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Challenging the Alzheimer’s Amyloid Hypothesis

Journal Club July 2021

Journal ClubJournal Club

Journal Club returns on July 27th at noon Eastern / 17:00 UK live on our Facebook page.

A new way to look at Alzheimer’s

The topic for this month will be a new study that challenges the amyloid hypothesis of Alzheimer’s disease with new human data. The data suggests that the cognitive impairment that accompanies Alzheimer’s may hinge not on amyloid accumulation but upon the presence, or lack thereof, of the soluble amyloid-beta peptide.

Join Dr. Oliver Medvedik and guests as we take a look at the data and discuss the findings. If you are a Lifespan Hero, you can even join us live on the call; details will go to the email you registered as a Hero with, and you can also check the Heroes corner.


Brain amyloidosis does not invariably predict dementia. We hypothesized that high soluble 42-amino acid β amyloid (Aβ42) peptide levels are associated with normal cognition and hippocampal volume despite increasing brain amyloidosis. This cross-sectional study of 598 amyloid-positive participants in the Alzheimer’s Disease Neuroimaging Initiative cohort examined whether levels of soluble Aβ42 are higher in amyloid-positive normal cognition (NC) individuals compared to mild cognitive impairment (MCI) and Alzheimer’s disease (AD) and whether this relationship applies to neuropsychological assessments and hippocampal volume measured within the same year. All subjects were evaluated between June 2010 and February 2019. Brain amyloid positivity was defined as positron emission tomography-based standard uptake value ratio (SUVR) ≥1.08 for [18] F-florbetaben or 1.11 for [18]F-florbetapir, with higher SUVR indicating more brain amyloidosis. Analyses were adjusted for age, sex, education, APOE4, p-tau, t-tau, and centiloids levels. Higher soluble Aβ42 levels were observed in NC (864.00 pg/ml) than in MCI (768.60 pg/ml) or AD (617.46 pg/ml), with the relationship between NC, MCI, and AD maintained across all amyloid tertiles. In adjusted analysis, there was a larger absolute effect size of soluble Aβ42 than SUVR for NC (0.82 vs. 0.40) and MCI (0.60 vs. 0.26) versus AD. Each standard deviation increase in Aβ42 was associated with greater odds of NC than AD (adjusted odds ratio, 6.26; p < 0.001) or MCI (1.42; p = 0.006). Higher soluble Aβ42 levels were also associated with better neuropsychological function and larger hippocampal volume.

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[1] Sturchio, A., Dwivedi, A. K., Young, C. B., Malm, T., Marsili, L., Sharma, J. S., … & Espay, A. J. (2021). High cerebrospinal amyloid-β 42 is associated with normal cognition in individuals with brain amyloidosis. EClinicalMedicine, 100988.

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