A new study finds that Alzheimer’s disease is caused by low levels of beta amyloid protein and not by amyloid plaques


A new study led by researchers from the University of Cincinnati-USA has found that Alzheimer’s Disease is caused by low levels of a soluble protein called amyloid beta and not by amyloid plaques.

The study findings were published in the peer reviewed Journal of Alzheimer’s Disease.

Key support for the toxic amyloid hypothesis comes from the observation that mutations in any of three genes (APP, PSEN1, and PSEN2) lead to Alzheimer’s disease (AD) with complete penetrance [1].

The genetic evidence causally implicates the fibrillogenic 42-amino acid amyloid-β peptide (Aβ42). However, the disease pathogenesis may arise from either of two ends of the protein aggregation process: the increase in insoluble amyloid plaques or the depletion of the soluble Aβ42 peptide, which has important functions. While insoluble amyloid plaques can be present in normal individuals, low soluble levels of Aβ42 are an invariable feature of AD [2–4].

The hypothesis of Aβ toxicity has traditionally been supported by the notion that AD-causing mutation carriers must have high levels of soluble Aβ42 relative to non-mutation populations. In fact, mutation carriers have lower Aβ42 levels compared to non-mutation populations [3].

The reduction in soluble Aβ42 levels among mutation carriers begins as many as 25 years before the onset of cognitive symptoms [4]. Therefore, the toxicity in the process of accelerated protein aggregation among mutation carriers may conceivably be due to the depletion in soluble Aβ42 to a greater extent than the corresponding increase in amyloid [5].

This alternative hypothesis offers an explanation for the failures in translating amyloid reduction into cognitive improvement [6], even among mutation carriers [7], and for the paradoxes posed by the large proportion of amyloid-positive individuals without dementia and even of centenarians without history of cognitive abnormalities, half of whom have autopsy-confirmed AD pathology [8–10].

We recently observed that among amyloid positron emission tomography (PET)-positive individuals, higher levels of soluble Aβ42 were associated with normal cognition and brain volumes in all tertiles of brain amyloidosis, with an effect size greater than that of increases in brain amyloid burden [11].

We here tested the hypothesis that in amyloid PET-positive individuals with AD-causing APP, PSEN1, or PSEN2 mutations, higher CSF Aβ42 levels reduce the risk of cognitive progression to a greater extent than lower levels of brain amyloidosis and lower levels of CSF phosphorylated tau (p-tau) and total tau (t-tau).


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