Aducanumab was discontinued in January 2024 and the FDA put donanemab on hold for further safety review in March 2024. So, I think one should be cautious about lecanemab.
After the CLARITY-AD clinical trial results of lecanemab were interpreted as positive, and supporting the amyloid hypothesis, the drug received accelerated Food and Drug Administration approval. However, we argue that benefits of lecanemab treatment are uncertain and may yield net harm for some patients, and that the data do not support the amyloid hypothesis. We note potential biases from inclusion, unblinding, dropouts, and other issues. Given substantial adverse effects and subgroup heterogeneity, we conclude that lecanemab’s efficacy is not clinically meaningful, consistent with numerous analyses suggesting that amyloid-β and its derivatives are not the main causative agents of Alzheimer’s disease dementia.
There is a recent meta analysis of published studies in animal models finding that rapamycin helps prevent and reduce plaque deposition.
“ Rapamycin therapy reduced age-related plaque deposition by decreasing AβPP production and down-regulating β-secretase and γ-secretase activities, furthermore increased amyloid-β clearance by promoting autophagy, as well as reduced tau hyperphosphorylation by up-regulating insulin-degrading enzyme levels.”
This is highly misleading (not on your part, @MAC — on the part of the authors). The passage Mac references says:
Interestingly, everolimus has been found to delay aging and reduce the risk of Alzheimer’s disease in preclinical trials (67). A study found that everolimus increased hippocampal neurogenesis and synaptogenesis to improve cognitive function and prevent cognitive decline (68).
"Preclinical trials is a nonsense phrase, but put that aside. The reference 67 says absolutely nothing about rapa or everolimus having an effect on AD or even a mouse model of AD. Reference 68 is more on point, but not super-hopeful: "“Everolimus improves memory and learning while worsening depressive- and anxiety-like behavior in an animal model of depression”. And depression is a risk factor for dementia in humans …
Update: I was not permitted to participate in the AHEAD study because I am taking Repatha, which is a monoclonal antibody. Lecanemab is also a monoclonal antibody. Was disappointed at first but have come to feel that I (fortuitously) dodged a bullet. I had really wanted that blood test though.
Rapamycin Reduces Amyloid-β Plaques and Improves Behavioral Performance in a Sex-Dependent Manner in Mouse Models of Alzheimers
Background: Alzheimer’s disease (AD), the most common form of dementia, lacks effective disease-modifying treatments. Rapamycin, an mTOR inhibitor with immunomodulatory properties, may mitigate AD pathology by restoring microglial functions.
Results: Rapamycin treatment reduced the cerebral Aβ plaque burden, alleviated dystrophic neurites, suppressed glial hyperactivation, and increased plaque-associated microglial density in both mouse models, with more pronounced effects in female mice. These pathological improvements were associated with attenuated deficits in hippocampal-dependent memory tasks (spontaneous alternation in the Y-maze and contextual fear conditioning tasks). Mechanistically, rapamycin enhances microglial lysosomal degradation, promotes lipid droplet clearance in BV2 cells, and increases Aβ phagocytic clearance in primary microglial cells.
Conclusions: Our findings suggest that rapamycin reduces amyloid pathology and associated behavioral deficits in AD mice, an effect associated with enhanced microglial lysosomal activity and Aβ clearance, highlighting its therapeutic potential in AD treatment.