What’s New in Alzheimer’s Disease Clinical Trials?

01:09:58
https://www.youtube.com/watch?v=drBo5UnkKII

Sintesi

TLDRDurant la conferència, es va discutir extensament la investigació i els assaigs clínics relacionats amb la malaltia d'Alzheimer, amb un enfocament especial en els anticossos antiamiloide. La Dra. Judy Heidebrank va explicar les diferents fases dels assaigs clínics que van des de la seguretat inicial fins a la comprovació de l'eficàcia dels tractaments, especialment centrant-se en el recurs als anticossos monoclonals per intentar eliminar la placa amiloide del cervell i tractar així els simptomatologia de l'Alzheimer. Es va esmentar que, tot i que s'ha vist que aquests tractaments poden eliminar amiloides, encara existeixen interrogants sobre quins beneficis clínics resultants ofereixen. Aquests assaigs han demostrat que poden retardar la progressió dels símptomes per uns quants mesos, tot i que presenten desafiaments pel que fa als efectes secundaris. En la gran discussió posterior, es va abordar la necessitat de futurs estudis que podrien oferir aproximacions més personalitzades i eficients per combatre la malaltia, així com l'impacte d'intervencions en la qualitat de vida dels pacients. També es va reflexionar sobre la importància de combinar diversos mètodes, com l’exercici i la interacció social, com una forma de reduir el risc d'aparició d'Alzheimer.

Punti di forza

  • 👩‍⚕️ La Dra. Judy Heidebrank va explicar les fases dels assaigs clínics sobre Alzheimer.
  • 🧪 Es van discutir els anticossos antiamiloide com a tractament clau.
  • ⚠️ Els tractaments poden eliminar amiloides però tenen efectes secundaris.
  • ⏳ S'ha demostrat que poden retardar els símptomes durant mesos.
  • 🔬 Encara no es coneix completament el benefici clínic final.
  • 🧠 Hi ha diversos assaigs enfocat en prevenir símptomes en fases inicials.
  • 🔍 Necessitem més estudis per confirmar els beneficis a llarg termini.
  • 🏋️ L'exercici i la interacció social poden ajudar a reduir el risc d'Alzheimer.
  • 💊 La personalització del tractament és un focus d'interès en la recerca.
  • 📈 S'exploren maneres més realístiques d'administrar teràpies.

Linea temporale

  • 00:00:00 - 00:05:00

    La presentació s'inicia amb la introducció de la Dra. Judy Heidebrank, especialista en proves clíniques en malalties relacionades amb la demència, especialment l'Alzheimer. Ha participat en proves que van des de fases inicials fins a avançades centrades en la prevenció i tractament de la demència d'Alzheimer.

  • 00:05:00 - 00:10:00

    Es descriuen les diferents fases d'assaigs clínics per a medicaments, des de la fase 1 on es prova la seguretat en humans, fins a la fase 3 que avalua l'eficàcia sobre una mostra més gran i amb comparació placebo. Es destaca la importància de distingir entre les proves dirigides específicament a l'Alzheimer.

  • 00:10:00 - 00:15:00

    En aquest segment es revisen els assaigs clínics que utilitzen anticossos monoclonals per tractar la demència d'Alzheimer, centrant-se en l’eliminació de les plaques d’amiloide al cervell. Aquestes plaques són un segell distintiu de l’Alzheimer i els anticossos poden ajudar a eliminar-les.

  • 00:15:00 - 00:20:00

    Un dels medicaments, l’aducanumab, va ser aprovat pel seu efecte en l’eliminació de l’amiloide, però no tots els estudis han confirmat el benefici clínic significatiu, i hi ha sol·licituds per realitzar estudis addicionals per determinar el seu veritable impacte en la progressió de la malaltia.

  • 00:20:00 - 00:25:00

    Esmenta l’acceleració en l'aprovació del FDA per a educanumab, condicionada a una base biològica més que a beneficis clínics contundents, la qual cosa implica necessitar més estudis que determinin si l’eliminació de l’amiloide tradueix realment en beneficis clínics palpables.

  • 00:25:00 - 00:30:00

    Un nou medicament, la canemab, es vertebrarà en una nova fase d'aprovació després d'haver demostrat disminuir l'acumulació d'amiloide i presentar una reducció de la progressió de la demència en comparació al placebo, malgrat els efectes secundaris.

  • 00:30:00 - 00:35:00

    La discussió destaca que, tot i que s'han notat algunes millores en la reducció de la placa amb la canemab i d’altres compostos similars, els efectes adversos mostren riscos que han de ser monitoritzats rigorosament, sobretot en pacients amb certs factors genètics de risc.

  • 00:35:00 - 00:40:00

    Hi ha notícies de nous estudis que investiguen teràpies alternatives que permetin una administració més pràctica i eficient, com ara formulacions subcutànies per facilitar el tractament de pacients amb Alzheimer.

  • 00:40:00 - 00:45:00

    Es parla dels estudis en marxa que tracten de prevenir les símptomes d’Alzheimer en pacients asimptomàtics amb plaques d’amiloide mitjançant teràpies en fases avançades com a part d'una aproximació preventiva.

  • 00:45:00 - 00:50:00

    S'aclareix la correlació entre Tau i la pèrdua funcional cognitiva, i es parla de noves investigacions que apunten a plaques de Tau com a objectiu terapèutic, tot i que les proves inicials han mostrat eficàcia limitada fins al moment.

  • 00:50:00 - 00:55:00

    La investigació sobre la Tau també contempla estudis curiosos sobre animals en hibernació que poden oferir noves perspectives sobre com el cervell pot gestionar la patologia de la Tau.

  • 00:55:00 - 01:00:00

    Les proves clíniques també contemplen altres vies de tractament no centrades en la placa o Tau, incloent intervencions de tipus comportamental o relacionades amb el benestar general que podrien influir positivament en la progressió de la malaltia.

  • 01:00:00 - 01:09:58

    Finalment, es repassen els numerables estudis en marxa que busquen comprendre millor el mecanisme de l’Alzheimer, amb la finalitat d'identificar nous objectius terapèutics i millorar la qualitat de vida dels pacients.

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Mappa mentale

Mind Map

Domande frequenti

  • Qui va ser la ponent de l'esdeveniment?

    La Dra. Judy Heidebrank.

  • Quines fases inclouen els assaigs clínics de medicaments?

    Les fases dels assaigs clínics inclouen fases I, II i III, amb nombrosos individus i durades variades.

  • Quina recerca específica va ser destacada durant la conferència?

    S'expliquen les recerques relacionades amb els anticossos antiamiloide per a l'Alzheimer.

  • Quins efectes i resultats tenen les teràpies amb anticossos monoclonals per a Alzheimer?

    La teràpia amb monoclonal antibodi pot eliminar la placa amiloide al cervell, però té efectes secundaris avaluats segons el benefici potencial.

  • Quin és el benefici potencial d'eliminar l'amiloide en fases inicials de la malaltia?

    És probable que pugui ajudar a reduir o retardar l'aparició dels símptomes.

  • L'eliminació de la placa amiloide significa immediatament un èxit total en el tractament de l'Alzheimer?

    No, es necessita més temps per a avaluar els resultats clínics de benefici complet de la intervenció.

  • Les proves clíniques estudien la qualitat de vida dels pacients?

    Són mesurades en molts assaigs per entendre el seu impacte, encara que els resultats poden variar entre pacients.

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Sottotitoli
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Scorrimento automatico:
  • 00:00:11
    I think we're going to have quite a few
  • 00:00:13
    people here today so that's exciting
  • 00:01:17
    all right well I think we'll go ahead
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    and get started
  • 00:01:20
    um thank you all so much for coming to
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    our speaker series today and I am
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    honored to introduce our speaker Dr Judy
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    heidebrank is the director of the
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    neurology cognitive disorders clinic and
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    is the co-leader of the clinical core of
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    the Michigan Alzheimer's disease
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    Research Center
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    she has been involved in collaborative
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    clinical trials and dementia for over 20
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    years including phase one through three
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    studies focusing on the prevention and
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    treatment of Alzheimer's Dementia in
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    addition she has led the University of
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    Michigan's participation in the
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    Alzheimer's disease neuroimaging
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    initiative since the Inception of this
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    longitudinal observational study of
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    brain images and other biomarkers in the
  • 00:02:10
    progression from normal aging to
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    dementia I am very pleased to
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    um have Judy High to bring with us today
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    well good afternoon everyone and thank
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    you for joining me to hear this update
  • 00:02:24
    about clinical trials in Alzheimer's
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    disease you probably know from the news
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    that there have been lots of reports
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    regarding recent information from
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    clinical trials and Alzheimer's disease
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    so this topic could not have been more
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    timely even if it did mean updating my
  • 00:02:41
    slides literally on a weekly basis as
  • 00:02:43
    some of these news releases are coming
  • 00:02:45
    in so here's what I'd like to go over
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    today I'll just start with a little bit
  • 00:02:50
    of background information about clinical
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    trials and the focus of the ones that
  • 00:02:55
    I'm going to review today and then spend
  • 00:02:58
    a fair amount of time about the trials
  • 00:03:00
    looking at the anti-amyloid antibodies
  • 00:03:03
    because those have really been in the
  • 00:03:05
    news in particular lately and then I'll
  • 00:03:07
    just give some brief highlights about
  • 00:03:09
    some other clinical trials that aren't
  • 00:03:11
    necessarily targeting amyloid or using
  • 00:03:13
    the anti-amyloid antibodies
  • 00:03:16
    so just as a reminder what I'm going to
  • 00:03:19
    focus on today are clinical trials
  • 00:03:21
    looking at potential treatments for
  • 00:03:24
    Alzheimer's disease but Alzheimer's
  • 00:03:27
    disease is one of many potential causes
  • 00:03:30
    of dementia so dementia is a syndrome
  • 00:03:33
    where individuals experience changes in
  • 00:03:35
    their thinking abilities that impact
  • 00:03:37
    their daily activities Alzheimer's is
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    the most common cause of dementia
  • 00:03:41
    particularly later in life but it's not
  • 00:03:43
    the only cause of dementia so some of
  • 00:03:46
    the other causes of dementia are
  • 00:03:47
    pictured here and it's important to pay
  • 00:03:51
    attention whenever you're hearing
  • 00:03:52
    information about clinical trials to
  • 00:03:54
    know whether the trial was focused
  • 00:03:56
    specifically on persons with Alzheimer's
  • 00:03:58
    as a cause of their Dementia or kind of
  • 00:04:00
    impairment or whether it was a different
  • 00:04:02
    type of dementia because treatments
  • 00:04:04
    against the specific pathology of
  • 00:04:06
    Alzheimer's like the plaques and Tangles
  • 00:04:08
    wouldn't necessarily be expected to have
  • 00:04:10
    an impact on a different type of
  • 00:04:12
    dementia that doesn't have plaques and
  • 00:04:13
    Tangles for example some studies though
  • 00:04:16
    might look more Broad readily at ways to
  • 00:04:18
    protect the brain from loss of nerve
  • 00:04:20
    cells in the setting of any number of
  • 00:04:22
    dementia causes so some potential
  • 00:04:24
    therapies might be studied in more than
  • 00:04:26
    one type of dementia but again I'm going
  • 00:04:28
    to focus today on clinical trials
  • 00:04:30
    related to Alzheimer's disease
  • 00:04:33
    and so you heard Stephanie mention that
  • 00:04:35
    at the University of Michigan we've been
  • 00:04:37
    involved in trials in different phases
  • 00:04:40
    what are these clinical trial phases
  • 00:04:42
    that she mentioned so before any type of
  • 00:04:46
    medication is reviewed for approval by
  • 00:04:49
    the Food and Drug Administration it
  • 00:04:51
    typically goes through a series of
  • 00:04:53
    phases of clinical trials and they are
  • 00:04:57
    ordered numerically phase one phase two
  • 00:04:59
    and phase three and they basically
  • 00:05:02
    expand in terms of the numbers of
  • 00:05:04
    individuals participate how long they're
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    being given the treatment and what type
  • 00:05:09
    of measurements are being looked at so
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    the first time a drug is given to a
  • 00:05:14
    human after it's gone through some early
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    studies in animals for example the first
  • 00:05:19
    round humans is a phase one trial and
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    the real question is here is this
  • 00:05:24
    medication safe it's been looked at in
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    animals we think it might be promising
  • 00:05:28
    for a particular disease but if it's
  • 00:05:30
    never been given to humans before we
  • 00:05:31
    just have to start out by saying is this
  • 00:05:33
    safe and how much can someone take how
  • 00:05:36
    long does it last in their body does it
  • 00:05:39
    need to be given every day every week
  • 00:05:41
    multiple times a day so these are very
  • 00:05:43
    early studies looking at how the drug
  • 00:05:46
    gets into the body where it goes how
  • 00:05:47
    long it lasts and are there any side
  • 00:05:49
    effects of any type so sometimes in
  • 00:05:52
    these initial phase one trials healthy
  • 00:05:54
    individuals are picked just to be able
  • 00:05:56
    to study the metabolism of the drug it
  • 00:06:00
    might be older adults if ultimately the
  • 00:06:02
    study is going to be used to if the drug
  • 00:06:05
    is going to be used to treat a condition
  • 00:06:06
    that's more common in older adults but
  • 00:06:07
    sometimes to begin with it's younger
  • 00:06:09
    healthy adults just to be able to see
  • 00:06:11
    how someone tolerates it how long it
  • 00:06:14
    lasts and really is it safe and at what
  • 00:06:16
    dose and duration so these might be
  • 00:06:18
    small numbers of individuals they may
  • 00:06:21
    all get the active drug there might not
  • 00:06:23
    be a placebo for comparison and
  • 00:06:25
    depending on the type of drug these
  • 00:06:27
    studies might just last a few days for a
  • 00:06:29
    few weeks
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    and as long as the medication looks like
  • 00:06:33
    it's safe and there's at least some
  • 00:06:34
    doses that look like they might be
  • 00:06:37
    useful I have to carry forward then a
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    phase two trial starts to introduce a
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    larger number of individuals these are
  • 00:06:43
    typically persons who have the condition
  • 00:06:46
    for which the treatment is being studied
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    and you still want to know is it safe
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    but this time individuals are given a
  • 00:06:52
    more standard dose over a longer period
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    of time to see again how do they
  • 00:06:56
    tolerate over a longer period of time
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    and is there some initial evidence that
  • 00:06:59
    it might be helpful for the condition
  • 00:07:01
    for which it's being studied so this
  • 00:07:04
    might have a few hundred patients and
  • 00:07:06
    they might be taking the intervention
  • 00:07:08
    for several months
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    with really trying to learn does this
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    drug look like it's potentially
  • 00:07:13
    beneficial and then sort of the pivotal
  • 00:07:16
    trial is at the phase three stage where
  • 00:07:18
    even more individuals are given the
  • 00:07:21
    medication often again with a placebo
  • 00:07:23
    group at this point phase two and phase
  • 00:07:25
    three typically have a placebo group so
  • 00:07:27
    you can compare if we're seeing
  • 00:07:29
    something is it because of the drug or
  • 00:07:31
    is it just by random chance to learn
  • 00:07:33
    that you really need to compare the
  • 00:07:35
    active drug versus a placebo and again
  • 00:07:37
    this would be many individuals over a
  • 00:07:39
    longer period of time to really answer
  • 00:07:41
    the overall question is there a benefit
  • 00:07:44
    to this treatment in this condition that
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    outweighs any potential risk so these
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    might be longer term trials many months
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    or even a few years just depending on
  • 00:07:53
    what type of condition is being studied
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    so today I'm going to focus on a lot of
  • 00:07:58
    the phase three information because
  • 00:07:59
    again that's sort of the pivotal stage
  • 00:08:01
    that aside is this drug ultimately going
  • 00:08:04
    to be helpful and potentially be
  • 00:08:06
    approved by by the FDA
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    foreign
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    so as I mentioned earlier a lot of the
  • 00:08:12
    trial information in the Alzheimer's
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    disease realm has been with compounds
  • 00:08:17
    that are targeting the amyloid plaque
  • 00:08:20
    buildup that happens in the brain when
  • 00:08:22
    someone develops Alzheimer's disease and
  • 00:08:25
    so there are a handful of medications
  • 00:08:26
    that are called monoclonal antibodies
  • 00:08:30
    these are antibodies that can get into
  • 00:08:32
    the brain bind to the buildup of the
  • 00:08:34
    amyloid protein and help the brain's
  • 00:08:37
    immune system remove that amyloid
  • 00:08:39
    protein from the brain and so all of
  • 00:08:42
    these they have some unusual names but
  • 00:08:44
    they end in m a b which stands for
  • 00:08:47
    monoclonal antibody so any drug that
  • 00:08:49
    ends in mab is an antibody not all mab
  • 00:08:52
    medications are anti-amyloid antibodies
  • 00:08:55
    but this slide shows the family of
  • 00:08:59
    amyloid antibodies that have been used
  • 00:09:01
    recently in clinical trials and this
  • 00:09:04
    just shows how the amyloid protein in
  • 00:09:07
    the setting of Alzheimer's disease it's
  • 00:09:09
    starts to form first smaller and then
  • 00:09:12
    larger clumps that eventually turn into
  • 00:09:15
    these more dense plaques that build up
  • 00:09:17
    in the brain and depending on the
  • 00:09:19
    specific antibody some of these
  • 00:09:21
    antibodies are geared to bind to the
  • 00:09:23
    more initial clumping stages some are
  • 00:09:26
    geared to design to the more dense
  • 00:09:28
    plaque aggregations that occur in the
  • 00:09:30
    brain it's not clear yet whether it
  • 00:09:32
    matters what stage the the antibody
  • 00:09:34
    binds to but there may be some reasons
  • 00:09:36
    that that could be important but all of
  • 00:09:38
    these have been studied as potential
  • 00:09:40
    therapies for Alzheimer's disease in
  • 00:09:43
    people with symptoms
  • 00:09:45
    and as you may know one of them called
  • 00:09:49
    adducanumab was approved as a treatment
  • 00:09:52
    for Alzheimer's disease in the early
  • 00:09:54
    symptomatic stages was approved by the
  • 00:09:57
    FDA back in June of 2021 and as you can
  • 00:10:01
    see from this picture it's different
  • 00:10:03
    from all the medications we were
  • 00:10:04
    previously using that were pills this is
  • 00:10:07
    an intravenous medication because the
  • 00:10:10
    antibody doesn't come in a pilliform and
  • 00:10:12
    can't get into the brain in a pill form
  • 00:10:14
    so it's delivered intravenously gets
  • 00:10:16
    into the brain binds to the amyloid
  • 00:10:18
    plaque to help it remove it so what do
  • 00:10:21
    we know about educanuman the drug that
  • 00:10:23
    was approved back in 2021
  • 00:10:26
    well in its initial phase trials they
  • 00:10:29
    looked specifically to see does this
  • 00:10:32
    drug help do what we think it can do and
  • 00:10:35
    that is remove amyloid buildup from the
  • 00:10:37
    brain and so this slide shows the
  • 00:10:39
    results of one of the early phase Trials
  • 00:10:41
    of educanumab in this case all the
  • 00:10:44
    individuals had the condition of
  • 00:10:45
    interest because they were looking to
  • 00:10:47
    see can it remove amyloid so you had to
  • 00:10:49
    know that individuals had amyloid in the
  • 00:10:51
    brain so this study was done in about
  • 00:10:54
    165 individuals with either very early
  • 00:10:58
    symptoms at the mild cotton impairment
  • 00:11:00
    stage or mild dementia due to
  • 00:11:02
    Alzheimer's disease and all the
  • 00:11:04
    individuals underwent specialized brain
  • 00:11:07
    scans that showed they had buildup of
  • 00:11:09
    the amyloid fat protein so the left hand
  • 00:11:12
    column here these are just some of the
  • 00:11:15
    specific amyloid pet scans before the
  • 00:11:17
    start of the study they use a tracer
  • 00:11:20
    that gets into the brain and if there is
  • 00:11:21
    amyloid buildup there the Tracer will
  • 00:11:24
    bind and the visual signal of that is
  • 00:11:26
    this red bright red coloration that
  • 00:11:29
    indicates the Tracer is fine so all
  • 00:11:31
    these individuals had evidence of
  • 00:11:33
    amyloid buildup in the brain at the
  • 00:11:34
    start of the study and they were
  • 00:11:36
    randomly assigned to receive regular
  • 00:11:39
    infusions of educanumab essentially on a
  • 00:11:43
    monthly basis for a year and they could
  • 00:11:45
    receive either the placebo or one of
  • 00:11:48
    three different doses
  • 00:11:50
    and they look to see at the end of the
  • 00:11:52
    year what did the pet scans look like
  • 00:11:54
    and the individuals who received the
  • 00:11:56
    placebo essentially showed a similar
  • 00:11:58
    degree if not perhaps slightly higher
  • 00:12:00
    amount of amyloid buildup in the brain
  • 00:12:02
    whereas the individuals receiving the
  • 00:12:04
    active drug you could see a
  • 00:12:06
    dose-dependent removal of the amyloid so
  • 00:12:09
    the individuals receiving the highest
  • 00:12:10
    dose had what essentially looked like a
  • 00:12:13
    normal pet scan there really wasn't
  • 00:12:15
    detectable binding of the Tracer so it
  • 00:12:17
    was clear that this drug could do what
  • 00:12:19
    it was intended to do get into the brain
  • 00:12:22
    and help remove the amyloid however in
  • 00:12:26
    addition to seeing a dose-dependent
  • 00:12:28
    benefit or effect in terms of removing
  • 00:12:31
    the amyloid from the brain there were
  • 00:12:33
    dose-dependent side effects and those
  • 00:12:36
    were often picked up on standard MRI
  • 00:12:39
    scans where at higher doses in
  • 00:12:42
    particular some individuals developed
  • 00:12:45
    either small amounts of swelling as sort
  • 00:12:47
    of fluid was shifting into the brain or
  • 00:12:50
    tiny areas of bleeding what are called
  • 00:12:51
    micro hemorrhages and those were
  • 00:12:54
    detected more commonly among individuals
  • 00:12:56
    who received the higher dose of the drug
  • 00:12:58
    so the question has been is the benefit
  • 00:13:02
    of removing the plaque is it more
  • 00:13:05
    important than the potential side effect
  • 00:13:06
    of this bleeding or swelling a lot of
  • 00:13:09
    times that bleeding or swelling was
  • 00:13:11
    clinically silent the people who had
  • 00:13:13
    those radiologic changes didn't have any
  • 00:13:15
    symptoms but in some cases they did as a
  • 00:13:19
    group those radiologic changes are
  • 00:13:20
    called Aria stands for amyloid related
  • 00:13:23
    Imaging abnormality because again
  • 00:13:25
    they're often detected on Imaging scans
  • 00:13:28
    on brain scans even if the individual
  • 00:13:30
    isn't experiencing symptoms
  • 00:13:33
    um so the big question was is removing
  • 00:13:35
    the amyloid actually beneficial to the
  • 00:13:37
    individual or does it just make a pet
  • 00:13:39
    scan look better after a year of therapy
  • 00:13:42
    so as you can I'm actually skipped sort
  • 00:13:46
    of the phase two and went directly into
  • 00:13:48
    two large phase three studies
  • 00:13:50
    specifically designed to try to answer
  • 00:13:52
    the question what is the benefit of
  • 00:13:55
    receiving this drug removing the amyloid
  • 00:13:57
    from the brain and again what are the
  • 00:13:59
    potential risks in terms of the Aria or
  • 00:14:01
    any other types of side effects so two
  • 00:14:04
    large studies were designed to answer
  • 00:14:06
    that specific question
  • 00:14:07
    together they enrolled more than 3 000
  • 00:14:10
    individuals again these individuals all
  • 00:14:13
    had early symptoms of Alzheimer's either
  • 00:14:15
    in the mild dementia stage or in the
  • 00:14:18
    mild cognitive impairment stage and they
  • 00:14:20
    all had evidence of brain amyloid
  • 00:14:22
    buildup by undergoing studies such as
  • 00:14:24
    those amyloid pet scans and they were
  • 00:14:27
    randomly assigned to receive either
  • 00:14:29
    Placebo a low dose or a higher dose and
  • 00:14:32
    the intention was to follow everyone
  • 00:14:34
    over a year and a half to see if there
  • 00:14:38
    was a difference in terms of the
  • 00:14:40
    Dementia or mild counter impairment a
  • 00:14:42
    difference in their cognitive symptoms
  • 00:14:43
    over that time frame depending on
  • 00:14:46
    whether they got the active drug versus
  • 00:14:48
    the placebo
  • 00:14:50
    and the main thing that they looked at
  • 00:14:52
    to determine whether the drug was having
  • 00:14:55
    an effect was a rating of someone's
  • 00:14:58
    cognitive impairment and this rating is
  • 00:15:01
    something called the clinical dementia
  • 00:15:03
    rating scale it's not something that's
  • 00:15:05
    typically done in the setting of a
  • 00:15:07
    standard Clinic visit when someone's
  • 00:15:09
    being followed for Alzheimer's disease
  • 00:15:11
    dementia this is a more lengthy
  • 00:15:14
    interview both with the person
  • 00:15:16
    experiencing the symptoms and someone
  • 00:15:18
    who knows them well a close friend or
  • 00:15:20
    family member and the interview asks
  • 00:15:22
    questions about how are their how
  • 00:15:24
    they're doing in terms of tests that
  • 00:15:26
    involve memory do they seem to know in
  • 00:15:29
    general the day and date and where
  • 00:15:30
    they're at or not how do they do out and
  • 00:15:33
    about in the community are they able to
  • 00:15:35
    function independently go run errands
  • 00:15:36
    things like that or do they need regular
  • 00:15:39
    assistance and how do they do in the
  • 00:15:40
    home environment in terms of their
  • 00:15:42
    household activities or hobbies and what
  • 00:15:45
    about their personal care and so both
  • 00:15:47
    someone who knows the individual well
  • 00:15:49
    and the individual dual him or herself
  • 00:15:51
    are interviewed and tested as part of
  • 00:15:53
    that interview and in the end the Raider
  • 00:15:56
    makes a decision about whether they are
  • 00:15:59
    seeing impairments in one of six
  • 00:16:01
    different areas and how much of an
  • 00:16:03
    impairment they are seeing so if this
  • 00:16:04
    individual is felt to be functioning
  • 00:16:06
    perfectly normal Lee they would get a
  • 00:16:08
    rating of zero in each of their areas
  • 00:16:10
    their memory isn't changing they're well
  • 00:16:12
    oriented they know where they are they
  • 00:16:14
    know that the time of day their judgment
  • 00:16:17
    seems intact they can function
  • 00:16:19
    independently in the community at home
  • 00:16:21
    and in their personal care they get a
  • 00:16:23
    rating of 0.5 that suggests there's been
  • 00:16:25
    a mild change maybe they don't forget
  • 00:16:28
    things entirely but some of the details
  • 00:16:30
    whereas if they're rated a one recent
  • 00:16:33
    events are really slipping from their
  • 00:16:34
    memory they might not remember them at
  • 00:16:36
    all for example for orientation maybe
  • 00:16:38
    they're off on the day or date
  • 00:16:40
    frequently but if they're rated a one
  • 00:16:43
    they may not know the month or the year
  • 00:16:45
    but they may still not know where they
  • 00:16:47
    are if they are confused about their
  • 00:16:49
    location they might marry a higher level
  • 00:16:51
    of impairment so in the end each of
  • 00:16:53
    these areas is rated
  • 00:16:55
    and you can either create a global score
  • 00:16:58
    by in the sense averaging them or you
  • 00:17:00
    can just sum up their total score and
  • 00:17:02
    see how what's their total score a
  • 00:17:05
    higher score would be more impairment so
  • 00:17:08
    individuals who are maybe still function
  • 00:17:10
    independently but not quite at the level
  • 00:17:12
    they were before they may get a lot of
  • 00:17:14
    0.5s individuals who are starting to
  • 00:17:16
    need assistance may get a lot of ones
  • 00:17:18
    and then you just track these scores
  • 00:17:20
    over time to see how they do and compare
  • 00:17:23
    this in the treatment group in the
  • 00:17:25
    placebo group
  • 00:17:26
    well it gets a little more complicated
  • 00:17:28
    because in the end these large phase
  • 00:17:30
    three studies were halted before their
  • 00:17:34
    intended completion date because they
  • 00:17:36
    did an interim analysis that predicted
  • 00:17:38
    the drug would not show a benefit in the
  • 00:17:41
    two studies combined but when they
  • 00:17:43
    looked at the data after they had halted
  • 00:17:45
    it so not everyone had made it through
  • 00:17:47
    to the 18-month time point but they
  • 00:17:49
    looked at the data that they'd
  • 00:17:51
    accumulated and lo and behold the two
  • 00:17:53
    studies ended up giving somewhat
  • 00:17:55
    different results so in the emerge study
  • 00:17:58
    if you tracked that score on the
  • 00:18:00
    clinical dementia rating scale and in
  • 00:18:03
    this graph a higher score is higher up
  • 00:18:06
    on the y-axis so as this as these uh
  • 00:18:10
    as these lines are increasing that means
  • 00:18:13
    a higher CDR score which means more
  • 00:18:16
    impairment so in the emerge study a
  • 00:18:19
    higher dose group didn't have as much of
  • 00:18:22
    an increase in their CDR score as the
  • 00:18:25
    placebo so there was a difference of
  • 00:18:27
    about 0.39 which is about the difference
  • 00:18:31
    between one box here and here so not
  • 00:18:35
    quite a full half point but it means
  • 00:18:36
    that an individual might have stayed in
  • 00:18:39
    this box instead of Shifting to this box
  • 00:18:41
    over the course of the study if they
  • 00:18:42
    receive treatment but all other boxes
  • 00:18:45
    change the same way
  • 00:18:47
    another way of looking at it is that the
  • 00:18:50
    high-dose treatment group was
  • 00:18:52
    functioning at a level that the placebo
  • 00:18:55
    group was functioning at maybe four to
  • 00:18:58
    five months earlier so it's as though
  • 00:18:59
    it's slowed that decline by four to five
  • 00:19:01
    months over the 18 months of the study
  • 00:19:04
    so it's suggested a benefit in slowing
  • 00:19:06
    down the progression of the symptoms in
  • 00:19:09
    one study but in the other study study
  • 00:19:11
    there wasn't a detectable difference so
  • 00:19:13
    the cdrs the scores people were
  • 00:19:16
    progressing gradually declining whether
  • 00:19:18
    they got the high dose or the placebo
  • 00:19:19
    and so the question was what what does
  • 00:19:22
    this mean it does the drug maybe work
  • 00:19:24
    sometimes work there are a lot of
  • 00:19:26
    technical reasons why these different
  • 00:19:28
    results may have occurred but ultimately
  • 00:19:30
    we don't know well you might say gosh
  • 00:19:32
    even if we don't know if it's clearly
  • 00:19:34
    helpful even if there's a chance it
  • 00:19:36
    slows things down is it it might be
  • 00:19:38
    worth it for a disease that we know
  • 00:19:39
    progresses without therapy but we have
  • 00:19:42
    to balance that with the side effects
  • 00:19:43
    and as I mentioned before with the
  • 00:19:46
    monoclonal antibodies we know when they
  • 00:19:47
    get into the brain and bind there can be
  • 00:19:50
    some Associated swelling of the brain
  • 00:19:52
    tissue or bleeding and in this case with
  • 00:19:54
    educanumab on the high dose
  • 00:19:58
    40 percent of individuals had at least
  • 00:20:00
    radiologic evidence of either the
  • 00:20:03
    swelling the edema or the Hemorrhage or
  • 00:20:06
    some combination thereof most of the
  • 00:20:09
    time it didn't cause symptoms but about
  • 00:20:11
    a quarter of those who had detectable
  • 00:20:13
    changes on the scans did experience
  • 00:20:15
    symptoms that kind of correlated with
  • 00:20:17
    either where that swelling was so if the
  • 00:20:19
    swine was in the back of the brain they
  • 00:20:21
    might experience some visual changes
  • 00:20:23
    because that's where our brain processes
  • 00:20:24
    visual information or just from the
  • 00:20:26
    swelling no matter where it occurred
  • 00:20:28
    they might develop a headache or nausea
  • 00:20:30
    or things like that so
  • 00:20:32
    um in in these individuals often the
  • 00:20:34
    dose had to be stopped and they had to
  • 00:20:36
    be monitored to see if those symptoms
  • 00:20:37
    recovered
  • 00:20:39
    so what do you do with information that
  • 00:20:41
    says the drug may or may not have a
  • 00:20:43
    benefit but it does have some known side
  • 00:20:45
    effects well what the FDA did was they
  • 00:20:49
    granted approval but through a mechanism
  • 00:20:51
    that's a little different than the
  • 00:20:53
    traditional approval they granted what's
  • 00:20:55
    called accelerated approval which is a
  • 00:20:58
    conditional type of approval that's
  • 00:21:00
    based on a Drug's biological effect and
  • 00:21:03
    I think it's very clear this drug has a
  • 00:21:05
    biological effect it can remove the
  • 00:21:07
    amyloid buildup from the brain
  • 00:21:09
    but with an accelerated approval that
  • 00:21:12
    biological effect is hoped to be
  • 00:21:15
    translated into a clinical effect but
  • 00:21:17
    that doesn't have to be established yet
  • 00:21:19
    so when accelerator approval is granted
  • 00:21:21
    there is typically a requirement to have
  • 00:21:23
    an additional study to confirm does that
  • 00:21:26
    biological effect really translate into
  • 00:21:28
    a clinical benefit or not and so there
  • 00:21:31
    is an additional trial underway to try
  • 00:21:33
    to see ultimately does this drug have a
  • 00:21:36
    clinical benefit but given that it's
  • 00:21:39
    only a conditional approval Medicare
  • 00:21:41
    last year decided that it would not
  • 00:21:44
    cover it except in the context of a
  • 00:21:46
    clinical trial to really help understand
  • 00:21:48
    does this drug have benefits that
  • 00:21:50
    outweigh the risk which means for all
  • 00:21:52
    practical purposes we aren't prescribing
  • 00:21:55
    this medication because it's not covered
  • 00:21:57
    by insurers so it's really only
  • 00:21:59
    continuing on in clinical trials and in
  • 00:22:02
    fact many institutions individually
  • 00:22:04
    reviewed the risk and benefit
  • 00:22:06
    information and decided there wasn't
  • 00:22:07
    enough benefit to outweigh that risk to
  • 00:22:10
    offer it and so again its use is really
  • 00:22:13
    restricted at this point to to clinical
  • 00:22:15
    trials but again it is approved by the
  • 00:22:18
    FDA for individuals at an early
  • 00:22:20
    symptomatic stage of Alzheimer's either
  • 00:22:22
    mild cutter impairment or mild dementia
  • 00:22:24
    but it needs to be given very carefully
  • 00:22:27
    for example individuals need to be able
  • 00:22:29
    to be followed with the MRI scans to
  • 00:22:32
    look for some of these radiologic
  • 00:22:34
    findings to be able to adjust the dose
  • 00:22:36
    or halt the dose if that's appropriate
  • 00:22:38
    to do so
  • 00:22:39
    so that's kind of where we stood last
  • 00:22:41
    year but what's been the more recent
  • 00:22:44
    development well now if you've been
  • 00:22:45
    hearing the news you've heard about a
  • 00:22:47
    drug called luck in a lab rather than
  • 00:22:49
    adjectana map and somebody might say
  • 00:22:51
    well la Cana map is it just the French
  • 00:22:53
    version of edge Academy no it's it's a
  • 00:22:55
    different drug but it's the same idea
  • 00:22:57
    it's another monoclonal antibody and
  • 00:23:00
    just as with that you canimab it did an
  • 00:23:03
    early study to look to see what is the
  • 00:23:06
    effect of this drug on the amyloid
  • 00:23:08
    buildup in the brain and so in this
  • 00:23:10
    study individuals had amyloid cut scans
  • 00:23:13
    were assigned to different doses of the
  • 00:23:15
    drug and lo and behold they also showed
  • 00:23:18
    a dose-dependent removal of the amyloid
  • 00:23:21
    plaque so they didn't publish nice
  • 00:23:22
    pictures the way they educator map study
  • 00:23:24
    did but they published their graph
  • 00:23:26
    showing the drop in the amyloid buildup
  • 00:23:28
    that was most impressive with the
  • 00:23:31
    highest most frequent dose and less
  • 00:23:33
    impressive with lower or less frequent
  • 00:23:36
    dosing and So based on this biological
  • 00:23:40
    effect the FDA just just granted Latina
  • 00:23:44
    map that same accelerated or conditional
  • 00:23:47
    approval that educantum have received
  • 00:23:49
    previously so this again has been
  • 00:23:52
    approved by the FDA because it has a
  • 00:23:55
    biological effect in a disease that
  • 00:23:56
    doesn't have good therapies at this time
  • 00:23:59
    so the hope is further studies would be
  • 00:24:01
    able to be done to show that not only
  • 00:24:03
    does it reduce the amyloid but it has a
  • 00:24:05
    clinical benefit well in fact one of
  • 00:24:07
    those studies has already been done just
  • 00:24:10
    not reviewed yet by the FDA but the
  • 00:24:13
    results of it were just announced in the
  • 00:24:15
    last few months this was a phase three
  • 00:24:18
    trial called Clarity and as the name
  • 00:24:21
    implies it was designed to give Clarity
  • 00:24:23
    does this drug have a clinical benefit
  • 00:24:26
    not just a benefit in terms of changing
  • 00:24:29
    a pet scan and so this phase three Taro
  • 00:24:32
    nearly 1800 individuals all again in an
  • 00:24:36
    early symptomatic stage of Alzheimer's
  • 00:24:38
    disease they were followed over time and
  • 00:24:41
    compared with that same clinical
  • 00:24:43
    dementia rating scale outcome measure
  • 00:24:45
    now for their publication they flipped
  • 00:24:47
    it so that as the CDR score is
  • 00:24:51
    increasing you actually fall further
  • 00:24:53
    down on this graph and so falling down
  • 00:24:56
    means that the dementia is worsening or
  • 00:24:59
    the cognitive impairment is worsening
  • 00:25:00
    but you see a difference between the
  • 00:25:03
    group who received the placebo their
  • 00:25:06
    decline was greater at the end of 18
  • 00:25:08
    months compared to the group receiving
  • 00:25:10
    the lakina map and that absolute
  • 00:25:13
    difference on that CDR scale was about
  • 00:25:16
    0.45 so again sort of one box different
  • 00:25:20
    on the left hand side of the scale but
  • 00:25:23
    that did represent a 27 percent slowing
  • 00:25:26
    of that rate of decline one thing that
  • 00:25:29
    looks even more promising is that these
  • 00:25:33
    curves or these lines seem to be
  • 00:25:35
    separating more as time goes on so it's
  • 00:25:39
    possible if the trial had continued more
  • 00:25:41
    than 18 months you might see an even
  • 00:25:44
    greater separation between the treatment
  • 00:25:45
    group and the placebo group we don't
  • 00:25:47
    know that because the trial did end at
  • 00:25:49
    18 months but at this point we can say
  • 00:25:52
    if an individual had been coming in and
  • 00:25:54
    getting infusions of lacanumab in this
  • 00:25:56
    case they are infusions every two weeks
  • 00:25:58
    rather than the monthly infusions with
  • 00:26:00
    Edge Academy but at the end of those 18
  • 00:26:03
    months of infusions they would be
  • 00:26:05
    functioning roughly where the placebo
  • 00:26:07
    group was functioning at about 12 months
  • 00:26:11
    so it appears to sort of again slow that
  • 00:26:13
    decline by about six months over the one
  • 00:26:17
    and a half years or 18 months of the
  • 00:26:19
    trial so you could look at it saying if
  • 00:26:21
    someone was doing something
  • 00:26:22
    independently if they received a
  • 00:26:24
    treatment they may be able to keep doing
  • 00:26:26
    that for six months longer than someone
  • 00:26:28
    who only received the placebo
  • 00:26:30
    what's the downside again was there any
  • 00:26:33
    evidence of Arya yes
  • 00:26:35
    um swelling and small bleeding did occur
  • 00:26:37
    the rate was lower than in the
  • 00:26:40
    educanumab trial so it was about 22
  • 00:26:42
    percent and in in most cases again it
  • 00:26:45
    was clinically silent it didn't change
  • 00:26:47
    people's day-to-day function or cause
  • 00:26:49
    any symptoms but at a small percent
  • 00:26:51
    um there were symptoms and this data
  • 00:26:54
    will all be reviewed by the FDA to
  • 00:26:56
    determine whether to Grant the drug full
  • 00:26:58
    approval or not and we'll have to wait
  • 00:27:00
    and see do insurers like Medicare will
  • 00:27:04
    they continue to approve it only in the
  • 00:27:08
    context of clinical trials or will they
  • 00:27:10
    say yes we'll approve it for regular use
  • 00:27:12
    if the FDA grants a full approval or if
  • 00:27:15
    um if they review this information as
  • 00:27:17
    well
  • 00:27:19
    um they did look at other outcome
  • 00:27:20
    measures too besides that clinical
  • 00:27:22
    dementia rating scale if you looked at
  • 00:27:24
    the pet scans again a dramatic dropping
  • 00:27:26
    of the amyloid on the treatment group
  • 00:27:28
    compared to the placebo if you looked at
  • 00:27:30
    other clinical measures these are either
  • 00:27:31
    tests of thinking or measurements of
  • 00:27:34
    day-to-day activities all of them showed
  • 00:27:36
    less decline in the treatment group
  • 00:27:38
    compared to the placebo so really
  • 00:27:41
    consistent evidence that there is a
  • 00:27:43
    difference between like anime and
  • 00:27:44
    Placebo unfortunately it's not a major
  • 00:27:47
    difference it's more modest but it does
  • 00:27:49
    appear to slow that progression again we
  • 00:27:52
    need to balance that out against the
  • 00:27:54
    potential side effects which were not
  • 00:27:56
    equally experienced among all members of
  • 00:27:59
    the trials it turns out that those
  • 00:28:02
    individuals who carry a specific genetic
  • 00:28:04
    risk factor or Alzheimer's disease
  • 00:28:07
    called the APO lipoprotein E4 genotype
  • 00:28:11
    those individuals particularly if they
  • 00:28:13
    have two copies if both of their apoe
  • 00:28:15
    genes are the type 4 they had a much
  • 00:28:18
    greater likelihood of experience the
  • 00:28:20
    Aria types of side effects so if they
  • 00:28:23
    divided the likelihood of detecting
  • 00:28:25
    swelling on an MRI scan if you didn't
  • 00:28:27
    have any copies of the apoe4 it was only
  • 00:28:30
    five percent compared to if you had two
  • 00:28:32
    copies it was up at 30 percent and ten
  • 00:28:36
    percent of the time that almost 10
  • 00:28:37
    percent of the time that led to symptoms
  • 00:28:39
    so this has really led to the thought
  • 00:28:42
    that if we do offer this medication we
  • 00:28:45
    will really want to know who genetically
  • 00:28:47
    is going to be at a higher risk of some
  • 00:28:50
    of these side effects because that may
  • 00:28:51
    change ultimately the decision about
  • 00:28:53
    whether to pursue this type of treatment
  • 00:28:57
    but in the end we say gosh is this going
  • 00:28:59
    to be a practical way of treating most
  • 00:29:02
    individuals with early Alzheimer's
  • 00:29:04
    symptoms coming in every two weeks for
  • 00:29:05
    infusions that's a that's a lot of time
  • 00:29:10
    and Logistics are there other ways of
  • 00:29:13
    making these types of therapies more
  • 00:29:15
    realistic to be used on the numbers of
  • 00:29:17
    individuals experiencing this condition
  • 00:29:19
    well one of the other antibodies
  • 00:29:21
    antenerimab was studied in a
  • 00:29:24
    subcutaneous form so just small needle
  • 00:29:27
    injections under the skin that could be
  • 00:29:28
    given at home and potentially even be
  • 00:29:30
    you know administered by someone in the
  • 00:29:32
    home rather than needing to come into
  • 00:29:33
    infusion center so there was promising
  • 00:29:36
    hope for this as a more straightforward
  • 00:29:38
    or a logistically more feasible way of
  • 00:29:41
    treating individuals but unfortunately
  • 00:29:42
    in its large phase three studies they
  • 00:29:45
    didn't show any significant slowing of
  • 00:29:47
    Decline and it turns out that the
  • 00:29:49
    amyloid removal when they measured it
  • 00:29:51
    was lower than the expected suggesting
  • 00:29:54
    this drug just may not have been
  • 00:29:55
    powerful enough to either see the a
  • 00:29:57
    benefit in amyloid removal or a clinical
  • 00:29:59
    benefit so it really hasn't been seen as
  • 00:30:03
    an option
  • 00:30:04
    there's another drug that the FDA
  • 00:30:08
    reviewed just last week it's another
  • 00:30:11
    monoclonal antibody called dinanumab and
  • 00:30:14
    it looks like it can remove plaque very
  • 00:30:17
    quickly they actually interestingly did
  • 00:30:20
    just a pet only study looking at pet
  • 00:30:23
    scans before and after six months of
  • 00:30:25
    treatment with their drug donatumab and
  • 00:30:28
    that previous drug that I mentioned
  • 00:30:29
    educanumab and we're able to show that
  • 00:30:31
    in six months there was much more plaque
  • 00:30:34
    removal with danina map compared to
  • 00:30:35
    educanuman well why is this important
  • 00:30:38
    well one thought was maybe you don't
  • 00:30:39
    have to treat someone with this drug as
  • 00:30:42
    long as you might have to with some of
  • 00:30:44
    the others maybe you can remove that
  • 00:30:45
    plaque rapidly and don't have to keep
  • 00:30:47
    dosing once that plaque is gone so it
  • 00:30:50
    may not be 18 months of therapy maybe
  • 00:30:51
    it's only 6 or 12 months of therapy and
  • 00:30:54
    then you can stop dosing when the plaque
  • 00:30:56
    is gone we don't know yet whether that
  • 00:30:58
    will truly have a clinical benefit
  • 00:31:00
    because those trials are ongoing but
  • 00:31:02
    this was submitted for the FDA to review
  • 00:31:04
    you to see if they would Granite
  • 00:31:06
    accelerator approval again accelerate
  • 00:31:08
    approval saying does this drug have a
  • 00:31:10
    promising biological effect in terms of
  • 00:31:12
    amyloid removal and interestingly the
  • 00:31:15
    FDA decided not to Grant approval not
  • 00:31:17
    because they weren't convinced I think
  • 00:31:19
    by this type of data or other data were
  • 00:31:21
    submitted but they said gosh there
  • 00:31:23
    haven't been enough people on the drug
  • 00:31:24
    for long enough periods of time very few
  • 00:31:27
    people have been on this drug for a year
  • 00:31:28
    for example and in some cases you might
  • 00:31:31
    need to give it for a year to fully
  • 00:31:32
    remove that AMOLED plaque but in some
  • 00:31:34
    ways because the plaque has been removed
  • 00:31:36
    so quickly they didn't have enough
  • 00:31:38
    people on the drug for a year for the
  • 00:31:40
    FDA to say we've seen enough safety data
  • 00:31:43
    about it to feel comfortable approving
  • 00:31:45
    it so the FDA declined to granted
  • 00:31:47
    accelerated approval but these phase
  • 00:31:50
    three trials looking at not just plaque
  • 00:31:52
    removal but clinical benefit as well are
  • 00:31:55
    expected to release their results later
  • 00:31:57
    on this year and so the FDA will then
  • 00:31:59
    likely review it to determine if it
  • 00:32:01
    should receive traditional approval so
  • 00:32:03
    we might have yet enough other potential
  • 00:32:05
    therapy in terms of a monoclonal
  • 00:32:07
    antibody again some benefits slowing the
  • 00:32:10
    disease we hope but some risk as well so
  • 00:32:12
    these need to be balanced very carefully
  • 00:32:15
    so in the end you say well gosh if we
  • 00:32:18
    can get rid of amyloid from the brain
  • 00:32:19
    and we know that's one of the Hallmarks
  • 00:32:21
    of Alzheimer's why aren't we getting a
  • 00:32:23
    more dramatic effect why aren't we
  • 00:32:24
    really halting the disease or reversing
  • 00:32:26
    the disease and the answer is we don't
  • 00:32:28
    know but one possible reason is by the
  • 00:32:31
    time we're giving these drugs to people
  • 00:32:33
    with symptoms of either mild Dementia or
  • 00:32:36
    mild kind of impairment the amyloid
  • 00:32:39
    plaque has really been building up for
  • 00:32:41
    many years in a silent phase so that
  • 00:32:44
    amyloid pathology begins before the
  • 00:32:46
    symptoms are ever apparent so by the
  • 00:32:48
    time we're treating individuals who have
  • 00:32:50
    symptoms we're trying to address a
  • 00:32:52
    problem that's been changing in the
  • 00:32:54
    brain for several years so maybe it just
  • 00:32:56
    isn't isn't going to be enough once
  • 00:32:58
    people have developed the symptoms of
  • 00:33:00
    Alzheimer's disease but potentially
  • 00:33:03
    maybe there would be a greater benefit
  • 00:33:05
    maybe you could forestall symptoms not
  • 00:33:07
    just for six months but maybe for years
  • 00:33:09
    or more if you delivered these
  • 00:33:12
    treatments as people were starting to
  • 00:33:14
    develop the plaque rather than many
  • 00:33:15
    years years later so that in fact is the
  • 00:33:18
    question that's been posed to a lot of
  • 00:33:20
    prevention trials using the same
  • 00:33:22
    monoclonal antibody agents so many of
  • 00:33:26
    the ones that I just mentioned have
  • 00:33:27
    either been studied in trials in
  • 00:33:30
    individuals at risk for Alzheimer's one
  • 00:33:33
    of them unfortunately didn't show a
  • 00:33:34
    benefit but the dosing was felt to
  • 00:33:36
    probably too low at the time
  • 00:33:39
    when the get to narimab data that I
  • 00:33:41
    presented earlier when it didn't show a
  • 00:33:44
    clinical benefit the company decided to
  • 00:33:46
    sort of stop development so there isn't
  • 00:33:47
    going to be a prevention trial with it
  • 00:33:49
    but both like canimab and denatumab have
  • 00:33:53
    trials in individuals at risk for
  • 00:33:55
    Alzheimer's to see if giving infusions
  • 00:33:58
    early on can prevent the risk of those
  • 00:34:01
    symptoms emerging and there's a trial
  • 00:34:04
    that has been going on for several years
  • 00:34:05
    using another monoclonal antibody called
  • 00:34:08
    solanasumab and we expect to hear the
  • 00:34:11
    results of that trial later on this year
  • 00:34:13
    so so stay tuned and I will just mention
  • 00:34:16
    that we are currently participating in
  • 00:34:19
    this so we hope to hear the results
  • 00:34:20
    release those results in the next
  • 00:34:23
    several months and we're currently at
  • 00:34:25
    the University of Michigan recruiting
  • 00:34:26
    individuals to participate in the
  • 00:34:28
    lakinumab prevention trial it's called
  • 00:34:31
    the ahead study and it's looking for
  • 00:34:33
    individuals who may be at risk for
  • 00:34:35
    developing Alzheimer's symptoms later in
  • 00:34:37
    life partly just because there are aging
  • 00:34:40
    we know that's a number one risk but
  • 00:34:42
    also maybe if you're younger but have a
  • 00:34:44
    strong family history or you know you
  • 00:34:46
    carry one of those genetic risk factors
  • 00:34:48
    like the April lipoprotein E4 Gene that
  • 00:34:51
    would enable you to be screened for this
  • 00:34:53
    study ultimately individuals in this
  • 00:34:56
    trial will undergo those amyloid pet
  • 00:34:59
    scans to see if they have amyloids
  • 00:35:01
    silently building up and depending on
  • 00:35:04
    the level of that buildup they'll
  • 00:35:06
    receive the active drug or Placebo
  • 00:35:08
    either on a essentially a monthly basis
  • 00:35:11
    or every two weeks so pitching the more
  • 00:35:13
    frequent infusions to individuals who
  • 00:35:15
    have a higher level of amyloid buildup
  • 00:35:17
    and the less frequent infusions to those
  • 00:35:19
    who have a more intermediate level of
  • 00:35:20
    buildup
  • 00:35:22
    um but this trial is also unique but
  • 00:35:24
    besides just being a prevention trial
  • 00:35:25
    it's actually doing a pre-screening
  • 00:35:27
    stage before people get to the amyloid
  • 00:35:30
    pet scan stage by looking at blood
  • 00:35:33
    levels of amyloid because it turns out
  • 00:35:35
    you can measure very very tiny
  • 00:35:37
    quantities of amyloid in the blood that
  • 00:35:40
    can give you a reasonable indication
  • 00:35:41
    about whether amyloid may be building up
  • 00:35:44
    in the brain now these tests aren't
  • 00:35:45
    perfect yet and so they're just being
  • 00:35:47
    used as an initial screen to say is
  • 00:35:50
    there some chance we might find amyloid
  • 00:35:52
    in the brain based on this Blood result
  • 00:35:54
    and if so those individuals can move
  • 00:35:56
    forward to have the Pet Scan and we know
  • 00:35:58
    in many cases the Pet Scan may not show
  • 00:36:00
    any buildup so the blood biomarkers
  • 00:36:02
    aren't being used as a substitute but
  • 00:36:04
    just as a way to take an initial look
  • 00:36:06
    and see can we refine who needs to have
  • 00:36:09
    the Pet Scan based on a blood prediction
  • 00:36:12
    about amyloid buildup and so individuals
  • 00:36:15
    in the study will have regular pet scans
  • 00:36:17
    regular MRI scans for safety reasons and
  • 00:36:20
    tracking to see how their cognition does
  • 00:36:23
    over time they're all starting with
  • 00:36:25
    normal thinking abilities and we want to
  • 00:36:26
    know does treatment change the course
  • 00:36:29
    over the next several years in terms of
  • 00:36:30
    whether they develop cognitive symptoms
  • 00:36:32
    or other types of changes
  • 00:36:36
    so let me spend a little time now
  • 00:36:37
    Switching gears away from amyloid again
  • 00:36:40
    that's where all the big news has been
  • 00:36:42
    lately but just at least mention some of
  • 00:36:44
    the other types of studies that are out
  • 00:36:46
    there in Alzheimer's disease clinical
  • 00:36:48
    trials some of them have focused on the
  • 00:36:51
    other main pathology and Alzheimer's
  • 00:36:53
    disease the Tau protein that builds up
  • 00:36:56
    in the form of the tangles inside the
  • 00:36:59
    nerve cell compared to the plaques that
  • 00:37:01
    are building up outside the nerve cell
  • 00:37:02
    so why might that be an important Target
  • 00:37:05
    well it turns out that the Tau pathology
  • 00:37:08
    actually correlates better with the loss
  • 00:37:11
    of nerve cells and the clinical symptoms
  • 00:37:13
    compared to the amyloid pathology as you
  • 00:37:16
    could imagine from what I've already
  • 00:37:18
    said people can have a lot of amyloid in
  • 00:37:20
    their brain and it can be completely
  • 00:37:21
    silent that's why they're being enrolled
  • 00:37:23
    in prevention trials because they aren't
  • 00:37:25
    having symptoms but we're trying to
  • 00:37:26
    prevent those symptoms but when towels
  • 00:37:29
    start spreading their brain that's when
  • 00:37:30
    symptoms really start to develop and so
  • 00:37:32
    perhaps targeting the town might help
  • 00:37:35
    people who are already exhibiting the
  • 00:37:38
    symptoms it may be more effective than
  • 00:37:40
    targeting the amyloid maybe the amyloid
  • 00:37:42
    treatments need to be earlier but the
  • 00:37:43
    Tau treatments could still be given
  • 00:37:45
    later and in fact it turns out in at
  • 00:37:48
    least animal studies you can have a lot
  • 00:37:49
    of amyloid in your brain but if you
  • 00:37:51
    control the Tau you might be able to
  • 00:37:53
    prevent or modify those cognitive
  • 00:37:55
    deficits so that was the conclusion of
  • 00:37:58
    this study from years ago where
  • 00:38:00
    essentially laboratory mice who are
  • 00:38:04
    genetically engineered to develop a form
  • 00:38:06
    of Alzheimer's they could manipulate
  • 00:38:08
    whether amyloid or Tau became expressed
  • 00:38:11
    in their brain and they looked to see
  • 00:38:13
    could a mouse learn the position of a
  • 00:38:16
    submerged platform in kind of a Milky
  • 00:38:18
    pool of water because the mice didn't
  • 00:38:20
    like swimming around constantly they
  • 00:38:21
    want to find that platform in rest and
  • 00:38:23
    so they put them in this container which
  • 00:38:27
    has some
  • 00:38:28
    basically has some landmarks they can
  • 00:38:30
    look around and sort of decide where
  • 00:38:32
    they are and once they learn where that
  • 00:38:33
    submerged platform is the next time they
  • 00:38:35
    put them in the container they look at
  • 00:38:37
    the landmarks and say aha I know where
  • 00:38:39
    to go to find that platform if they can
  • 00:38:40
    remember it so a normal Mouse after
  • 00:38:44
    they've learned it is you know pretty
  • 00:38:45
    much spending its time right where the
  • 00:38:46
    platform is but a mouse that has a lot
  • 00:38:49
    of amyloid and talent its brain is
  • 00:38:51
    really randomly swimming around the
  • 00:38:53
    different quadrants can't find that
  • 00:38:54
    submerged platform but a mouse that's
  • 00:38:57
    not allowed to develop the town buildup
  • 00:38:59
    that can develop the amyloid build up
  • 00:39:01
    still can learn where that submerged
  • 00:39:03
    platform is so again the Tau May
  • 00:39:06
    correlate better with the cognition so
  • 00:39:07
    Tau therapies may help people once
  • 00:39:10
    symptoms have already been present
  • 00:39:12
    so where do we stand in town therapies
  • 00:39:15
    for Alzheimer's disease well just like
  • 00:39:17
    there are amyloid antibodies there are
  • 00:39:19
    also Tau antibodies under development
  • 00:39:21
    for Alzheimer's disease unfortunately
  • 00:39:24
    the studies so far have not shown great
  • 00:39:26
    promise as they've moved along from
  • 00:39:29
    phase one to phase two for example so
  • 00:39:31
    many of the ones that have been studied
  • 00:39:33
    so far have not shown a clear clinical
  • 00:39:36
    benefit
  • 00:39:37
    One Drug showed a slight difference at
  • 00:39:40
    the very end of the study on one measure
  • 00:39:42
    but not on any of the other measures of
  • 00:39:44
    cognition and the thought might be that
  • 00:39:47
    not all Tau antibodies are equally
  • 00:39:50
    effective it may depend on what part of
  • 00:39:52
    the tile protein the antibody is
  • 00:39:54
    targeting so other antibodies aimed at
  • 00:39:57
    different sections of the Tau protein or
  • 00:39:59
    other immune approaches vaccines that
  • 00:40:01
    allow you to develop your own Tau
  • 00:40:03
    antibodies those are now moving forward
  • 00:40:05
    in clinical trials so we'll have to stay
  • 00:40:07
    tuned to see if those are potentially
  • 00:40:09
    more effective and there have been a lot
  • 00:40:11
    of other agents trying to block just the
  • 00:40:14
    buildup of the towel itself not by an
  • 00:40:17
    antibody to remove it by but just
  • 00:40:19
    preventing the towel from accumulating
  • 00:40:21
    the form of Tangles
  • 00:40:22
    um so there's a company that in fact is
  • 00:40:24
    so dedicated to
  • 00:40:26
    um towel therapy specifically it's
  • 00:40:28
    called Tau RX so they're really looking
  • 00:40:30
    at therapies for Alzheimer's that Target
  • 00:40:32
    Tau and they've looked at compounds that
  • 00:40:35
    again are thought to be able to prevent
  • 00:40:37
    the accumulation of the Tau in the form
  • 00:40:39
    of the tangles
  • 00:40:41
    and the most recent compound they
  • 00:40:43
    studied it goes by name that is too long
  • 00:40:45
    to pronounce so it's abbreviated hmtm
  • 00:40:48
    but it's an oral compound so it doesn't
  • 00:40:50
    have to be given intravenously it's
  • 00:40:52
    chemically related to a dye called
  • 00:40:54
    methylene blue
  • 00:40:56
    so one of its interesting side effects
  • 00:40:59
    is that someone takes it my mouth it
  • 00:41:01
    will turn body fluid specifically urine
  • 00:41:04
    will turn blue and so it makes it very
  • 00:41:06
    easy to know if you're taking the active
  • 00:41:08
    drug compared to a placebo which is
  • 00:41:10
    always made it a challenge if you want
  • 00:41:12
    to do comparative studies so in their
  • 00:41:15
    phase three trial called Lucidity they
  • 00:41:17
    gave individuals either the hmtm or a
  • 00:41:21
    related compound that was meant to
  • 00:41:23
    function as a placebo but had still that
  • 00:41:26
    blue chemical effect so people couldn't
  • 00:41:28
    tell whether they were getting the
  • 00:41:29
    active drug or the placebo just by that
  • 00:41:31
    blue coloration and so in the end when
  • 00:41:34
    they compared how cognition changed in
  • 00:41:37
    individuals with different levels of
  • 00:41:39
    cognitive impairment from Alzheimer's
  • 00:41:40
    they didn't see a difference between
  • 00:41:42
    those taking the hmtm and those taking
  • 00:41:45
    the MTC but as it turned out when they
  • 00:41:49
    started measuring blood levels of what
  • 00:41:51
    they thought was the active component
  • 00:41:53
    they could detect it both in those who
  • 00:41:55
    receive the h MTM and in those who
  • 00:41:58
    receive what they thought was the
  • 00:42:00
    placebo so maybe it wasn't that the drug
  • 00:42:03
    didn't work it's just that both worked
  • 00:42:05
    and so you couldn't tell the difference
  • 00:42:07
    so this is going to need some further
  • 00:42:09
    thought to tease that out because it's
  • 00:42:10
    really hard to make a comparison if both
  • 00:42:13
    people are getting sort of active
  • 00:42:14
    treatments during this study
  • 00:42:17
    um so I think is still a viable approach
  • 00:42:19
    we just need more information and more
  • 00:42:21
    compounds but there have been some
  • 00:42:23
    really interesting studies presented
  • 00:42:25
    recently not clinical trials in humans
  • 00:42:27
    but some research researchers are
  • 00:42:30
    focusing on Tau changes in animals it
  • 00:42:33
    was known from previous studies that Tau
  • 00:42:35
    can accumulate in the brain of
  • 00:42:37
    hibernating animals in a way that's
  • 00:42:40
    similar to how the Tau Tangles build up
  • 00:42:42
    in humans when they experience
  • 00:42:44
    Alzheimer's disease they get these
  • 00:42:46
    tangle-like structures this was known
  • 00:42:48
    from I think hibernating squirrels that
  • 00:42:50
    they studied in the lab or other animal
  • 00:42:51
    species but someone got the idea to look
  • 00:42:54
    at this in hibernating bears and so some
  • 00:42:57
    researchers actually went out and
  • 00:42:58
    collected blood samples from bears
  • 00:43:00
    during their hibernation and later on in
  • 00:43:03
    the summer when they woke back up these
  • 00:43:05
    were measurements of towel in the blood
  • 00:43:06
    again I mentioned we can now measure
  • 00:43:09
    these proteins in the blood and get
  • 00:43:10
    predictions about what's going on in the
  • 00:43:12
    brain and it turns out they did have
  • 00:43:14
    more of the tangle like how in their
  • 00:43:17
    bloodstream when they were hibernated
  • 00:43:19
    but those levels fell back to normal
  • 00:43:21
    during the summer very interesting
  • 00:43:23
    observation we don't know what it means
  • 00:43:25
    we don't know if that tau is protecting
  • 00:43:29
    the brain while the animal is in
  • 00:43:30
    hibernation is it is it a good response
  • 00:43:33
    or is it a not great response but the
  • 00:43:35
    good part is when the animal wakes up
  • 00:43:37
    from hibernation it clears it and what's
  • 00:43:38
    the secret of clearing that can we study
  • 00:43:41
    that as a way of potentially clearing
  • 00:43:43
    Tau buildup in humans so you know can we
  • 00:43:45
    figure out what that process is and I
  • 00:43:47
    think the other interesting question was
  • 00:43:48
    who is heroic enough to draw blood from
  • 00:43:52
    hibernating bears and awaken them from
  • 00:43:54
    their sleep to be able to collect these
  • 00:43:57
    samples so a lot more to be learned I'm
  • 00:44:00
    going to switch gears in the final few
  • 00:44:02
    minutes and talk about some studies that
  • 00:44:04
    don't have anything to do or at least
  • 00:44:05
    not directly with amyloid or Tau but
  • 00:44:08
    maybe have a little bit of a link with
  • 00:44:09
    hibernating bears obviously a
  • 00:44:11
    hibernating bear might get rather upset
  • 00:44:13
    if you awaken it and ask it to do
  • 00:44:14
    something it doesn't want to do like
  • 00:44:16
    provide a blood sample and we also know
  • 00:44:18
    that individuals with Alzheimer's
  • 00:44:20
    dementia they can also develop agitation
  • 00:44:23
    particularly later on in the disease
  • 00:44:25
    course where you know being asked to get
  • 00:44:27
    dressed or take a shower can be
  • 00:44:29
    confusing tasks and they can resist that
  • 00:44:31
    care or react sometimes verbally or
  • 00:44:34
    physically in an aggressive Manner and
  • 00:44:36
    at this point there are no approved
  • 00:44:38
    medications for the agitation or
  • 00:44:40
    aggression associated with Alzheimer's
  • 00:44:42
    dementia but that could change because
  • 00:44:45
    there are studies looking at specific
  • 00:44:47
    compounds this is a study of a drug
  • 00:44:49
    called Rex piprazole it's used currently
  • 00:44:53
    for treating disorders like
  • 00:44:55
    schizophrenia where people can have
  • 00:44:57
    confusion misperceptions that can be so
  • 00:44:59
    associated with agitation but these
  • 00:45:02
    individuals in this study all had
  • 00:45:03
    Alzheimer's dementia with frequent
  • 00:45:05
    aggressive behavior and they received
  • 00:45:08
    either Placebo or a daily dose of this
  • 00:45:10
    medication and they just measured how
  • 00:45:12
    much agitation
  • 00:45:14
    their study partner or family member
  • 00:45:16
    reported while they were receiving
  • 00:45:18
    either the active drug or the placebo
  • 00:45:20
    and in the end those who got the active
  • 00:45:23
    drug at either dose had fewer points on
  • 00:45:27
    this agitation scale it was about five
  • 00:45:29
    fewer points which means that either one
  • 00:45:32
    disruptive behavior might go from almost
  • 00:45:35
    a daily basis to almost not at all or
  • 00:45:38
    maybe five different behaviors that were
  • 00:45:39
    happening several times a week were now
  • 00:45:41
    only happening once a week so it could
  • 00:45:43
    have been a marked change in one
  • 00:45:44
    Behavior or a slight change in multiple
  • 00:45:46
    behaviors any of those would have a
  • 00:45:49
    translated into a five-point difference
  • 00:45:51
    so this looks promising but I think the
  • 00:45:54
    other thing that's very interesting is
  • 00:45:55
    that everybody's score on the agitation
  • 00:45:58
    scale dropped even even if they were
  • 00:46:00
    just receiving the placebo there was
  • 00:46:02
    actually about a 15 Point drop in the
  • 00:46:04
    placebo group alone and then an added
  • 00:46:07
    five-point drop in the treatment group
  • 00:46:09
    suggesting that just the benefits of
  • 00:46:11
    being in a trial working with folks who
  • 00:46:13
    can help understand these behaviors or
  • 00:46:16
    having the that interaction perhaps that
  • 00:46:19
    itself was associated with less
  • 00:46:21
    agitation and that's obviously hard to
  • 00:46:23
    replicate by simply giving someone a
  • 00:46:26
    medication every day so the FDA will
  • 00:46:28
    review this and it potentially may
  • 00:46:30
    become the first medication approved to
  • 00:46:33
    treat the agitation associated with
  • 00:46:34
    Alzheimer's dementia
  • 00:46:37
    um and then I'm going to just finish
  • 00:46:39
    with a final few slides looking at
  • 00:46:41
    non-medication trials some related to
  • 00:46:44
    Alzheimer's disease recently was
  • 00:46:46
    announced the result of a trial looking
  • 00:46:48
    at exercise the exert trial we know
  • 00:46:51
    exercise can have a lot of helpful
  • 00:46:54
    effects biochemically on the brain and
  • 00:46:57
    so the researchers wanted to know did
  • 00:47:00
    different types of exercise help
  • 00:47:02
    individuals with mild cognitive
  • 00:47:04
    impairment individuals showing some
  • 00:47:05
    memory changes but still independent in
  • 00:47:07
    Daily activity so not at the dementia
  • 00:47:09
    level but at the mild counter impairment
  • 00:47:11
    level and so they compared individuals
  • 00:47:13
    receiving an aerobic regimen of exercise
  • 00:47:16
    but they were targeting certain heart
  • 00:47:18
    rates versus those who did more toning
  • 00:47:20
    and stretching and they hypothesized
  • 00:47:22
    that those with the more aerobic
  • 00:47:24
    activity would show less cognitive
  • 00:47:26
    decline over time compared to just the
  • 00:47:28
    toning and stretching and as it turned
  • 00:47:30
    out both groups were remarkably stable
  • 00:47:33
    over 12 months whereas many individuals
  • 00:47:35
    with mild kind of impairment would
  • 00:47:37
    expect to have a decline over that
  • 00:47:39
    period of time and so the conclusion
  • 00:47:41
    would be even a modest or low level of
  • 00:47:44
    activity if it's stretching and toning
  • 00:47:46
    may help protect the brain cells or
  • 00:47:48
    maybe it was some other aspect of the
  • 00:47:50
    study because these individuals were
  • 00:47:52
    working at their local YMCA with
  • 00:47:54
    trainers on a regular basis so maybe it
  • 00:47:57
    was a social social interactions or some
  • 00:47:59
    other aspect that also helped to
  • 00:48:01
    preserve the memory over time because we
  • 00:48:03
    know from other studies those types of
  • 00:48:06
    activities social rather than just
  • 00:48:08
    physical activity can be helpful as well
  • 00:48:10
    so Dr hiroko Dodge who was previously
  • 00:48:13
    with our Michigan Alzheimer's center she
  • 00:48:16
    has done several studies looking at the
  • 00:48:18
    benefits of social contact to
  • 00:48:21
    individuals who either are older with
  • 00:48:23
    normal cognition or have this mild
  • 00:48:25
    counter impairment and in her study she
  • 00:48:28
    arranged volunteers to have regular
  • 00:48:30
    video sort of Zoom chats this was
  • 00:48:32
    planned pre-pandemic but became very
  • 00:48:35
    important when the pandemic hit because
  • 00:48:37
    they were able to continue the
  • 00:48:38
    intervention and so individuals either
  • 00:48:41
    receive these regular video chats plus a
  • 00:48:43
    weekly phone call or the control group
  • 00:48:45
    just had a weekly phone call and they
  • 00:48:48
    compare their cognitive scores and those
  • 00:48:49
    in the video chat group if they started
  • 00:48:52
    with memory impairment they actually
  • 00:48:53
    showed improvements on some of the
  • 00:48:55
    memory measures over the six and 12
  • 00:48:57
    months that these interventions were
  • 00:48:59
    being applied
  • 00:49:01
    and so you might say well gosh what if
  • 00:49:03
    we start doing all these things together
  • 00:49:04
    not just regular exercise but we engage
  • 00:49:07
    with others socially we follow a good
  • 00:49:09
    diet we treat our other health
  • 00:49:12
    conditions our blood pressure diabetes
  • 00:49:14
    what if we do all of these sort of
  • 00:49:16
    Lifestyle interventions what might the
  • 00:49:17
    outcome be then that's exactly what the
  • 00:49:20
    finished geriatric prevention trial or
  • 00:49:22
    the finger trial did where individuals
  • 00:49:25
    received either very structured
  • 00:49:26
    counseling about nutrition exercise they
  • 00:49:29
    were engaged in cognitive activities or
  • 00:49:32
    they were just sort of told we think
  • 00:49:33
    it's good for you to focus on these but
  • 00:49:35
    there wasn't any structured interaction
  • 00:49:36
    and these were older individuals at risk
  • 00:49:39
    for cognitive symptoms they followed
  • 00:49:41
    them over two years and showed better
  • 00:49:44
    test scores cognitively and those with
  • 00:49:46
    the more structured intervention and a
  • 00:49:48
    lot lower risk for certain health
  • 00:49:50
    conditions and chronic diseases as well
  • 00:49:52
    this was in Scandinavia but now as being
  • 00:49:55
    replicated across multiple locations so
  • 00:49:57
    there are multiple finger like studies
  • 00:50:00
    being done the one that's being done
  • 00:50:02
    here in the U.S is called the pointer
  • 00:50:04
    study an acronym for protecting
  • 00:50:07
    essentially the brain through lifestyle
  • 00:50:09
    interventions to reduce the risk of
  • 00:50:12
    cognitive impairment so a very similar
  • 00:50:14
    program where a large number of older
  • 00:50:17
    individuals who might be at risk because
  • 00:50:19
    of other health conditions or their age
  • 00:50:22
    or their family history but they either
  • 00:50:24
    receive a very structured lifestyle
  • 00:50:26
    intervention or just kind of a
  • 00:50:27
    self-guided one to see if we can
  • 00:50:29
    replicate that impact on cognitive
  • 00:50:31
    function and ultimately other health
  • 00:50:34
    conditions as well so this is an ongoing
  • 00:50:36
    study at several locations throughout
  • 00:50:38
    the US that we'll learn about more in
  • 00:50:40
    the coming years
  • 00:50:42
    but there's a lot more out there as well
  • 00:50:45
    so um you know I focused a lot on this
  • 00:50:48
    part of the biochemical pathway the
  • 00:50:50
    amyloid practice
  • 00:50:52
    aggregation or deposition talked a
  • 00:50:55
    little bit about this part the tangles
  • 00:50:57
    but there's lots and lots of other steps
  • 00:51:00
    that are going on in the brain when
  • 00:51:02
    someone is developing the pathology of
  • 00:51:04
    Alzheimer's and this slide isn't meant
  • 00:51:06
    to explain any one particular part of
  • 00:51:08
    them but just to say it's a complex
  • 00:51:10
    disease it's not just a simple thing
  • 00:51:12
    where one change happens there are a lot
  • 00:51:14
    of things going on which makes it
  • 00:51:16
    challenging but it also means there are
  • 00:51:18
    many potential steps for which we could
  • 00:51:21
    develop therapies or targets to
  • 00:51:23
    intervene and so we hope at the
  • 00:51:26
    University of Michigan to be involved in
  • 00:51:27
    some of these other treatments that
  • 00:51:30
    maybe aren't necessarily directly
  • 00:51:31
    attacking amyloid or Tau but other
  • 00:51:34
    important aspects in these biochemical
  • 00:51:36
    processes of Alzheimer's disease so I'll
  • 00:51:39
    finish with just mentioning some of the
  • 00:51:41
    studies that I've been involved with or
  • 00:51:42
    hope to to be involved with there are
  • 00:51:44
    many many more going on at the
  • 00:51:46
    University of Michigan through our
  • 00:51:47
    Alzheimer's Research Center that my
  • 00:51:49
    colleagues are leading so feel free to
  • 00:51:51
    take a look at our website if you want
  • 00:51:53
    to know what's happening right now we
  • 00:51:55
    were involved in the phase two trial of
  • 00:51:57
    lakinumab as I mentioned we've got a
  • 00:52:00
    prevention trial using the drug
  • 00:52:01
    solanasumab that is just finishing up
  • 00:52:04
    and one that is enrolling folks using
  • 00:52:06
    laquinimab as a prevention trial we have
  • 00:52:09
    other studies where we just follow folks
  • 00:52:11
    without any specific intervention but
  • 00:52:13
    using some of these specialized brain
  • 00:52:14
    schemes to track how things progress
  • 00:52:16
    over time some of these studies were the
  • 00:52:18
    ones that led us to understand that
  • 00:52:20
    amyloid can build up silently many years
  • 00:52:23
    before symptoms develop and in the
  • 00:52:25
    future we hope to be involved in some
  • 00:52:28
    really sophisticated trials where
  • 00:52:31
    compounds have been engineered to Target
  • 00:52:33
    you know very specific parts of this
  • 00:52:35
    pathway like these Sigma receptors here
  • 00:52:37
    and some using compounds that are a
  • 00:52:39
    little more I would call sort of natural
  • 00:52:41
    or organic like this medication or
  • 00:52:44
    compound called benefitiamine is kind of
  • 00:52:47
    an analog of thiamine a normal vitamin
  • 00:52:49
    that we have there are reasons to think
  • 00:52:52
    that in Alzheimer's disease there might
  • 00:52:54
    be insufficient levels of thiamine in
  • 00:52:57
    the brain or related compounds so giving
  • 00:52:59
    a simple sort of natural supplement
  • 00:53:01
    would that help slow down the
  • 00:53:03
    progression of Alzheimer's so there are
  • 00:53:04
    a couple trials planned using these
  • 00:53:06
    compounds that we hope to be involved
  • 00:53:08
    with and in the future one looking at
  • 00:53:11
    more specific therapies targeting the
  • 00:53:13
    Tau aspect in what's called a platform
  • 00:53:15
    trial where you can simultaneously
  • 00:53:18
    compare different Tau therapies or
  • 00:53:20
    anti-cal therapies against the placebo
  • 00:53:22
    rather than having to do separate trials
  • 00:53:24
    to sort of kind of speed up whether we
  • 00:53:26
    learn if a particular compound is
  • 00:53:28
    helpful or not so as I mentioned these
  • 00:53:30
    are just some of the things that we're
  • 00:53:32
    they're doing right now or hope to be
  • 00:53:33
    involved with many more available so
  • 00:53:36
    feel free to take a look at the Michigan
  • 00:53:38
    Alzheimer's disease Research Center
  • 00:53:40
    website specifically under the research
  • 00:53:42
    part to see what studies are enrolling
  • 00:53:45
    now and just keep an eye out there
  • 00:53:46
    because we add more all the time and
  • 00:53:49
    with that I will pause I think we've got
  • 00:53:51
    a few minutes if we are able to open up
  • 00:53:54
    questions
  • 00:53:55
    yeah absolutely thank you so much that
  • 00:53:57
    was a lot of really great information we
  • 00:53:59
    do have time for a couple questions so
  • 00:54:02
    if you do have a question you can go
  • 00:54:04
    ahead and put it in the Q a box and I
  • 00:54:06
    will pass that along to Judy
  • 00:54:09
    yeah
  • 00:54:10
    that box like we got one right away
  • 00:54:14
    already
  • 00:54:17
    this one says given that drugs have
  • 00:54:20
    demental side effects I'm interested in
  • 00:54:24
    finding out if the university has an
  • 00:54:27
    entertained or would entertain a
  • 00:54:29
    clinical trial to replicate results of
  • 00:54:32
    Dr Dale bresden
  • 00:54:35
    work that has produced stunning results
  • 00:54:39
    and not just slowing and advancing and
  • 00:54:42
    the advance of dementia but in reversing
  • 00:54:45
    the decline of cognition his protocol
  • 00:54:48
    isn't drug based and I would like to
  • 00:54:50
    know if the university would ever
  • 00:54:52
    consider such an approach to treating
  • 00:54:54
    Alzheimer's yeah I think that's a really
  • 00:54:57
    great great question so Dr bredesen has
  • 00:54:59
    designed
  • 00:55:01
    um not necessarily a specific regimen
  • 00:55:03
    but more of an approach to treat
  • 00:55:06
    Alzheimer's on an individual basis
  • 00:55:09
    taking into account a lot of the science
  • 00:55:11
    that says it you know there may be a
  • 00:55:14
    different aspect of Alzheimer's that's
  • 00:55:16
    more prominent in one person than
  • 00:55:18
    another so in one person there might be
  • 00:55:20
    a lot more inflammation and another
  • 00:55:22
    person it might be more oxidation or
  • 00:55:24
    some other component and so the idea of
  • 00:55:27
    his approach is to do a lot of blood
  • 00:55:31
    work and other markers related to these
  • 00:55:33
    and sort of design a specific
  • 00:55:35
    intervention tailored to that person's
  • 00:55:38
    blood work and it also involves aspects
  • 00:55:41
    of diet or sometimes even caloric
  • 00:55:43
    restriction like not eating During
  • 00:55:45
    certain hours of the day so it's not a
  • 00:55:47
    it's not a one-size-fits all but it's
  • 00:55:49
    sort of an algorithm and so that makes
  • 00:55:51
    it hard to study you know how do you
  • 00:55:54
    study it when each person is going to
  • 00:55:55
    get a little different combination of
  • 00:55:58
    supplements or things like that but I
  • 00:56:01
    think it really does deserve study
  • 00:56:02
    because right now what we're hearing is
  • 00:56:04
    largely sort of and anecdotal reports
  • 00:56:06
    not really rigorous scientific results
  • 00:56:08
    but I think it would have to be a
  • 00:56:10
    collaborative effort probably something
  • 00:56:12
    more than any one Center could tackle
  • 00:56:15
    but you'd have to think about it
  • 00:56:17
    creatively how do you what's your
  • 00:56:19
    comparison group so maybe you look at
  • 00:56:21
    all the different possible supplements
  • 00:56:24
    that might be recommended and in one
  • 00:56:26
    group you say okay we're going to do a
  • 00:56:27
    very careful match to the blood work and
  • 00:56:30
    the other group we're going to randomly
  • 00:56:31
    assign some combination to see is it
  • 00:56:34
    really that individual tailoring that
  • 00:56:36
    makes a difference or is it just doing
  • 00:56:37
    something focusing on your health helps
  • 00:56:40
    you be better and it really doesn't have
  • 00:56:41
    to do anything with a specific compound
  • 00:56:43
    so I think that's a great question but
  • 00:56:45
    not a simple answer
  • 00:56:48
    all right I'm gonna go into another
  • 00:56:51
    question having read Sebastian Walsh at
  • 00:56:54
    all's
  • 00:56:55
    bmj editorial La Canada map and
  • 00:56:58
    Alzheimer's disease with the subtitle
  • 00:57:01
    new trial reports little to celebrate
  • 00:57:04
    for patients and carriers I'd like to
  • 00:57:07
    hear Dr heidebring's perspectives on the
  • 00:57:11
    clinical meaningfulness
  • 00:57:13
    of the amount of reduction in cognitive
  • 00:57:15
    decline based on the clinical dementia
  • 00:57:19
    rating
  • 00:57:19
    that is reported in the pivotal trial
  • 00:57:22
    which seems to be an important
  • 00:57:24
    consideration along with the trial's
  • 00:57:26
    safety findings the authors conclude
  • 00:57:30
    against the scale and severity of
  • 00:57:34
    adverse
  • 00:57:35
    events and substantial practical
  • 00:57:38
    barriers to widespread use lecanomev is
  • 00:57:42
    unlikely to represent a favorable risk
  • 00:57:44
    benefit balance for patient or value for
  • 00:57:48
    money for Health Systems
  • 00:57:50
    wow that was a mouthful of a question
  • 00:57:53
    but it was very well um proposed because
  • 00:57:57
    I think that's really the key question
  • 00:57:58
    is uh we have a drug I think there's
  • 00:58:02
    consistent evidence of a benefit in
  • 00:58:05
    terms of slowing progression but
  • 00:58:07
    numerically that benefit is small and we
  • 00:58:11
    have side effects that we know again
  • 00:58:13
    most of the time those are clinically
  • 00:58:16
    silent but if not adhere to carefully or
  • 00:58:20
    monitor carefully they could become more
  • 00:58:22
    problematic and so ultimately what's the
  • 00:58:24
    risk benefit and I think that answer is
  • 00:58:26
    going to be different in different
  • 00:58:28
    people I think one way of posing it is
  • 00:58:30
    the way I sort of suggested earlier
  • 00:58:33
    would it have been worth it to you to be
  • 00:58:35
    coming in every two weeks for this
  • 00:58:36
    infusion if now at the end of the study
  • 00:58:38
    you were back to where you were six
  • 00:58:39
    months ago and I think some people would
  • 00:58:41
    say absolutely I could be doing this for
  • 00:58:43
    six months longer I could be doing that
  • 00:58:44
    I could be independent in these
  • 00:58:46
    different ways and what's you know
  • 00:58:47
    what's the value of Independence how do
  • 00:58:49
    you measure that other people would say
  • 00:58:51
    I didn't really feel that much different
  • 00:58:53
    six months ago I'm not changing much I'm
  • 00:58:57
    not sure it's worth it so again it's a
  • 00:58:59
    very hard question to answer I think
  • 00:59:00
    everyone's going to have their own take
  • 00:59:02
    and we don't know whether that benefit
  • 00:59:04
    might be greater as time goes on that's
  • 00:59:08
    an unanswered question at this point I
  • 00:59:10
    agree that this is not going to be the
  • 00:59:12
    way we treat Alzheimer's logistically
  • 00:59:14
    it's just not a drug we can administer
  • 00:59:16
    to the numbers of people who are even
  • 00:59:18
    you know potentially falling into that
  • 00:59:20
    eligibility range but I think it's a
  • 00:59:23
    breakthrough in saying you know we can
  • 00:59:25
    do something on the ambly basis that
  • 00:59:27
    modifies we just need to develop even
  • 00:59:29
    more powerful I guess and safer drugs
  • 00:59:32
    ultimately
  • 00:59:34
    great uh do you have time for a few more
  • 00:59:36
    questions Judy sure sure okay great
  • 00:59:39
    um are there any trials looking at the
  • 00:59:42
    quality of life
  • 00:59:44
    um often that is an embedded measure in
  • 00:59:47
    the clinical trials so that lacena mab
  • 00:59:50
    study did include measurements where
  • 00:59:52
    they asked both the participant about
  • 00:59:54
    their quality of life trying to rate it
  • 00:59:56
    numerically had their study partner
  • 00:59:59
    provide a sense of what they thought the
  • 01:00:01
    participant's quality of life was like
  • 01:00:03
    and they also had the study partner rate
  • 01:00:05
    their own burden so to speak as a
  • 01:00:08
    caregiver how much you know of your time
  • 01:00:10
    do you think is spent providing care for
  • 01:00:12
    this person and is that in any way you
  • 01:00:14
    know a detriment and so those caregiver
  • 01:00:17
    burden and Quality of Life ratings were
  • 01:00:19
    tracked those haven't been published yet
  • 01:00:22
    to my understanding but they did show a
  • 01:00:24
    difference in the treatment group versus
  • 01:00:26
    duplicity group again a small difference
  • 01:00:28
    but those are things that are really
  • 01:00:30
    hard to to to measure trying to put
  • 01:00:33
    numbers on on quality of life but you're
  • 01:00:35
    right I think that's an important aspect
  • 01:00:36
    of trying to understand the
  • 01:00:38
    meaningfulness of scales like that CDR
  • 01:00:42
    all right how long does the removal of
  • 01:00:46
    amyloid last after treatment another
  • 01:00:49
    great question it probably lasts quite a
  • 01:00:53
    bit longer than just you know the last
  • 01:00:55
    infusion and
  • 01:00:57
    um we know that in part from individuals
  • 01:01:00
    who participated in the phase two study
  • 01:01:03
    of locina mab
  • 01:01:05
    um some got the active drugs at
  • 01:01:06
    different doses some got the placebo
  • 01:01:08
    they had pre-imposed pet scans and then
  • 01:01:11
    some were invited later on to enter an
  • 01:01:14
    open label but there was a lag period
  • 01:01:16
    between when they finished the phase two
  • 01:01:18
    and when they finish the open label what
  • 01:01:20
    everyone got the drug and so if they got
  • 01:01:22
    a new pet scan when they entered the OPA
  • 01:01:24
    label you could say if they'd gotten the
  • 01:01:26
    active rug and their and their amyloid
  • 01:01:28
    was lower did it stay lower for that
  • 01:01:30
    year or two years when they weren't
  • 01:01:32
    receiving further therapy and the answer
  • 01:01:34
    was yes it did seem to stay low so that
  • 01:01:37
    is encouraging that maybe you don't need
  • 01:01:39
    to keep dosing forever with these agents
  • 01:01:42
    on the other hand if you track their
  • 01:01:44
    cognition there was a sense that if it
  • 01:01:47
    was being slowed down that benefit was
  • 01:01:50
    starting to slide when they weren't
  • 01:01:52
    receiving the treatment so so yes we
  • 01:01:54
    were able to keep the amyloid low even
  • 01:01:56
    without continuous therapy but one of
  • 01:01:59
    the benefits persist is a harder
  • 01:02:00
    question but researchers trying to
  • 01:02:02
    answer that right now
  • 01:02:06
    all right
  • 01:02:07
    why did the number of participants
  • 01:02:10
    reduce so much during the study of
  • 01:02:13
    educatamab
  • 01:02:15
    Oh you mean looking at the numbers I
  • 01:02:16
    don't know if it's referring to looking
  • 01:02:17
    at the numbers of people at different
  • 01:02:19
    time points well
  • 01:02:21
    um if that's the question
  • 01:02:23
    um because the styles were halted early
  • 01:02:25
    not all people made it to the 18-month
  • 01:02:28
    time point that they designed and
  • 01:02:30
    everybody enters the trial at a
  • 01:02:31
    different time you don't enroll all 3
  • 01:02:33
    000 people at day one some people
  • 01:02:35
    enrolled you know at one point other
  • 01:02:37
    people a few months later and other
  • 01:02:38
    people a few months later you continue
  • 01:02:39
    to accumulating people they halt the
  • 01:02:41
    trial part way through some people at
  • 01:02:43
    that point have made it to 18 months but
  • 01:02:45
    it's only a fraction of those that they
  • 01:02:47
    originally intended to follow the whole
  • 01:02:49
    way through so the numbers at each time
  • 01:02:51
    point is smaller and smaller because the
  • 01:02:53
    trial is halted early so fewer and fewer
  • 01:02:55
    people had the opportunity to get to
  • 01:02:57
    those later time points and there are
  • 01:02:59
    other things that happen too people drop
  • 01:03:00
    out of the trials for any number of
  • 01:03:02
    reasons so it's common for up to maybe
  • 01:03:05
    15 20 of people not to finish a trial
  • 01:03:09
    for all sorts of reasons
  • 01:03:11
    all right
  • 01:03:13
    wasn't there a research peer-reviewed
  • 01:03:16
    Journal article where an invested an
  • 01:03:19
    investigator manipulated data regarding
  • 01:03:22
    amyloid plaque will that affect any
  • 01:03:24
    amyloid clinical trials yeah that's
  • 01:03:26
    another great question that was another
  • 01:03:28
    big news story in the past year it was a
  • 01:03:32
    publication looking at a specific
  • 01:03:35
    form of amyloid where the thought was
  • 01:03:39
    that the actual scientific data had been
  • 01:03:43
    either manipulated or the same result
  • 01:03:45
    was published in multiple ways and not
  • 01:03:47
    really reflecting unique unique data
  • 01:03:51
    many people had actually questioned that
  • 01:03:54
    original publication because they they
  • 01:03:56
    was sort of identifying a toxic species
  • 01:03:58
    of the amyloid several Labs early on and
  • 01:04:01
    said we really can't replicate that it
  • 01:04:04
    was kind of one piece in the big amyloid
  • 01:04:07
    puzzle and no specific therapies were
  • 01:04:10
    ever designed towards that specific
  • 01:04:12
    species in part because the early data
  • 01:04:14
    couldn't be replicated so the fact that
  • 01:04:16
    that data May well have been falsified
  • 01:04:18
    is a huge you know it's a huge
  • 01:04:20
    disappointment and that you know
  • 01:04:21
    scientific Integrity is so important so
  • 01:04:23
    that really does need to be reviewed and
  • 01:04:26
    corrected but fortunately it didn't
  • 01:04:28
    really change the larger course of
  • 01:04:31
    treatments geared towards amyloid
  • 01:04:33
    okay all right here's another one
  • 01:04:36
    because social contact is able to slow
  • 01:04:40
    decline of memory does the exert or
  • 01:04:43
    other exercise trials have a beneficial
  • 01:04:46
    effect merely due to social contact with
  • 01:04:50
    exercise coaches is this why the balance
  • 01:04:53
    group showed as strong results as the
  • 01:04:57
    cardiovascular exercise group I think
  • 01:05:00
    that is an unanswerable question because
  • 01:05:02
    you couldn't separate out the social
  • 01:05:04
    contact from the exercise since all of
  • 01:05:07
    these exercise sessions were being
  • 01:05:08
    conducted with that social contact piece
  • 01:05:11
    of it working with a YMC trainer for
  • 01:05:13
    example so you'd have to design a
  • 01:05:15
    separate experiment where you can still
  • 01:05:18
    monitor people and know that they're
  • 01:05:19
    exercising you know like they have to
  • 01:05:21
    turn on a zoom camera with the exercise
  • 01:05:22
    and someone just you know behind the
  • 01:05:24
    scenes documents that they don't they
  • 01:05:26
    are exercising but isn't actually
  • 01:05:27
    interacting with them during their
  • 01:05:29
    exercise to be able to separate that
  • 01:05:32
    component out so we don't know which of
  • 01:05:34
    those components led to the benefits
  • 01:05:36
    whether it was to come combination
  • 01:05:37
    either one separately can't answer that
  • 01:05:40
    question right now
  • 01:05:41
    all right just a comment I have observed
  • 01:05:45
    a significant provement of
  • 01:05:48
    once winter ended last year and he
  • 01:05:51
    resumed considerable biking and weight
  • 01:05:54
    workouts that along with sunshine and
  • 01:05:57
    more social interaction really seemed to
  • 01:05:59
    help I'm glad to hear that it is not my
  • 01:06:01
    imagination now we're looking into
  • 01:06:04
    cardio equipment for Indoor Winter use
  • 01:06:06
    we already have a weight machine perfect
  • 01:06:09
    perfect maybe you could describe that
  • 01:06:11
    what your husband went through was sort
  • 01:06:12
    of like that bear Awakening from
  • 01:06:14
    hibernation it was you know doing
  • 01:06:15
    something biologically that was helpful
  • 01:06:18
    as he got more light exposure more
  • 01:06:21
    exercise all those other activities so
  • 01:06:23
    good for you
  • 01:06:24
    all right what are the risks of taking
  • 01:06:27
    uh
  • 01:06:30
    okay I can't pronounce it betho tiamine
  • 01:06:34
    oh the benphotiamine yeah which is
  • 01:06:37
    available as a supplement if it doesn't
  • 01:06:40
    help if it doesn't prove beneficial
  • 01:06:42
    could Alzheimer's patients take it just
  • 01:06:45
    in case there might be a benefit yeah I
  • 01:06:48
    mean in theory that's true with a lot of
  • 01:06:50
    supplements that people are proposing
  • 01:06:53
    that might be helpful whether it's a
  • 01:06:54
    vitamin supplement an anti-inflammator
  • 01:06:57
    you know things that are over the
  • 01:06:58
    counter
  • 01:06:59
    um we'd really like to know because some
  • 01:07:02
    people are out there selling quite
  • 01:07:03
    expensive version of these things and so
  • 01:07:06
    um rather than just saying what do we
  • 01:07:08
    got to lose we'd really like to know
  • 01:07:11
    um partly because we want to know if
  • 01:07:13
    it's helpful to prescribe it but also to
  • 01:07:15
    know in a rigorous way are there side
  • 01:07:17
    effects because without those studies
  • 01:07:19
    we're just relying on people's just sort
  • 01:07:21
    of anecdotally saying hey I tried it and
  • 01:07:23
    it bothered my stomach which is probably
  • 01:07:24
    the most common side effect that we hear
  • 01:07:26
    with most of these supplements but we
  • 01:07:28
    wouldn't know without rigorous study are
  • 01:07:29
    there electrical effects on the heart
  • 01:07:31
    are there interactions with other
  • 01:07:33
    medications so that's why we really like
  • 01:07:35
    to have that rigorous study to say not
  • 01:07:37
    only is this that you know not only does
  • 01:07:38
    it help people but we know it's safe to
  • 01:07:40
    take in combination with other things
  • 01:07:41
    too
  • 01:07:43
    okay one last question
  • 01:07:46
    um
  • 01:07:47
    uh Risperdal worked wonders for my loved
  • 01:07:51
    one with A.D as far as agitation and
  • 01:07:55
    angry outbursts it was a game changer
  • 01:07:57
    have you ever recommended Risperdal for
  • 01:08:00
    those same behaviors
  • 01:08:02
    um yes Risperdal is sort of in the same
  • 01:08:05
    category as the drug that I mentioned
  • 01:08:07
    and so we will in many cases use those
  • 01:08:11
    types of medications because we know on
  • 01:08:13
    an individual basis they can be helpful
  • 01:08:16
    unfortunately there isn't a magic one
  • 01:08:18
    that works for every person every time
  • 01:08:20
    and you know that's partly why there
  • 01:08:22
    hasn't been a drug that's approved yet
  • 01:08:24
    because when you study groups of people
  • 01:08:25
    they don't all behave the same way
  • 01:08:28
    um but yeah Simpsons we don't have any
  • 01:08:30
    technically approved therapies for the
  • 01:08:32
    agitation and behavioral challenges we
  • 01:08:34
    resort to using medications that we
  • 01:08:36
    think might be helpful even without that
  • 01:08:38
    FDA stamp of approval
  • 01:08:41
    okay just one more I I fibbed that's
  • 01:08:44
    perfect
  • 01:08:44
    is it true that general anesthesia
  • 01:08:47
    causes pitau to elevate oh I think I
  • 01:08:51
    would say
  • 01:08:52
    um I will defer on that one I mean there
  • 01:08:54
    are a lot of there are a lot of
  • 01:08:56
    interesting questions about anesthesia
  • 01:09:00
    and whether its effects are only
  • 01:09:03
    temporary you know turning the mind off
  • 01:09:05
    and you know rebounding afterwards or
  • 01:09:07
    whether there are any links to any
  • 01:09:09
    Alzheimer's type changes some of the
  • 01:09:10
    things that I had heard about were
  • 01:09:12
    related really more to
  • 01:09:14
    inhaled anesthetic agents that we don't
  • 01:09:16
    use anymore so at this point I would say
  • 01:09:18
    there's not anything convincing in my
  • 01:09:20
    mind that an anesthesia is a direct risk
  • 01:09:23
    for Alzheimer's changes but a lot a lot
  • 01:09:25
    more is being done to look at that
  • 01:09:28
    okay I think that is all that we had
  • 01:09:32
    um be on the lookout for an email that
  • 01:09:35
    will come out
  • 01:09:37
    um um I will be sending out an
  • 01:09:38
    evaluation for this so it'd be really
  • 01:09:40
    helpful
  • 01:09:41
    um we like to make sure that we're
  • 01:09:43
    serving everybody uh properly and and
  • 01:09:46
    I'm glad everybody had a chance to
  • 01:09:48
    attend so thank you so much for coming
  • 01:09:50
    all right thanks everyone
Tag
  • Alzheimer
  • Investigació mèdica
  • Anticossos monoclonals
  • Plaques amiloides
  • Assaigs clínics
  • Qualitat de vida
  • Neurodegeneració
  • Prevenció
  • Medicina
  • Salut mental