to Alzheimer Therapeutics          Dennis J. Selkoe   Center for Neurologic Diseases   ...
β-amyloid deposits in normal peopleMostly diffuse, i.e., lacking fibrillar amyloid, microgliosis, dystrophic neuritesSolub...
Amyloid as both a cause and an effect of ADSystemic amyloidoses can occur as primary or secondary disorders  (e.g., transt...
It’s not oligomers or plaques – it’s bothThe now widely confirmed bioactivity of soluble oligomers (including from AD cort...
Aβ receptors: an embarrassment of richesMost studies implicating a specific receptor have used synthetic Aβ (high nM to lo...
AD – the most common tauopathyTau expression appears necessary for Aβ oligomers to induce neuronal/neuritic changes and be...
Recent trial failures are not predicative of the future-- Alzhemed had very weak POC trails and questionable MOA-- R-flurb...
Basic	  research	  to	  iden.fy	                             Screen	  for	  agents	                                    Ass...
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Selkoe webinar slides

  1. 1. Resolving Controversies on thePath to Alzheimer Therapeutics Dennis J. Selkoe Center for Neurologic Diseases Brigham and Women’s Hospital Harvard Medical School
  2. 2. β-amyloid deposits in normal peopleMostly diffuse, i.e., lacking fibrillar amyloid, microgliosis, dystrophic neuritesSoluble oligomer levels not quantified in such brainsAbsence of subtle memory deficits before death not confirmed; indeed, PET+ Aβ deposits seen in “normal elderly” often associated with subtle cognitive changesAll chronic diseases (CAD, cancer, etc.) show substantial pathology prior to earliest symptoms
  3. 3. Amyloid as both a cause and an effect of ADSystemic amyloidoses can occur as primary or secondary disorders (e.g., transthyretin: mutant vs. wild-type)Similarly, Aβ accumulation is a primary cause in pts. with APP or PS mutations; in LOAD, it occurs secondary to other causes (e.g., ApoE4, BACE activity?)Aging (time on the planet) may be a key pathogenic factor: time gradually overcomes the energy barrier to the initial oligomerization of the physiologically secreted Aβ monomer in long-lived primates
  4. 4. It’s not oligomers or plaques – it’s bothThe now widely confirmed bioactivity of soluble oligomers (including from AD cortex) does not mean that plaques play no role in the progressive degeneration of neurons and their processesDiffusible, oligomeric assemblies of Aβ immediately surround the plaques and are intimately associated with local spine loss and neuritic dystrophyIndeed, bioactive dimers and larger oligomers have been shown to be “trapped” within AD plaque cores, suggesting that plaques serve as local reservoirs of small oligomers that can diffuse away from them
  5. 5. Aβ receptors: an embarrassment of richesMost studies implicating a specific receptor have used synthetic Aβ (high nM to low uM) without defining its precise assembly state at the time of receptor bindingExposed hydrophobic residues on an oligomer (ready to receive another monomer) predict that they would bind far more avidly to lipid membranes than the hydrophilic ectodomains of protein receptorsInitial binding of soluble oligomers in vivo probably involves lipids, but membrane proteins may promote, stabilize or otherwise modulate oligomer-lipid interactionsReceptor(s) for soluble Aβ monomers should be distinct from those for oligomers, given their quite different structures (Study Αβ40, not Aβ42!)
  6. 6. AD – the most common tauopathyTau expression appears necessary for Aβ oligomers to induce neuronal/neuritic changes and behavioral deficitsHistopathology is inextricably linked with biochemistry: the subunit proteins of the two classical lesions of AD play a decisive role in inducing dementia togetherTherapeutics that down-regulate pathological features of tau (hyper- phosphorylation, oligomerization, etc) should complement Aβ-lowering agents
  7. 7. Recent trial failures are not predicative of the future-- Alzhemed had very weak POC trails and questionable MOA-- R-flurbiprofen had a very poor IC50 and entered CNS poorly-- Semagacestat had a Th. Index <3 (and thus had to be dosed q.d., not b.i.d), so patients had Notch (and other substrate-based?) SAE’s Most importantly, patients must be treated in the mild stage of AD (e.g., MMSE of 21-27 -- plus high tau/low Aβ in CSF at entry), and many patients must be tested. Secondary prevention trials should be started soon, but they have substantial logistical, regulatory and ethical challenges and high costs
  8. 8. Basic  research  to  iden.fy   Screen  for  agents   Assess  ADME  and  safety     and  characterize  a   (compounds,  biologics)   to  iden.fy  agent  with  op.mal   poten.al  pathogenic   that  can  up-­‐  or  down-­‐ Therapeu.c  Index  in  rodents,   step  (target)   regulate  the  target   then  larger  mammals   AD  Drug   Discovery   Discover  how  to  up-­‐  and     Confirm  that  potent  agents  engage   Only  advance   down-­‐regulate  the    target     the  target  in  mice  and  lessen  AD-­‐like   compounds  that  meet   biochemically    in  AD  mice   phenotypes  (neuropath,   all  above  preclinical   biochemistry,  behavior,  biomarkers)   criteria  to  INDs   Secondary   MCI     Mild  AD   Clinical  Trials:   Preven(on   Trials   Trials   Trials   Hypothe(cal   Rising  Aβ42  oligomers,   diffuse  &  fibrillar  Aβ   Time  Course   deposi.on  associated   Worsening  Aβ  and  tau   with:  microgliosis,   biochemistry  &  pathology   of  AD:   altered  tau,  PHF   with  more  neuronal  loss.   accumula.on,  subtle   Altered  CSF  biomarkers   Worsening  biochemical   Slowly  rising   neuri.c  dystrophy,   (falling  Aβ42,     changes  (including  tau)   As  in  prior  stage,   brain  Aβ42  levels   astrocytosis,  altered  ionic   then  rising  tau).   and  neuronal/neuri.c   Worsening  neuronal/ plus   and  early  Aβ42   homeostasis,  oxida.ve   Subtle  cogni.ve  deficits   glial  pathology.     neuri.c/glial  changes.     Increasing   oligomeriza.on   injury,  many  2o   detected  only  with   Mild  cogni.ve   Progressive  cogni.ve   behavioral  &   with  membrane   biochemical  changes  (but   challenging  tests.   symptoms,  signs.   deficits.   motor  signs.   associa.on.   limited  neuronal  loss).   LATE  PRESYMPTOMATIC  AD     MCI   MILD  AD   MOD  AD  ~40  years  old   ~50   ~60   ~70   ~75   ~80   40  

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