Ten years ago to the month, AlzGadfly’s Op-Ed was published in the Seattle Times, decrying the lack of progress in clinical, bedside dementia therapeutics. The contrast was stark when compared to cancer or even HIV/AIDS.  Alzheimer’s Dementia [AD]  researchers then described a 99.6% failure rate of their “drug pipeline,” which included anti-amyloid antibodies. But just this month, ten years later…two papers may provide some substantiation of hope (for early patients).  However the big headliner/social media star, semaglutide, was disappointing. [most edits after first posting in square brackets]

The company that makes donanemab had posters at the CTAD [Clinical Trials on AD] 2025 meeting this month, and provided a link to an online preprint.  [Open Access]. They make summary statements in the online proof:

  • “Donanemab-treated participants with early symptomatic Alzheimer’s disease demonstrated increasing clinical benefits over 3 years
  • Similar clinical benefits were observed in early-start participants who completed treatment course within 1 year (based on reduced amyloid plaque levels)
  • Reaccumulation of amyloid plaque was slow and comparable to the natural history of the disease
  • No new safety signals compared to the established profile of donanemab”

“Fig. 2. Clinical efficacy measured by change from baseline in the CDR-SB score. Efficacy was measured by change from baseline in the CDR-SB score versus the external weighted ADNI control cohort for participants in the (a) early-start group…”

The “ADNI” cohort are non-concurrent “historical control” patients.  [The curves of subjects’ performance] shows worsening over time, but the authors make statements about clinically meaningful efficacy in their discussion.

The text about the safety: “Safety data from the LTE [long term extension] period are shown in Table 1. The incidences of death, serious AEs, [adverse events] and TEAEs [treatment emergent adverse event] in delayed-start participants who received at least one infusion during the LTE were 1.1 %, 19.6 %, and 86.5 %, respectively. Two deaths during the LTE period were previously reported [13]; one was due to ARIA-E [amyloid related imaging abnormality-edema], and one was due to intracranial hemorrhage. The death due to intracranial hemorrhage occurred following thrombolytic administration in a participant where an MRI scan on the same day showed severe ARIA-E. The frequencies of infusion-related reaction (IRR), ARIA-E, and ARIA-microhemorrhages and hemosiderin deposits (ARIA-H) in the delayed-start group were 7.5 %, 26.0 %, and 39.7 %, respectively, during the LTE period. The event frequencies and overall safety profile of this group are comparable to the previously reported data for donanemab-treated participants during the placebo-controlled period [2].”

Researchers in the lecanemab Clarity AD trial (early AD, 18 months data) reported in the follow-up that the improvement [Open Access] over placebo was maintained. From the authors’ abstract “highlights:”

  • …”Overall, the results show participants continue to accrue a lecanemab treatment benefit up to 36 months and highlight the importance of continued long-term lecanemab treatment.
  • Results presented in our paper demonstrate that lecanemab continued suppression of amyloid plaque levels and significantly slowed clinical decline on multiple measures of cognition, function, and quality of life in early AD at 18 months and continued for 36 months to date…”

“When data from a matched ADNI observational cohort are added to the graph (which represents the exact population of those in the Clarity AD study), the ADNI participants show a similar degree of decline to the placebo group out to 18 months (Figure 3B).”

From this paper: “Limitations of this paper include that the OLE [Open Label Extension] phase of Clarity AD was an open-label, single-arm study with no control arm randomization in the OLE since efficacy was demonstrated at 18 months. In addition, historical controls are used for some analyses, which have limitations…”

One notes that all the performance lines [in these studies] do decline.  The plots from these papers use CDR-SB (a cognitive test metric).  They are not Kaplan-Meier survival curves, but the results seem similar to cancer drug trial results which show incremental progress, but for this reader, the statistics of significance  may be beyond me.  Again, the patients in this trial were all “early” AD, MCI or mild AD. The latter paper does also show graphics of data based on amyloid and tau PET scans, along with a quality of life metric.

[Addendum:  The similarity in the slopes of the curves, even though the Y-axis scales are slightly different, and the data of both “early-start” and “delayed-start data” in the second paper made me wonder whether the “Will Rogers Effect” or some kind of “lead-time bias” or even some frame-shift could be at work here…but maybe not.]

Of course, older drugs in observational studies had been reported to slow cognitive decline [also] (from the Swedish Dementia Registry, 2021) even though they are not considered “disease-modifying,” (they didn’t have or do PET scans):

“…The matched cohort included 11,652 ChEI [Cholinesterase Inhibitor] users and 5,826 nonusers. During an average of 5 years of follow-up, 255 cases developed severe dementia, and 6,055 (35%) died. ChEI use was associated with higher MMSE score at each visit (0.13 MMSE points per year; 95% confidence interval [CI] 0.06–0.20). ChEI users had a 27% lower risk of death (0.73, 95% CI 0.69–0.77) compared with nonusers. Galantamine was associated with lower risk of death (0.71, 95% CI 0.65–0.76) and lower risk of severe dementia (0.69, 95% CI 0.47–1.00) and had the strongest effect on cognitive decline of all the ChEIs (0.18 MMSE points per year, 95% CI 0.07–0.28).”

One wonders if there will ever be “head to head” studies of ChEI and anti-amyloid antibodies, or better yet, combination trials: after all, the first successful combination chemotherapy trials in childhood leukemia were being performed about 70 years ago (!)

Semaglutide (Ozempic ® and Wegovy®), FDA approved for type 2 diabetes, cardiovascular event prevention and obesity, was used in a “repurposing” clinical trial in AD.  Results were reported at the CTAD (with abstracts embargoed at this time?) but the company does have a press release:

“…The evoke and evoke+ trials did not confirm superiority of semaglutide versus placebo in the reduction of progression of Alzheimer’s disease, as measured by the change in Clinical Dementia Rating – Sum of Boxes (CDR-SB) score compared to baseline. While treatment with semaglutide resulted in improvement of Alzheimer’s disease-related biomarkers in both trials, this did not translate into a delay of disease progression….”

If this agent does improve biomarkers and that means something, does that again suggest a combination trial?  Ah, speculations, and hope, for the future, but always tempered by the reality of the data, its current strengths…and current weaknesses…Happy New Year!