What initiates the formation of senile plaques? The origin of Alzheimer-like dementias in capillary haemorrhages

SummaryAlthough the key pathologies of the demented brain have been known for over a century, and the senile plaque is the focus of intense research, the mechanisms that cause plaques to form are not established. This paper proposes that the formation of each plaque is initiated by bleeding from a cerebral capillary, which creates the conditions for formation of an amyloid-rich plaque. Specifically, it is argued that ischaemia caused by the haemorrhage upregulates the expression of β-amyloid by local neural cells, and that haemoglobin released into the neuropil binds to the β-amyloid and promotes its oligomerisation. The premise that the event that initiates plaque formation is vascular explains why the risk factors for ALDs and cardiovascular diseases overlap; why drugs and lifestyle changes with vaso-protective effects protect against dementia; and why oxidative stress is prominent early in the genesis of Alzheimer-like dementias. The vascular premise also suggests that the anatomical substrate for the spread of plaque formation is the capillary bed of the cerebral cortex, and provides an explanation of why plaque formation is age-related, occurring as the capillary bed becomes fragile with age. The more specific premise, that haemorrhage creates the conditions for plaque formation, explains many of the features of plaques: their small and relatively uniform size, each being the site of a capillary bleed; why plaques form around capillaries; why haem is found in every plaque; why an inflammatory response is prominent where plaques form; why plaque formation and haemorrhagic stroke commonly co-occur in both sporadic and familial dementias; why plaques form around vessels in mouse models of plaque formation induced by transgenes that mimic the mutations that cause familial disease; why the acute petechial bleeding caused by brain trauma can lead to the formation of plaques. The hypothesis also suggests an explanation of how ALD’s can occur without plaque formation, as when the cerebral capillaries become blocked or constricted in flow, without haemorrhage. Advances in the prevention of dementia will be gained, it is argued, from understanding of why the cerebral capillary bed becomes unstable with age, and how that instability can be prevented, delayed or slowed. Advances in the treatment of dementia will be gained from techniques that minimise the neural damage caused by a multitude of tiny strokes.