The role of Aβ1- 40 in the Aβ1-42/Aβ1- 40 ratio

Aβ1-40 is the most abundant amyloid peptide in CSF, while Aβ1-42 accounts for only about 10% of the total Aβ peptide population.¹⁵ Total Aβ concentration does not vary significantly between various disorders. Accordingly, Aβ1-40 concentration does not differ significantly between AD (or presymptomatic AD) patients, healthy controls, and non-AD dementia patients. CSF Aβ1-40 concentration could, therefore, be considered to most closely reflect total Aβ load in the brain.

​​​​​​Pathophysiologic role of the Aβ1-40 peptide in the brain

• Amyloid plaques found in AD are predominantly composed of Aβ1-42.
• Capillary cerebral amyloid angiopathy (CAA) is associated with accumulation of the more soluble Aβ1-40 species.

At this point, it is also relevant to consider the role of Aβ1-40 in the pathophysiological processes in the brain during development of AD.

Most subjects diagnosed with AD (85-95% of cases) have some degree of cerebrovascular lesions and/or capillary cerebral amyloid angiopathy (CAA). Therefore, there is a known overlap between CAA and AD pathologies. At the pathophysiological level, cerebral amyloid angiopathy appears to be in part a “protein elimination failure” angiopathy and leads to worsening vascular Aβ accumulation and impaired vascular physiology. In contrast to amyloid plaques found in AD, predominantly composed of Aβ1-42 species, CAA results from a progressive loss of smooth muscle cells of parenchymal arterioles of the brain with simultaneous accumulation of the more soluble Aβ1-40 species.¹⁶

The balance between Aβ production-clearance from the brain and retention within the brain in the form of senile plaque or CAA determines what amount of soluble Aβ will diffuse in CSF. Recent findings suggest that CSF Aβ1-40 intra-individual variability could possibly relate to the specific mechanisms of sporadic development of CAA and the degree of cerebrovascular amyloid deposition.¹⁷ More studies investigating the link between CAA and Aβ1-40 are needed.