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

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Feb 13, 2023 238 likes •403 views

Rationale for interventions ! Epidemiology ! NSAIDS, estrogen, DHA, B vitamins, statins, antihypertensives, curcumin, exercise, cognitive interventions, social interventions ! Basic laboratory studies: cell culture (neuroprotection, abeta

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CANDIDATE TREATMENTS FOR FAD PREVENTION TRIALS 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)

! Polyphenols, antioxidants, neurotrophins, anti-amyloid, anti-

tangle

! Genetic leads ! Anti-amyloid ! Anti-tau ! APOE, CR-1, clusterin …

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Unfortunately …

! There is no intervention that has demonstrated

disease-modifying activity in AD

Choosing a preventive intervention

! Safety: ! Physical exercise, cognitive exercise, diet, DHA, B

vitamins, antioxidants

versus

! Efficacy (?): ! Anti-amyloid, anti-tangle, neuroprotective

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Prevention in FAD v. sporadic AD

! Anti-amyloid (?) ! Opportunity for very early intervention, ie, true

prevention

What is AD Prevention?

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AIBL: Amyloid deposition by PIB and by autopsy precedes AD dementia by 15 years

CC Rowe et al, Neurobiol Aging, 2010

AD Diagnosis Marching Leftward

Standard diagnosis Dubois research criteria: “early AD” Modified Dubois criteria: “earlier AD” Presymptomatic = Preclinical AD

No symptoms, biomarker evidence

f amyloid

dysregulation Very mild symptoms + amyloid biomarker Episodic memory impairment + any biomarker Dementia

Onset

f AD

path

Aisen PS. Alzheimers Res Ther. 2009;1:2. doi:10.1186/alzrt2.

SECONDARY PREVENTION

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ADNI Biomarker Study

Abnormal Normal Time Presymptomatic eMCI

LMCI Dementia CSF A!42 Amyloid imaging FDG-PET MRI hippocampal volume CSF Tau Cognitive performance Function (ADL)

FDG-PET MRI hippocampal volume CSF A!42 Amyloid imaging Cognitive performance Function (ADL) CSF Tau

Aisen PS, Petersen RC, Donohue MC, et al. Alzheimers Dement. 2010;6:239-246.

Secondary Prevention

AD Prevention Trials (Primary Prevention)

! Older individuals with no symptoms, no cognitive

impairment, normal biomarkers (no amyloid)

! Outcome: prevention of amyloid? ! Long trial duration ! Very safe treatment (safe and effective in later

stage trials?)

! Special populations: FAD (mutation, no amyloid),

APOE4 homozygotes or heterozygotes (no amyloid), Down syndrome (no amyloid)

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“Primary” prevention trial experience (mixed primary/secondary)

! Ginkgo (GEM, Guidage) ! Estrogen (Sano, WHIMS) ! NSAIDS (ADAPT: naproxen, celecoxib) ! Antioxidants (PreAdvise, HPS) ! Statin (HPS statins)

A4 design (secondary prevention)

! Anti-Amyloid trial in Asymptomatic AD ! Rationale ! Consensus on need to study anti-amyloid interventions

as early as possible; compounds may fail in mild AD

! Studies in “early” AD are starting ! Companies cannot yet move into very early

(asymptomatic AD)

! Perhaps we can move things along

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Feasibility of proof-of-concept study

! d ! “Aβ specific” change ! Randomized study in Aβ+ CN to detect 50%d ! 2 year study, 6 month visit intervals

Ventricular size

p<0.001

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Hippocampal volume

p=0.004

MMSE

p=0.007

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A4 screening

! Screen cognitively normal people age >= 70 with

amyloid PET (or LP)

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A4: outcomes

! Primary: feasibility, confirmation of “amyloid-related”

change

! Co primary efficacy: change in MRI volume, cognitive

test (MMMSE?, FCSRT?, Log Mem II?)

! Secondary: ! Impact of rx on CSF markers ! Impact of rx on amyloid imaging ! FDG-PET? ! Other cognitive tests (computerized battery?) ! Patient-reported outcomes

Early AD Trial Designs

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So where do we stand for prevention of FAD?

! Lifestyle interventions: recommend, but insufficiently

compelling for prevention trial

! Cardiovascular interventions: recommend, but

insufficiently compelling for prevention trial

! DHA, antioxidants, B vitamins, Ginkgo: insufficiently

compelling for a prevention trial

Genetic causes of AD

APP Aβ Neuron death

β-secretase γ-secretase inflammation

xidative stress

excitotoxicity direct toxicity Down syndrome (trisomy 21) APP mutations PS1, PS2 mutations

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Disease-Modifying Strategies

APP Aβ Neuron death

β-secretase γ-secretase inflammation

xidative stress

excitotoxicity direct toxicity secretase modulators immunotherapy amyloid binders anti-inflammatories antioxidants neuroprotectants

Anti-tangle interventions for FAD prevention

! NAP

, Rember, tau immunotherapy, paclitaxel …

! Insufficient supportive evidence (?)

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Neuroprotective interventions for prevention of FAD

! NGF gene delivery: need more evidence ! BDNF gene delivery: need more evidence ! Dimebon: need another positive trial (at least)

Anti-amyloid interventions for FAD

! Strongest rationale ! Large number of candidate agents ! Unfortunately, none has yet shown efficacy in

prevention or treatment of AD

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Immunotherapy: active

! ACC-001 (JAI) ! CAD-106 (Novartis)

Immunotherapy: passive

! Bapineuzumab (N-term) ! Solenezumab (mid sequence) ! Pf-04360365 (C-term) ! IVIG

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Anti-aggregation therapy

! Scyllo-inositol

Gamma secretase inhibiton/modulation

! BMS ! Steve Wagner/Torrey Pines ! Gamma-secretase activating protein (Greengard)

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Beta secretase inhibition

! Merck ! Lilly ! Pfizer

Opinion: best candidates for prevention trial in FAD

! BMS gamma secretase inhibitor ! Merck (or Lilly or Pfizer) beta secretase inhibitor ! JAI or Novartis active vaccination ! Bapineuzumab