Restoring amyloid-β42 and γ-secretase function in Alzheimer's disease
Alberto J Espay1, Kariem Ezzat1, Kasper P Kepp2
1James J. and Joan A. Gardner Family Center for Parkinson's Disease and Movement Disorders, Department of Neurology, University of Cincinnati, Cincinnati, OH 45219, USA.
Abstract:
Emerging evidence is challenging the long-standing notion that Alzheimer's disease (AD) is caused by increased γ-secretase function and overproduction of 42-amino acid amyloid-beta (Aβ42). CSF levels of soluble monomeric Aβ42 in AD are reduced to about half of those in healthy individuals and drop even further at dementia onset in genetic forms (APP, PSEN1, PSEN2 mutations) and in Down syndrome. Findings supporting a revised AD pathophysiology include: (i) ∼90% of pathogenic PSEN1 mutations reduce γ-secretase activity and Aβ42 production; (ii) lower γ-secretase activity is correlated with lower soluble Aβ42 levels, earlier onset of dementia, worse cognition, and faster progression; (iii) higher soluble Aβ42 levels associate with preserved cognition and delayed dementia in amyloid-positive sporadic and familial AD; (iv) apparent cognitive benefits from anti-amyloid monoclonal antibodies involve increased soluble Aβ42 levels; and (v) monomeric Aβ42 supports memory and other functions akin to a neuropeptide. These findings suggest that restoring, not reducing, γ-secretase activity and monomeric Aβ42 levels above a compensation threshold could offer disease-modifying therapeutic benefits. Drugs that increase soluble Aβ42, some already approved for other indications and linked to reduced dementia risk, may be repurposed to test whether they can slow disease progression in familial and sporadic AD.
Insights
Alzheimer's disease may not stem from excess amyloid-beta 42 (Aβ42). Lower Aβ42 levels correlate with worse outcomes, suggesting Aβ42 restoration could be a therapeutic strategy for Alzheimer's disease.
Area of Science:
- Neuroscience
- Neurology
- Biochemistry
Background:
- Traditional Alzheimer's disease (AD) models implicate increased gamma-secretase activity and amyloid-beta 42 (Aβ42) overproduction.
- Emerging data challenges this, showing reduced cerebrospinal fluid Aβ42 levels in AD patients, particularly those with genetic mutations or Down syndrome.
Purpose of the Study:
- To re-evaluate the role of gamma-secretase activity and Aβ42 levels in Alzheimer's disease pathophysiology.
- To explore the potential of restoring Aβ42 levels as a therapeutic strategy.
Main Methods:
- Analysis of existing evidence linking gamma-secretase function, Aβ42 levels, and AD progression.
- Review of findings from genetic studies (APP, PSEN1, PSEN2 mutations) and Down syndrome.
- Examination of the effects of anti-amyloid therapies and the potential neuropeptide function of Aβ42.
Main Results:
- Approximately 90% of pathogenic PSEN1 mutations decrease gamma-secretase activity and Aβ42 production.
- Lower gamma-secretase activity and soluble Aβ42 levels correlate with earlier dementia onset, poorer cognition, and faster progression.
- Higher soluble Aβ42 levels are associated with preserved cognition and delayed dementia in some AD forms.
Conclusions:
- Alzheimer's disease pathophysiology may involve reduced, not increased, gamma-secretase activity and Aβ42 levels.
- Restoring Aβ42 levels above a compensatory threshold could offer disease-modifying benefits.
- Repurposing drugs that increase soluble Aβ42 warrants investigation for slowing AD progression.
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