Rationale for interventions ! Epidemiology ! NSAIDS, estrogen, DHA, B - PowerPoint PPT Presentation

Rationale for interventions ! Epidemiology ! NSAIDS, estrogen, DHA, B vitamins, statins, antihypertensives, curcumin, exercise, cognitive interventions, social interventions ! Basic laboratory studies: cell culture (neuroprotection, abeta generation), animal models (transgenics, others) CANDIDATE TREATMENTS ! Polyphenols, antioxidants, neurotrophins, anti-amyloid, anti- tangle FOR FAD PREVENTION ! Genetic leads TRIALS ! Anti-amyloid ! Anti-tau ! APOE, CR-1, clusterin … 1

Unfortunately … Choosing a preventive intervention ! There is no intervention that has demonstrated ! Safety: disease-modifying activity in AD ! Physical exercise, cognitive exercise, diet, DHA, B vitamins, antioxidants versus ! Efficacy (?): ! Anti-amyloid, anti-tangle, neuroprotective 2

Prevention in FAD v. sporadic AD What is AD Prevention? ! Anti-amyloid (?) ! Opportunity for very early intervention, ie, true prevention 3

AIBL: Amyloid deposition by PIB and by autopsy AD Diagnosis Marching Leftward precedes AD dementia by 15 years SECONDARY PREVENTION Modified Dubois Standard Presymptomatic Dubois criteria: research criteria: diagnosis = Preclinical AD “earlier AD” “early AD” Onset of AD path No symptoms, Episodic Very mild biomarker memory symptoms evidence impairment Dementia + amyloid of amyloid + any biomarker dysregulation biomarker CC Rowe et al, Neurobiol Aging, 2010 Aisen PS. Alzheimers Res Ther. 2009;1:2. doi:10.1186/alzrt2. 4

AD Prevention Trials ADNI Biomarker Study (Primary Prevention) ! Older individuals with no symptoms, no cognitive CSF A ! 42 Abnormal Amyloid imaging impairment, normal biomarkers (no amyloid) FDG-PET FDG-PET MRI hippocampal volume ! Outcome: prevention of amyloid? MRI hippocampal CSF Tau volume Cognitive performance ! Long trial duration Function (ADL) CSF A ! 42 Cognitive performance Amyloid ! Very safe treatment (safe and effective in later imaging Function (ADL) stage trials?) CSF Tau ! Special populations: FAD (mutation, no amyloid), APOE4 homozygotes or heterozygotes (no amyloid), Normal Time Dementia Presymptomatic eMCI L MCI Secondary Prevention Down syndrome (no amyloid) Aisen PS, Petersen RC, Donohue MC, et al. Alzheimers Dement. 2010;6:239-246. 5

“Primary” prevention trial experience A4 design (secondary prevention) (mixed primary/secondary) ! Ginkgo (GEM, Guidage) ! Anti-Amyloid trial in Asymptomatic AD ! Estrogen (Sano, WHIMS) ! Rationale ! Consensus on need to study anti-amyloid interventions ! NSAIDS (ADAPT: naproxen, celecoxib) as early as possible; compounds may fail in mild AD ! Antioxidants (PreAdvise, HPS) ! Studies in “early” AD are starting ! Statin (HPS statins) ! Companies cannot yet move into very early (asymptomatic AD) ! Perhaps we can move things along 6

Ventricular size Feasibility of proof-of-concept study ! d ! “A β specific” change p<0.001 ! Randomized study in A β + CN to detect 50% d ! 2 year study, 6 month visit intervals 7

Hippocampal volume MMSE p=0.007 p=0.004 8

A4 screening ! Screen cognitively normal people age >= 70 with amyloid PET (or LP) 9

!"#$%&'%()"*#% +*)#,%&'%()"*#% -.),%+*)#,%&'%()"*#% Early AD Trial Designs A4: outcomes !"#$%&'()*+,+-.) /%01)1(2($&,) /%01)3"#$%&'() !"#$%&'(06)$"52,0) %24,%52($+) !0%$%3,0)7(2($&,)8,&$#) :;<=>) :;<) :) #0"9,0).3"5() ! Primary: feasibility, confirmation of “amyloid-related” //*?)5,$#() >@=A@) A<=B:) AC=B:) D%"2,5E(5)F"5).-9G(3+) $"$() H260"%1)%2,#%$#),$1I"5) H260"%1)%2,#%$#),$1I"5) change .(0(3&"$) !*J),9(+,KA) !*J),9(+,KA) ! Co primary efficacy: change in MRI volume, cognitive D%"2,5E(5)F"5).-9G(3+) M"$()"5)HNO?)#($"+64() HNO?)#($"+64() HNO?)#($"+64() .+5,&L3,&"$) test (MMMSE?, FCSRT?, Log Mem II?) N5%2,56)3"#$%&'() H7H*3"#>>) H7H*3"#>A)P%$30-1(.) *($.%&'()2(2"56),$1I"5) ! Secondary: "-+3"2()2(,.-5() 1(0,6(1)5(3,00Q) (R(3;)F-$3&"$)2(,.-5() N5%2,56)#0"9,0IF-$3&"$,0) !78=*D) !78=*D) $"$() ! Impact of rx on CSF markers "-+3"2()2(,.-5() H$,06.%.)3"',5%,+(.) D,.(0%$()3"#$%&"$),$1) D,.(0%$()3"#$%&"$),$1) 8(#%"$,0)95,%$)'"0-2() ! Impact of rx on amyloid imaging 5(#%"$,0)95,%$)'"0-2() 5(#%"$,0)95,%$)'"0-2() ! FDG-PET? D%"2,5E(5)"-+3"2()) 8(#%"$,0)95,%$),+5"4S6) 8(#%"$,0)95,%$),+5"4S6) 8(#%"$,0)95,%$),+5"4S6) ,$1I"5),260"%1)2(,.-5() ! Other cognitive tests (computerized battery?) P,.).-55"#,+()($14"%$+Q) ! Patient-reported outcomes 7-5,&"$)"F)+5(,+2($+) >C)2"$+S.) AK)2"$+S.) AK=B@)2"$+S.) N5%2,56),$,06.%.) !S,$#().3"5()"5).0"4()"F) !S,$#().3"5()"5).0"4()"F) 8(#%"$,0)95,%$),+5"4S6) 3"=45%2,5%(.T)H7H*3"#>>U) 3"=45%2,5%(.T)H7H*3"#>AU) 5,+(),$1)3"#$%&'()1(30%$() !78=*D) !78=*D) 10

So where do we stand for Genetic causes of AD prevention of FAD? ! Lifestyle interventions: recommend, but insufficiently Down syndrome (trisomy 21) compelling for prevention trial ! Cardiovascular interventions: recommend, but inflammation insufficiently compelling for prevention trial β -secretase oxidative stress Neuron death APP A β ! DHA, antioxidants, B vitamins, Ginkgo: insufficiently γ -secretase excitotoxicity compelling for a prevention trial direct toxicity APP mutations PS1, PS2 mutations 11

Anti-tangle interventions for FAD Disease-Modifying Strategies prevention ! NAP , Rember, tau immunotherapy, paclitaxel … anti-inflammatories immunotherapy secretase antioxidants amyloid binders modulators neuroprotectants ! Insufficient supportive evidence (?) inflammation β -secretase oxidative stress Neuron death APP A β γ -secretase excitotoxicity direct toxicity 12

Neuroprotective interventions for Anti-amyloid interventions for FAD prevention of FAD ! NGF gene delivery: need more evidence ! Strongest rationale ! BDNF gene delivery: need more evidence ! Large number of candidate agents ! Dimebon: need another positive trial (at least) ! Unfortunately, none has yet shown efficacy in prevention or treatment of AD 13

Immunotherapy: active Immunotherapy: passive ! ACC-001 (JAI) ! Bapineuzumab (N-term) ! CAD-106 (Novartis) ! Solenezumab (mid sequence) ! Pf-04360365 (C-term) ! IVIG 14

Anti-aggregation therapy Gamma secretase inhibiton/modulation ! Scyllo-inositol ! BMS ! Steve Wagner/Torrey Pines ! Gamma-secretase activating protein (Greengard) 15

Opinion: best candidates for Beta secretase inhibition prevention trial in FAD ! Merck ! BMS gamma secretase inhibitor ! Lilly ! Merck (or Lilly or Pfizer) beta secretase inhibitor ! Pfizer ! JAI or Novartis active vaccination ! Bapineuzumab 16