1- My current take on whether anti-amyloid therapies are likely to have meaningful impact on cognition, functioning & quality of life of people living w/ #dementia due to #Alzheimers disease:
Not likely.
For details, based on my recent Grand Rounds at Penn St, read on.
2- History:
After finding that active immunization with Abeta42 in mice that overexpressed APP resulted in virtual elimination of amyloid deposits, there was great enthusiasm for anti-amyloid therapies - and for the amyloid hypothesis.
6- But aducanumab had very little effect on cognition.
In ENGAGE, no sign of benefit relative to placebo.
There was slight benefit w/ high-dose aducanumab in EMERGE, though as @LonSchneiderMD pointed out, this could be due to cognition worsening more in placebo group.
7- There is reason to be skeptical of the hypothesis that reducing amyloid results in improved cognition.
To wit, this systematic review & meta-analysis found very weak correlation between amyloid reduction & improved cognition across 17 MAB studies:
7b - Take another look at this scatter plot. If you throw out the apparent outlier in the bottom left, do you think there would be any correlation between amyloid reduction & cognitive improvement?
8- Back to aducanumab studies.
How representative were the 3000+ subjects wrt race & ethnicity?
Not at all.
That's both a scientific problem (how generalizable are these results or, for that matter, the amyloid hypothesis?) and a problem of health equity (how did this happen?)
9- Then there are side effects, esp amyloid-related imaging abnormalities (ARIA).
31% of aducanumab subjects got ARIA-E (edema), more if higher dose or if apoE e4+.
It's usually mild & reverses w/ discontinuation. But, still, it's brain edema. And it requires MRI monitoring.
9b - 18% of aducanumab subjects got ARIA-H (hemorrhage), with significant overlap with ARIA-E.
Usually asymptomatic. But, again, we will increase the risk of brain bleeding.
We will need to be very mindful of contraindications: being on blood thinner, h/o CNS bleed or stroke.
10- Of course, there's the cost. The drug itself will be $28,000 per year.
But a recent analysis found that aducanumab would need to be < $3000/y to be cost effective.
1- A thread on the value of treating #Alzheimer’s disease w/ monoclonal antibodies:
As I read through the recently published appropriate use guidelines for #lecanemab, I am struck by the infrastructure & resources that will be necessary.
“Yes, Americans eat more calories and lack universal access to health care. But there's also higher child poverty, racial segregation, social isolation, and more. Even the way cities are designed makes access to good food more difficult.”
Interestingly, the US “has higher rates of cancer screening and survival, better control of blood pressure and cholesterol levels, lower stroke mortality, lower rates of current smoking, and higher average household income.”
But it’s not enough to offset the many other factors.
We are honored to welcome Dr. Holly Swartz, Prof of Psychiatry at @PittPsychiatry & Editor-in-Chief of American Journal of Psychotherapy (@APA_Publishing) to @uwsmph@UWHealth Psychiatry Grand Rounds to discuss:
"Psychosocial Interventions for #Bipolar Disorder"
Network meta-analysis indicated that psychotherapy, including CBT, family focused therapy, and interpersonal & social rhythm therapy (IPSRT), are effective interventions for bipolar depression and for prevention of recurrence of bipolar disorder.
Core strategies of bipolar-specific psychotherapies (cognitive therapy, family therapy, interpersonal & social rhythm therapy, psychoeducation & integrated care management):
@LonSchneiderMD 2- Note that the assn. between amyloid reduction & cognition goes in opposite directions in the 2 studies:
"High dose aducanumab was about as cognitively impairing in ENGAGE as it was beneficial in EMERGE [despite] both trials showing similar, substantial reductions in plaque."
3- It's also possible that the slight cognitive improvement found with high-dose aducanumab in EMERGE was due in part to the greater worsening of cognition in the placebo group of EMERGE compared with the placebo group of ENGAGE.