The slight slowing of cognitive decline achieved by Leqembi and perhaps by Aduhelm has revived debate around how much change is needed to be “clinically meaningful.” Two recent papers—one a report from a working group convened by the Alzheimer’s Association, the other from scientists at Roche—and a webinar hosted by the advocacy group UsAgainstAlzheimer’s, dug into this topic.

Scientists from academia, pharmaceutical companies, and healthcare analysis firms reached no consensus on a threshold for meaningfulness, but broadly agreed that meaningfulness should be determined for each patient, rather than based on mean differences between placebo and treated groups, which can wash out individual effects. They also said the effects of disease-modifying treatments, which slow the rate of decline, have to be considered in the context of time, and stressed the need for outcome measures that better reflect what’s most important to the patient.

While AD clinical trials determine, statistically, if a treatment group declines more slowly than the placebo control group, they do not set out to determine the minimum difference that would be noticeable by a patient, caregiver, or physician. That’s a tougher nut to crack. Why is clinical meaningfulness so hard to discern? “Meaningfulness is a multifaceted concept that necessarily involves the individual opinion of physicians, patients, and caregivers,” Nicolas Villain at Sorbonne University in Paris told Alzforum. Todd Golde at the University of Florida, Gainesville, agreed. “I don’t think we have enough data to make firm conclusions. But for the first time we might be able to rigorously assess this in a prospective fashion,” Golde wrote (comments below).

Alzheimer’s researchers have tried before to quantify the least amount of cognitive change that is detectable and meaningful to patients. One oft-cited paper, written by Eli Lilly researchers led by Scott Andrews, found that a 1- to 2-point worsening on the CDR-SB for a given patient was the minimum change associated with a noticeable decrease in that person’s abilities (Andrews et al., 2019). Andrews, now at Takeda Pharmaceuticals in Indianapolis, said this finding has been misapplied to discount the small, yet statistically significant, benefits seen with anti-amyloid immunotherapy, such as the 0.45-point CDR-SB difference between treatment groups in the 18-month lecanemab Phase 3 trial (Dec 2022 conference news).

“It would be inappropriate to apply our analysis by saying you need a 1-point CDR-SB difference between groups. It sets up unrealistic expectations for these emerging therapies,” Andrews said in the webinar. Half a point on the CDR-SB is about the benefit provided by cholinesterase inhibitors that are approved for AD, but they do not alter the rate of decline.

In the December 8 Journal of Prevention of Alzheimer’s Disease, Roche researchers led by Claire Lansdall reached similar conclusions, reporting the minimal meaningful difference as 1.0 to 2.5 points on the CDR-SB. Like Andrews et al., they specified that this applies to within-patient change, not group differences. In addition, in both papers the minimum meaningful difference varied by disease stage, being smaller at earlier stages. This is likely because people who are less impaired are more aware of slight alterations in their abilities.

Meanwhile, in the February 7 Alzheimer’s & Dementia, researchers led by Ron Petersen at the Mayo Clinic in Rochester, Minnesota, reported the findings of the Alzheimer’s Association Clinical Meaningfulness Work Group. They concluded that for a disease-modifying therapy, an 18- or 24-month trial is too short to fully assess its potential benefits. This is because if the slowing of decline remains constant, the numeric benefit would be expected to accrue over time. For example, an average slowing of 0.5 points on the CDR-SB at 18 months would become 1 point by three years.

A majority of researchers contacted by Alzforum concurred with this assessment. “Disease-modifying therapies that improve the disease progression rate must be evaluated considering their potential long-term effects,” said Oskar Hansson at Lund University, Sweden, adding “Most of my patients and their loved ones tell me a 25 to 35 percent slowing of clinical progression is meaningful.” A third less progression would mean that a person who stayed on the drug for three years would be where they would have been at two years without treatment, buying them a year of extra time. Other commentators cautioned that whether the benefit grows remains to be seen, and asked whether unwanted effects such as greater ventricular volume would likewise be projected to grow (comments below).

Key Concerns. This draft model from the What Matters Most study shows the abilities patients and caregivers say they value most. [Courtesy of UsAgainstAlzheimer's AD PACE Initiative.]

In addition, scientists think current scales, such as the CDR-SB, poorly capture the types of change that matter most to patients. The Alzheimer’s Disease Patient and Caregiver Engagement “What Matters Most” study interviewed 60 people at different stages of AD, and their care partners, to learn what skills were most important to them (DiBenedetti et al., 2020). Researchers distilled those responses into a list of 42 cognitive or functional abilities, which fell into categories such as social life, thought processing, daily activities, and independence. Specific items in these categories included continuing to enjoy hobbies, remembering people’s names, managing money, and being able to live alone (see graphic; Hauber et al., 2023).

Next, researchers compared the items to those measured by common cognitive outcomes. Even the outcome measures that overlapped best with the list, such as the ADCS-ADL and CDR-SB, included only 12 of the 42 items. “We need to find a scale to capture more relevant signs [of decline],” Andrews noted in the webinar. “This list is a blueprint to help measurement scientists do that.”—Madolyn Bowman Rogers


  1. My comments here are only in relation to lecanemab. (At least one more large study needs to be done with aducanumab in order for me to believe it is effective and safe). 

    The idea of focusing on an absolute minimum clinical important difference is thinking of this disease-modifying drug as if it were providing symptomatic benefit. You need to think about how this clinical difference will develop over time. Let's focus on activities of daily living in the ADCS-MCI-ADLs. Over 18 months, the average patient in the placebo group declined 5.5 points, whereas the lecanemab group declined 3.5 points. That's a 36 percent difference if I did the math right. And, if these slopes remain linear over the next 18 months, the total decline experienced by the placebo group over 36 months would be 11 points, compared to 7 for lecanemab, a difference of 4 points. According to Figure 2E in the paper, 4 points is the amount of decline experienced in one year. That means that if you are on this drug for three years, your Alzheimer's disease has only progressed for two years. If the MCI stage of AD lasts about three years, and the mild AD stage lasts about three years, there's no reason that you couldn't be on this drug for at least six years. That would produce a delay in decline of your ADLs equivalent to two years of function. Think of the human and economic benefits of keeping people functional for two additional years in these early stages of disease.

  2. The FDA approval of lecanemab and aducanumab both raise issues around what is a meaningful impact on cognitive and functional decline in AD. I don’t think we have enough data to make firm conclusions. But for the first time we might, as a field, be able to rigorously assess this in a prospective fashion with these and likely other emerging immunotherapies, given that the data demonstrates a limited slowing of decline in the trial populations.

    Given that there are many questions and, at this point, few definitive answers, I think the most useful exercise for the field is to think through the key questions and how we might collectively get to definitive answers on an extremely complex issue. With a goal of targeting resources toward answering those question.

    Before I list some questions we need to ask, I would like to give two examples of other therapeutics that are in wide use for other common indications to broaden our perspective on this issue of “What is approvable and what is clinically meaningful?”

    • Statins: The number needed to treat (NNT) to prevent one cardiovascular event over 10 years of high-intensity statin use is about ~25 +/- 5 (Mortensen and Nordestgaard, 2019). Putting this in the context of AD, I wonder, “If we had a drug with a statin-like impact for AD, could we prove it was working?” Cardiovascular events are discrete; cognitive and functional decline in AD are not. Altering cognitive course in one in 25 people over 10 years would probably not be measurable. But few question the clinical utility of statins.
    • Cancer Drugs: The FDA guidance on trial endpoints for cancer drugs and biologics makes for an interesting read. Approval comes down to showing some positive and statistically significant impact on one or more of these measures, which “outweighs” risks associated with the treatment, but often those impacts are pretty modest. Again, disease-free survival, overall survival, complete response, or progression-free survival are easier endpoints to assess in cancer than “cognitive and functional decline” in AD. Indeed, many cancer drugs have been approved with modest overall impacts that are similar to the impacts measured in the AD immunotherapy trials, i.e. ~25 percent on disease progression.

    Another issue is real-world benefit versus that observed in the trials. Trials of GLP1 agonists and combined GLP1/GIP agonists show impressive data with respect to weight loss and impact on many other metabolic measures. However, an initial report on real-world impact suggests that adherence rates over a year are ~50 percent, and only a minority of patients obtain weight loss of greater than 5 percent (Weiss et al., 2022). Again, no one argues that these are not effective drugs for some individuals but, for many reasons, participants who enroll in long-term drug trials may not reflect real-world populations and real-world experience. Even in this case, more data is needed, as this simply reflects one “real-world” study population.

    With that preamble, I consider these questions critical to understanding real-world impacts of lecanemab and aducanumab:

    • Is any clinical impact durable? Does it plateau, and does the relative impact increase over time?
    • Are there “responders”? How do we define a “responder"? In other words, does a subset of individuals treated with these drugs really show marked alterations in decline over extended periods? If so, what is the NNT to find one true responder? 
    • Are there biomarkers, or other factors, present at the time of treatment initiation that better predict clinical response?
    • Will the small benefit observed in the trials hold in a diverse real-world population?

    There are many more, but to my mind, answering these is of paramount importance.

    My broken-record statement: We now can say with reasonable assurance that there is a bit of impact on decline by targeting Aβ in symptomatic disease, but the impact is modest at best. The real test of these therapies will be whether they can have larger impacts on AD in its long prodromal phase. I, and likely many others, think the answer will be yes, but we need the data. Exactly how those studies are conducted will be critical to answering that question.

    Finally, we should rethink the Holy Grail of disease modification in the symptomatic phase of the disease. Patients don’t care about disease modification. They want their symptoms to improve. The field has not abandoned development of symptomatic therapies, but the efforts pale in comparison to the efforts behind disease modification. Reprioritizing development of symptomatic therapies seems like a reasonable approach to ensure that we meet the huge unmet medical need.


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  3. I think there is room for cautious optimism here. Small significant changes in clinical trials for a relatively slowly progressive chronic disease like AD measured in as little as 12 to 18 months could prove to be highly significant over a longer period of time. The caveat is that drugs may have adverse effects that also increase over time. Put another way, if this drug is given to someone with MCI and high risk of progression in their middle age, then (price of treatment notwithstanding) this could mean a very favorable difference in outcome by the time this patient is in their 80s. 

    We would never capture such benefits in a limited clinical trial, and one should thus be optimistic about a drug even with a modest effect like this. Nevertheless, we also don’t have data from such trials about long-term morbidities, including hemorrhage and immune responses. Ultimately the risk/benefit calculus will become clearer over time.

  4. The title of the Alzheimer’s Association’s presser sums it up: “EXPERTS REDEFINE 'CLINICAL MEANINGFULNESS' IN ALZHEIMER’S.” This is straight from the silver linings playbook. If you don’t like an outcome, then change the game plan, make up a rule, and blame the refs for the lousy call. If all else fails, then move the goal posts, kick a field goal, and declare victory. 

    The select group grudgingly acknowledges that the statistically significant, −0.45 CDR-SB effect with lecanemab at 18 months is very small and not an MCID. Yet they project or predict that the difference will enlarge over time, become a clinically important difference, and patients will benefit. The new mantra for disappointing and questionable clinical trial effects seems to be, “small now is big later.”

    "Small-effect-now-means-large-effect-in-the-future" is a prayer based on pretending that clinical worsening on placebo as measured by the CDR-SB is flat-out linear, that any therapeutic effect, no matter how small, is predictable, relentless, will get bigger tomorrow, and won’t poop out as so many medicines do. Optimism is good but not if it hurts others.

    The Alzheimer’s Association experts redefine the -0.45, 95 percent CI (-0.67 to -0.23) CDR-SB difference at 18 months as being 27 percent better than placebo and say this relative difference will only get bigger and better. This begs the question how the experts would parse the unwanted outcomes in the trial? Would they say that the 35 percent relative increase in ventricular volume and the 27 percent relative decrease in brain volume with lecanemab project to inexorably greater hydrocephalus and atrophy with lecanemab? Do they consider this a good thing, or something to ignore? 

    The expert committee quips that you can’t expect clinically meaningful change from a "disease-modifying" treatment within 18 months. Yet, the antibody trials are precisely designed with the sample size to detect the very small effects of −0.5 or even smaller −0.373. Why would we design trials this way if we didn’t want and predict these results in the first place? Despite the group’s nihilism that −0.50 is as good as it gets, it’s likely that we could see −1.0 CDR-SB mean effects if we were to keep pressing this trial design or test just slightly more effective treatments. We’ve seen a −1.0 lever of effect in the aducanumab and lecanemab subset analyses, among the oldest patients, those with AD dementia, men, APOE4 noncarriers, and Spanish and Japanese cohorts of the trials. 

    The reality is that with the types of preclinical and mild AD groups selected, the doses given, the adverse events and dropouts, the functional unblinding, likelihood for biases, limitations in study conduct, that the outcomes are what they are, a -0.45 CDR-SB and 1.44 ADAS-cog14 statistically significant difference. Eisai got what it planned for, what it expected. Rather than try to spin this big and unreal, we might try to make the best of it without claiming effects for which we have no data.

    The FDA will give lecanemab regular approval because it likely meets their “substantial evidence” criteria. They don’t regulate the practice of medicine, however, and CMS will likely provide coverage with evidence development. We should be able to live and work with this pending more effective treatments. Maybe the more effective treatment will be donanemab or solanezumab, as they each showed −0.36 and −0.34 CDR-SB effects in prior studies, essentially the same as lecanemab and aducanumab.

    If we wanted to extract more specific clinical meaning from the CDR-SB, then we would do a proper deconstruction to determine what an MCID is for each permutation of an allowable CDR-SB baseline score between 0.5 and 7.5. This would be 1 point for CDR-globals of 1, who have CDR-SB from 4.0 and 7.5, and from 0.5 to 2 for CDR-globals of 0.5, depending on baseline domain scores. This could allow us to count and directly compare the individual patients who decline, obviating the need to make inferences about mean differences.

  5. Beyond establishing that a drug has a statistically significant benefit compared to placebo, it is vital that new treatments for Alzheimer’s disease impact on outcomes that are clinically relevant for patients. While thresholds for determining the benefits of symptomatic therapies in patients with dementia are relatively well established, the situation becomes more complex as we move toward trials of disease-modifying drugs. With DMDs, benefits may be delayed and accrue over time. As we intervene earlier in the disease course, when cognitive decline may be slower, DMD benefits are more variable, hence more difficult to measure reliably. An extreme example is the scenario when at-risk, cognitively normal individuals are treated with DMDs. In the absence of any symptoms or measurable cognitive decline, it would not be appropriate to determine efficacy based on, say, relatively short-term decline on the CDR or ADAS-Cog.

    It follows that determining what represents a clinically meaningful benefit will depend on the stage of the disease, and may need to account for the proposed mechanism of drug action. By analogy, short-term fever reduction might be an appropriate outcome measure for a symptomatic trial of acetaminophen in pneumonia, but the same measure might well miss the very real disease-modifying effect of an antibiotic which will impact on survival in the longer term.

    Innovative trial designs (staggered starts, run-in designs), newer and more sensitive (e.g., digital, home-based) technologies providing more “real world” outcome measures may help, but ultimately longer-term follow-up of treated individuals will be vital to establish outcomes. In the meantime, it is important that by rigidly applying thresholds that may be appropriate in some scenarios, we do not dismiss the potential effects of drugs that may have significant impact in the longer term.

  6. Lecanemab achieved a statistically significant result on its primary outcome, its secondary outcomes, and many of the biomarkers. To me, this result appropriately deserves a discussion of clinical meaningfulness.

    The group-wise 27 percent reduction in decline on the CDR sum of boxes with lecanemab versus placebo over 18 months is an encouraging finding, but it is clearly modest. What we really need to know is whether the benefit attenuates or amplifies after three years or four years, not just 1.5 years (relative to a hypothetical untreated group). Only long-term, active-treatment extension studies will address this question.

    The existing data from open-label extensions from aducanumab Phase 3 and lecanemab Phase 2 are complicated to interpret, but they show that the treatment benefit persists but clinical decline proceeds without augmentation or attenuation compared to the trajectory of the previously untreated groups.

    There is no one number at 18 months that captures clinical meaningfulness.

  7. The many complex issues with “clinical meaningfulness” are well discussed in this paper. It’s also important and timely that the Alzheimer’s Association Clinical Meaningfulness Work Group has written this down and opens the discussion for the broader AD field on this topic.

    AD is a complex brain disease, which makes it very hard to unravel and treat. And with the current upcoming DMT we are not finished. We will need personalized combination therapies for all neurodegenerative disorders based on biomarkers and genetic phenotypes. This will probably generate better results for the future patients in our clinics.

    Furthermore, the AD field is moving more to a biomarker-defined brain disease, with an asymptomatic stage that’s longer than the symptomatic stage. We need strong surrogate biomarkers, which will accelerate the development of treatments, making the discussion of “what is clinical meaningfulness” easier, and helping the field reach consensus on when to approve and start treatment.

    Also, the clinical trials we conduct are as good as their outcome measures. For future clinical trials including symptomatic patients, we need better outcomes measures for cognition and function, like composite scores such as the Cognitive-Functional Composite (CFC) by Jutten et al., 2020. Function will relate much more to what patients find meaningful than cognition by itself. 

    If we zoom out, in general medicine, any intervention that can modify a disease 20 to 30 percent in the right direction is fully accepted as meaningful. For example, in oncology, if you can delay a later stage of a disease by six months or longer, the treatment is given. The 27 percent achieved in the lecanemab study on the CDR must be seen in this context. Delaying institutionalization, or care in general, is meaningful by any standard, and this is something we have never achieved before in this field.

    In our opinion, in the current and exciting state of the AD field, this is the best we can get in treating AD.


    . The Cognitive-Functional Composite is sensitive to clinical progression in early dementia: Longitudinal findings from the Catch-Cog study cohort. Alzheimers Dement (N Y). 2020;6(1):e12020. Epub 2020 Apr 17 PubMed.

  8. For me, "clinically meaningful" benefit has nothing to do with the numbers on tests, but rather the experience of the patients and caregivers living with the disease. If a loved one asks the same question twice instead of seven times in an hour, if someone can continue to use the toilet or take a shower without help for longer, if they can be safely left home alone for longer than they would have without the medication—these are the types of things that are meaningful in the clinical setting. Obviously for research purposes this needs to be quantified, and usually the CDR is the standard tool for this. But at the end of the day, it is not so much the CDR scores as it is the functions that inform them that really matter.

  9. Defining clinical meaningfulness is challenging. Meaningfulness is a multifaceted concept that necessarily involves the individual opinions of physicians, patients, and caregivers. Acknowledging this makes any quantifiable definition of clinical meaningfulness, not to mention a threshold for meaningfulness, impossible.

    First, what is the magnitude of the effect of lecanemab on clinical outcomes? The primary outcome, CDR-SB, is an 18-point hybrid functional/cognitive scale of dementia severity (zero being the absence of cognitive disorder, 18 being the most advanced stage of dementia) with a particular weighting for memory impairment and its consequences. The CDR scale allows the calculation of two scores: the global score, which allows classification in five stages of a neurocognitive disorder (CDR 0: no disorder; CDR 0.5: mild/uncertain neurocognitive disorder; CDR 1: major neurocognitive disorder at a mild stage; CDR 2: major neurocognitive disorder at a moderate stage; CDR 3: major neurocognitive disorder at a severe stage), and the "sum of boxes" which gives a score from zero to 18 including half points.

    Equivalences between the overall score and SB were established as follows: CDR 0: CDR-SB = 0; CDR 0.5: CDR-SB = 0.5-4; CDR 1: CDR-SB = 4.5-9; CDR 2: CDR-SB = 9.5-15.5; CDR 3: CDR-SB = 16-18 (O’Bryant et al., 2010). Patients in the Clarity-AD trial had an average baseline CDR-SB of ~3.2 points. At the end of the 18-month trial, the placebo group had reached an average of ~4.85 points on the CDR-SB and the treatment group, ~4.40 points (i.e., a 0.45 pts – 27 percent difference). Approximately 32 percent (placebo) versus ~24 percent (lecanemab) of individuals progressed to the next stage of disease by global CDR during the 18-month follow-up.

    Regarding the other outcomes, especially the functional outcomes that were underlined as the most relevant when referring to meaningfulness (American Academy of Neurology, 2023), activities of daily living were assessed as a secondary outcome in the Clarity AD trial using the ADCS MCI-ADL, a 53-point scale. The baseline values were ~41 in both groups, reaching ~37.5 points and ~35.5 points at the end of the trial (i.e., a 2 pts – 37 percent difference). Mean values were previously reported to be ~40 points in MCI individuals and ~18 points in demented individuals (Pedrosa et al., 2010). 

    At CTAD, results on scales assessing the quality of life were also disclosed, without providing baseline values. An ~3.5 pts (lecanemab) versus ~5.8 pts (placebo) evolution was observed during the 18-month follow-up on the 88-point Zarit Burden Interview scale (38 percent difference). A ~2 pts (lecanemab) versus ~4 pts (placebo) evolution during the 18-month follow-up was observed on the patient 100-point EQ-5D-5L scale (49 percent difference). A ~0.5 pts (lecanemab) versus ~1.2 pts (placebo) evolution during the 18-month follow-up was observed on the patient 45-point QOL-AD scale (56 percent difference), and a ~1.8 pts (lecanemab) versus ~2.35 pts (placebo) evolution during the 18-month follow-up was observed on the proxy 45-point QOL-AD scale (23 percent difference). As a whole, the absolute effect of lecanemab after 18 months impacts ~1.2 percent to 3.7 percent of the total disease course, as measured on these scales (23 to 56 percent of the parallel 18-month placebo group evolution).

    AD is a slow, long-lasting, exponentially worsening, incapacitating disease considered a major public health issue. These trials’ designs were optimized to evidence an effect of these drugs. Even so, they provide limited insight into the drug’s effectiveness in relation to the overall disease course (the 18-month placebo group evolution corresponded to ~4.0 to 10.3 percent of the total disease course as measured on the previously cited scales) and its long-term impact (loss of autonomy, need for institutionalization, etc.). As a matter of fact, the time to severe AD dementia is, on average, 7-17 years in this early AD population (Vermunt et al., 2019). 

    To overcome these limitations, pharmaceutical companies tried to establish minimal clinically important differences (MCIDs): i.e., within-subject differences corresponding to a meaningful evolution as judged by a specialized physician. Despite different methods and datasets, these values were consistently set to 1 to 2 points on CDR-SB (Lansdall et al., 2022; Andrews et al., 2019). The absolute difference between the lecanemab and placebo groups in Clarity-AD was well below these MCIDs (0.45 pts). Nevertheless, any drug will struggle to reach these values in an 18-month trial with early AD patients: reaching these MCIDs would mean almost stopping the natural disease course of AD (the mean placebo group 18-month evolution was 1.50 to 1.74 pts in aducanumab, lecanemab, and donanemab Phase 2 and 3 trials (Budd Haeberlein et al., 2022; Mintun et al., 2021; Swanson et al., 2021; van Dyck et al., 2022). 

    What about previously approved drugs? A meta-analysis of the effect of donepezil on mild to moderate AD patients (diagnosed without the use of biomarkers) in six-month trials evidenced a 0.53 points difference in the CDR-SB between groups (Birks and Harvey, 2018). 

    Overall, the 18-month lecanemab data provided so far do not demonstrate an important impact on the global disease course, do not reach the MCIDs, nor outperform the previously established effect of AChEIs. Mead and Fox (2023) underlined recently that “the key questions are whether slowing can be sustained and whether clinical benefits are cumulative.” Beliefs and hope of increasing benefits over time due to disease modification accompany the optimists’ arguments (Petersen et al., 2023Treating Alzheimer’s: A New Era Begins with Lecanemab, 2023). Skeptics balance these benefits with side effects: ARIA, which can be severe, and uncertainty regarding the enduring and cumulative clinical benefits (Villain et al., 2022; Walsh et al., 2022). 

    Beyond these debates and opinions, most specialists agree that these drugs are unlikely to work in the later stages of AD, tempering hopes regarding the cumulative clinical benefits over time (van Dyck, 2018). Postmortem observations of brains with high Aβ clearance following the anti-amyloid AN1792 vaccine but exhibiting late-stage dementia, tauopathy, and neurodegeneration could support this belief (Nicoll et al., 2019). Is the maximum effect of lecanemab in the global AD course a 0.45 pts difference on an 18-point scale of dementia severity or a 27 percent difference? That is the (crucial and unsolved) question.


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  10. I believe the results of lecanemab truly represent a change of paradigm. In a broad sense, a significant change in a clinical endpoint in an 18-month trial is quite surprising, given that the AD pathological process can span more than 30 years, and that we know that other comorbid pathologies also contribute to the clinical syndrome.

    We need more positive trials to fully understand the true effects of anti-amyloid therapies. It will be also key to wait for the long-term data to determine whether there is any cumulative benefit. Given the effect of anti-amyloid antibodies on tau pathology, it would be reasonable to expect an effect on multiple downstream factors that amplify the clinical benefit over time.

  11. Personally, I fully agree with the paper by Petersen et al., which I think is well written. It is very important to distinguish between interventions with only symptomatic effects and those that actually change the rate of clinical deterioration over time.

    For symptomatic therapies, it is very relevant to discuss what should be regarded as a meaningful change in the short-term perspective (e.g., an improvement of 1 to 2 points on CDR-SB over six months). In contrast, disease-modifying therapies that improve the disease progression rate must be evaluated considering their potential long-term effects. I think an intervention that has clear disease-modifying properties (as measured with relevant biomarkers) and exhibits a 25 to 35 percent slowing of clinical progression (as measured with both different cognitive tests and functional scales) should definitely be regarded as meaningful. That is also what most of my patients and their loved ones tell me.

    However, the beneficial effects of an intervention must also be discussed in light of its potential side effects, and the costs for society as a whole.

  12. I am sharing the following comments in my capacity as a clinical neuropsychologist and health disparities researcher. It is challenging to agree on an overarching definition of what makes a certain outcome “clinically meaningful,” as evidenced by a lack of consensus among existing studies on the topic. In clinical practice, a change is typically considered clinically meaningful based on a clinician’s assessment of current cognitive, behavioral, and functional status in relation to a previously established individual baseline. Estimation of clinically meaningful change in clinical practices also typically incorporates a person-centered approach and reflects needs, values, and expectations of patients and families.

    Several research studies reported on cutoffs for individual instruments that signify the minimal clinically important difference, e.g., CDR Sum of Boxes. However, application of these findings in real-life clinical practice is limited by high variability in clinical assessment measures used across settings and poor representativeness of research cohorts with regard to demographic characteristics and prevalent medical comorbidities in general population.

    The stage of the disease should certainly be considered in defining clinically relevant outcomes for an individual patient. For example, in earlier stages, clinical meaningfulness is likely best described as delaying or slowing down the progression of cognitive and functional changes, whereas in later stages successful management of symptoms and sustained independence can hold more significance.

    There are several important gaps that I believe need to be addressed to facilitate consensus on this topic in the field: 1) identification of a minimal set of sensitive, reliable, and efficient outcome measures (subjective and objective) that can be readily harmonized across research and clinical settings, 2) establishment of psychometric and ecological validity of outcome measures in racially/ethnically, linguistically, and socioeconomically diverse populations, and 3) development of harmonized guidelines on gold-standard methodological and analytical approaches for studies on longitudinal clinical outcomes across disease stages.

  13. Determining the best test to assess a clinically relevant benefit, and determining what counts as meaningful change, are difficult issues to agree on. An obvious consideration here is that cognitive test scores—global, functional, and specific domains—are highly related to one another. This means that a therapeutic benefit becomes more compelling when it is seen across multiple tests. Seeing a consistent effect across multiple tests, as has been seen with lecanemab, may give us more confidence about the cognitive benefit of a treatment than a successful result on a particular “best” test.

    However, the question of how beneficial cognitive effects of a treatment translate to clinically meaningful change is an empirical question. Clinically meaningful change should be assessed longitudinally, ideally past the length of the trial to the extent it is possible, since change over time is what is meaningful to individuals and their families.

    Petersen et al. make the critical point that the cognitive benefit seen in 12- or 18-month trials may be just the tip of the iceberg because of the relatively slow time course of cognitive changes in relation to pathophysiological change. So a small cognitive benefit with questionable clinical relevance may result into a much more significant effect in the years following treatment. This is especially true for individuals who are treated early in the course of disease, when the effects of pathology on cognition are difficult to detect. Following trial participants past the length of a usual trial will be critical for determining whether a treatment results in clinically relevant benefits.


  14. The recent publication by Petersen et. al., of which I am a co-author, represents an advance in the field regarding how we might interpret clinical trial results in patients with early AD (MCI and mild dementia due to AD). Some previous publications have assessed clinical meaningfulness determined by point differences alone, but this current paper adds a second variable, time, which is important in the assessment of disease-modifying treatments. For instance, the CDR-SB declines by approximately one point per year in patients with early AD, but obviously the point difference in decline would be less at six months and greater at two years.

    With a disease-modifying treatment, with slowing of disease progression, the expectation is that the difference between the treatment and placebo will increase over time, so the point difference will vary with the timepoint. Over the time period of most clinical trials, 18-24 months for early AD patients studied using investigational disease-modifying treatments, decline is roughly linear. Thus, the percent slowing will be generally the same at each time point, even though the point difference is not. This growing effect over time has been seen in the Clarity Phase 3 study of lecanemab (van Dyke et al., 2022), and other previous studies of solanezumab given to patients with mild dementia (Siemers et al., 2015Honig et al., 2018) for several outcome measures. 

    While point differences on various scales will continue to be discussed with regard to clinical meaningfulness, Petersen et al. emphasize that such point differences compared to placebo can change with a disease-modifying therapy, and thus time becomes an important variable to be considered.


    . Expectations and clinical meaningfulness of randomized controlled trials. Alzheimers Dement. 2023 Jun;19(6):2730-2736. Epub 2023 Feb 7 PubMed.

    . Lecanemab in Early Alzheimer's Disease. N Engl J Med. 2023 Jan 5;388(1):9-21. Epub 2022 Nov 29 PubMed.

    . Phase 3 solanezumab trials: Secondary outcomes in mild Alzheimer's disease patients. Alzheimers Dement. 2015 Aug 1; PubMed.

    . Trial of Solanezumab for Mild Dementia Due to Alzheimer's Disease. N Engl J Med. 2018 Jan 25;378(4):321-330. PubMed.

  15. At the end of the day, what is significant for an M.D. is what is significant for the patient/family. With AD, patients themselves are often unaware of their deficit and therefore unconcerned about it. Thus, the relatives are the primary gauge of clinical meaningfulness. With a progressive disease that leads to death, like AD, what the family wants is to know that they are doing all they can to help their loved one. Thus, in my opinion, any benefit is clinically significant, so long as it is real. For this reason, people would want their relative on the medication, even if the likelihood of any effect is questionable or null.

    The real problem is going to be overuse. Physicians need to be educated to articulate clearly that this is not a medication for Alzheimer’s, but a medication that lowers brain amyloid. Reducing brain amyloid seems to help to some degree, but only at the very early stages of the disease. I do subscribe to the existence of an “amyloid-dependent” stage, very early in the AD process, and an “amyloid-independent” stage later on, when reducing amyloid does nothing.

  16. There is no absolute answer to this. What constitutes a minimally significant clinical difference will inherently vary by the patient’s environment and how they interact with it; also by their baseline abilities as well as who the observer is and which domains they are interested in and their expectations. In the end, you can draw a consensus line but the answer will be different by the observer group—patients, family members, physicians.

  17. Defining a minimal clinically important difference is like defining a minimum financially important pay raise. Any detectable difference is meaningful. Whether the clinical benefit offsets the burden of receiving lecanemab is a decision for individuals and their doctors. Whether the clinical benefit offsets the price is a decision for payers. But debating the numerator (clinical difference) without considering a denominator (burden, price) is meaningless.

    Defining a minimum clinically important difference is also like defining a minimal important gain of yardage in American football. Any gain is meaningful. Improving the lives of patients with Alzheimer disease, like football, is a game of inches.

  18. If you take animal models seriously, then there is no reason to buy into the small now, bigger later mantra. The β-amyloid mouse models respond to antibodies with virtually instant relaxation of functional deficits, without affecting brain atrophy because there is none to begin with. The functional deficits may be sensationally large in these models because the pathology is exaggerated relative to native AD, but there is no reason to expect a different type of effect in humans on a smaller scale.

    The nature of this effect points to antibodies impacting a dynamic equilibrium, not a progressive process. The most plausible structural correlate for this is the highly reversible undermining of synaptic viability by β-amyloid peptides. Because the dissolution of existing plaques in humans takes months, the clinical effect may look like progression modification for a while, but isn't. I suspect we will come to this realization down the road. That will be a nice validation of what animal models really tell us if we are inclined to listen.

    The only unknown here is how the impact of antibodies on synaptic turnover affects the prion-type transmission of tauopathy through synaptic shedding. We know from pure tauopathies that tau can do this on its own with a dynamics essentially indistinguishable from AD. So, there is more reason to temper the fumes of hope put forward by vested interests than to fan the flames.

  19. The clinical meaningfulness for any approved drug should demonstrate sustained benefits on defined parameters that improve a patient’s quality of life. I find the analogy of gaining yards in American football very apt; however, I would disagree that “Any gain is meaningful,” as this does not take into consideration transient gains that are not sustained over time. American football teams have four chances (downs) to make a 10-yard gain, before possession switches to the opponent team.

    Current AD treatments that fail to confer sustained cognitive benefit are like a football team that ultimately fall short of the 10-yard gain needed to battle forward. Unlike transmissible diseases or cancer, where effective treatments can overcome the pathogenic opponent, effective treatments for neurodegenerative diseases like AD and PD need to pre-empt the overpowering forces of late-stage pathologies (plaques, tangles and neuroinflammation), by tackling early pathogenic changes that arise in the prodromal phase of the disease.

  20. Curative treatments with low side effects are the most meaningful, gold-standard example being penicillin, etc. The best treatments in history improve the patient from their current condition, increasing their health from a baseline level. Slowing progression is more akin to a preventative/non-curative therapy. Debatably, this is what the AD field is currently going for. Say you can give someone 10 years instead of five years. This is also important in cancer.

    Remember that we all have limited time to optimize health over the course of a life, so earlier non-medical prevention should be a key factor to consider. Perhaps more focus should be given at the mid-life, e.g., 30 to 55 years old, stages of the disease, where there are no symptoms, but brain health could be optimized through exercise, good immunological health, vascular health, diet and sleep. Sadly, after working in the field for several years on immunotherapy, I don't think AD can be cured with a pill or injection akin to bacterial infection or autoimmune disease treatment. I could be wrong, feel free to rebut.

  21. From a drug development point of view, the lecanemab results are clearly promising. But this antibody focuses on neutralizing Aβ's cytotoxicity. It cannot alter the pro-inflammatory state of the patient, nor maintain the needed immune homeostasis, all required to stop neuroinflammation damage.

    Also, Aβ oligomers are toxic at the nanomolar scale, thus one issue is: What is the affinity of this antibody? Can it neutralize them at this scale? In my opinion is simplistic to expect a full effect in a disease that most agree is multifactorial.

    Yet, lecanemab is better than nothing, if you can afford it. More important, it shows that we are dealing with a critical therapeutic target, that is not plaque. The latter are likely a protection mechanism against Alzheimer's.

  22. There are two methodological pitfalls to avoid in this conversation on minimally important difference. One is the conflation of mean between-group differences with within-individual differences. The other is anchoring MCID on clinicians' impressions rather than patients'. This comment focuses on the latter.

    The definition of MCID begins as "the smallest difference in score in the domain of interest which patients perceive as beneficial." Patients are central. Both Andrews et al. and Landsman et al. anchored their assessments on a clinician impression, a limitation which both noted, but which is so foundational that one must question the use of the term MCID. Indeed, the lead author on the paper that introduced the term “minimal clinically important difference” told our webinar audience that he later recommended a move away from that term and toward “minimally important difference,” as the original concept’s use of “clinically” was being misinterpreted as elevating clinicians’ judgments.

    Our work, both qualitative and quantitative, has asked patients what matters to them. While we did not set out to determine an MCID, we can bring some evidence to bear on that discussion. We consistently found when we asked patients at the early stages of the disease an open-ended question about what they would want from a treatment, they mentioned “stop progression” at the same rate as “restore or improve memory,” and “slow progression” is next in frequency. As one patient living with mild AD told us, “Just if it can’t cure it, just kind of stop the progression of it. Just, like, leave it where it is” (DiBenedetti et al). This suggests a time-to-event analysis of progression to the next stage of the disease as generally meaningful to patients.

    Patients might assess progression differently than clinicians. We know that the CDR-SB is not a comprehensive measure of what is important to patients. While our most-recent work found that CDR-SB does capture quite well 12 of the concepts that matter to patients, the ADCS-ADL-MCI captures well 14 patient-important concepts. With 42 concepts that matter at least moderately to patients, to focus exclusively on any one endpoint is to ignore the complexity of the disease from the patient’s perspective.


    . Disease severity and minimal clinically important differences in clinical outcome assessments for Alzheimer's disease clinical trials. Alzheimers Dement (N Y). 2019;5:354-363. Epub 2019 Aug 2 PubMed.

    . Establishing Clinically Meaningful Change on Outcome Assessments Frequently Used in Trials of Mild Cognitive Impairment Due to Alzheimer's Disease. J Prev Alzheimers Dis. 2023;10(1):9-18. PubMed.

    . Assessing what matters most to patients with or at risk for Alzheimer's and care partners: a qualitative study evaluating symptoms, impacts, and outcomes. Alzheimers Res Ther. 2020 Jul 30;12(1):90. PubMed.

    . Assessing What Matters to People Affected by Alzheimer's Disease: A Quantitative Analysis. Neurol Ther. 2023 Apr;12(2):505-527. Epub 2023 Feb 10 PubMed.

    . Technical Review of Clinical Outcomes Assessments Across the Continuum of Alzheimer's Disease. Neurol Ther. 2023 Apr;12(2):571-595. Epub 2023 Feb 15 PubMed.

  23. In van Dyck et al. 2023, the lecanemab-treated group's mean score on the primary endpoint, the CDR sum of the boxes, declined by 1.21 points over 76 weeks while the placebo group declined by 1.66 points. That test consists of subjective ratings in six domains of daily functioning: memory, orientation, judgment and problem solving, community affairs, home and hobbies, personal care. Each domain is rated on this five-point scale of functioning: 0 = no impairment; 0.5 = questionable impairment; 1 = mild impairment; 2 = moderate impairment; and 3 = severe impairment. This means a difference of 0.45 points equates to less than a rating of "questionable" in one of six domains, yet it was reported as significant at a p value of 0.001, (i.e., a one in 1,000 chance that it could have occurred by chance).

    How can such a small, subjectively-rated effect be present at such a high statistical value? It suggests that there was a recurrent source of bias, something about the patients that was not a clear clinical difference but something the assessors noted, possibly subconsciously. Given that lecanemab caused “infusion-related reactions in 26.4 percent of the participants (van Dyck et al., 2023) and that the reaction probably convinced patients that they were not given a placebo, it is quite possible that they would have been more optimistic than the placebo group, and that would have affected the way they interacted with the assessor. Another possibility is that the "amyloid-related imaging abnormalities with edema or effusions in 12.6 percent of the population" were accompanied by subtle clinical signs such as headaches that the CDR assessors were aware of and thought they meant the patient had not been given a placebo. If so, it would have subtly influenced them to rate the patients differently.

    This result means that despite the success of clearing some amyloid from the brain, the clinical effect was so small as to be negligible notwithstanding its statistical validity. This appears to be a logical outcome from the mode of action of all these antibody treatments, since simply removing the product of a stressed metabolism does not have any corrective effect on the fundamental fault.


    . Lecanemab in Early Alzheimer's Disease. N Engl J Med. 2023 Jan 5;388(1):9-21. Epub 2022 Nov 29 PubMed.

  24. Despite the high likelihood that the new FDA-approved AD treatment, Lequembi, may only benefit a select group of patients, we agree that it is a timely and positive step in the right direction. We need to understand how much amyloid immunotherapy will help patients in real-world settings. Moreover, we concur with Farlow and others that the net benefit would vary among patients, and that both patients and caregivers need to know the meaning of "statistically significant change in clinical scores" under actual life situations, e.g., recalling several fruits' names versus a specific executive task.

    All roads point toward the need for further research on the drug. Borrowing the analogy from clinical scale improvements, we wonder how many neurons and synapses are protected by Leqembi treatments. Could it protect against oxidative stress, one of the major hallmarks of AD?

    Research is a two-way process: bench to bed and bed to bench, which, in turn, connects the dots from cells (e.g., neurons) and tissues to the human body. What Leqembi does remains to be fully explored. To enhance our understanding, we need to know the drug's effect at the cellular and neurobiological levels. In this context, mechanisms of immunoglobulin therapies are beginning to emerge (Counts and Lahiri, 2014Galeotti et al., 2016;  Lünemann et al., 2015). 

    It is also relevant to point out previous studies with a different class of immunotherapy at the cellular level. For example, we have reported that treatment with intravenous immunoglobulin using blood-derived antibodies (IVIG, specifically Gammagard) exerts antioxidant and neuropreservatory effects (Counts et al., 2014). Gammagard also reduces tau pathology and promotes expression of plasticity-related markers in preclinical models of AD (Counts et al., 2014). Further, we have shown that the same IVIG treatment preserves primary rat hippocampal neurons and protects primary human brain (PHB) cultures against oxidative insults (Lahiri and Ray, 2014). Such studies are essential as oxidative stress and neuroinflammation are believed to be triggers for AD pathology. A quantitative assessment of IVIG at the neuronal level may at least inform whether these drugs are clinically meaningful. We also tested rivastigmine in PHB cultures and observed non-amyloidogenic properties (Ray et al., 2020) that may be combined with IVIG to have better efficacy than either treatment alone.

    Preclinical insights into the cellular and biochemical roles of IVIG, or similar drugs, beyond that of providing endogenous amyloid antibodies may help us better understand the timing and dosing of the present drug, spur future innovations, and help prioritize pathways for polypharmacological, personalized treatment approaches, including with existing drugs.


    . Overview of immunotherapy in Alzheimer's disease (AD) and mechanisms of IVIG neuroprotection in preclinical models of AD. Curr Alzheimer Res. 2014;11(7):623-5. PubMed.

    . Intravenous immunoglobulin (IVIG) treatment exerts antioxidant and neuropreservatory effects in preclinical models of Alzheimer's disease. J Clin Immunol. 2014 Jul;34 Suppl 1:S80-5. Epub 2014 Apr 24 PubMed.

    . Intravenous immunoglobulin reduces tau pathology and preserves neuroplastic gene expression in the 3xTg mouse model of Alzheimer's disease. Curr Alzheimer Res. 2014;11(7):655-63. PubMed.

    . Heme oxygenase-1 is dispensable for the anti-inflammatory activity of intravenous immunoglobulin. Sci Rep. 2016 Jan 22;6:19592. PubMed.

    . Intravenous immunoglobulin in neurology--mode of action and clinical efficacy. Nat Rev Neurol. 2015 Feb;11(2):80-9. Epub 2015 Jan 6 PubMed.

    . Intravenous immunoglobulin treatment preserves and protects primary rat hippocampal neurons and primary human brain cultures against oxidative insults. Curr Alzheimer Res. 2014;11(7):645-54. PubMed.

    . Rivastigmine modifies the α-secretase pathway and potentially early Alzheimer's disease. Transl Psychiatry. 2020 Feb 3;10(1):47. PubMed.

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Therapeutics Citations

  1. Leqembi
  2. Aduhelm

News Citations

  1. Dare We Say Consensus Achieved: Lecanemab Slows the Disease

Paper Citations

  1. . Disease severity and minimal clinically important differences in clinical outcome assessments for Alzheimer's disease clinical trials. Alzheimers Dement (N Y). 2019;5:354-363. Epub 2019 Aug 2 PubMed.
  2. . Assessing what matters most to patients with or at risk for Alzheimer's and care partners: a qualitative study evaluating symptoms, impacts, and outcomes. Alzheimers Res Ther. 2020 Jul 30;12(1):90. PubMed.
  3. . Assessing What Matters to People Affected by Alzheimer's Disease: A Quantitative Analysis. Neurol Ther. 2023 Apr;12(2):505-527. Epub 2023 Feb 10 PubMed.

Further Reading

Primary Papers

  1. . Editorial: Usefulness of Anchor Based Methods for Determining Clinically Meaningful Change in MCI due to AD. J Prev Alzheimers Dis. 2023;10(1):7-8. PubMed.
  2. . Editorial: Change on Clinical Trial Outcome Assessments: The Search for Meaningfulness. J Prev Alzheimers Dis. 2023;10(1):5-6. PubMed.
  3. . Expectations and clinical meaningfulness of randomized controlled trials. Alzheimers Dement. 2023 Jun;19(6):2730-2736. Epub 2023 Feb 7 PubMed.
  4. . Establishing Clinically Meaningful Change on Outcome Assessments Frequently Used in Trials of Mild Cognitive Impairment Due to Alzheimer's Disease. J Prev Alzheimers Dis. 2023;10(1):9-18. PubMed.