Genetic, Transcriptome, Proteomic, and Epidemiological Evidence for Blood-Brain Barrier Disruption and Polymicrobial Brain Invasion as Determinant Factors in Alzheimer’s Disease

Carter, Chris J.

Aging itself results in a loss of BBB integrity [165] and in immune function (immunosenecence) [31] and these two factors would be expected to favor blood-borne pathogen survival and cerebral pathogen entry. In normal human aging, loss of barrier integrity appears to begin in the hippocampus, a crucial area in AD and in learning and memory [166] . The BBB consists of a series of capillaries, capillary arterioles, and capillary venules serving neurons throughout the brain. This network of fine blood vessels, which shows early pathological changes in AD, is in turn controlled by a perivascular neuronal plexus originating mainly from the locus coeruleus, the nucleus basalis of Meynert, and the basal forebrain area, each of which suffer early extensive damage in AD [167] . A recent MRI study suggests that degenerative changes in the basal forebrain including the nucleus basalis of Meynert are early events in AD that precede cortical degeneration [168] . Degeneration of the cortical cholinergic innervation originating from the basal forebrain was one of the first neurochemically characterized lesions in AD [169, 170] . The basal forebrain cholinergic system receives many olfactory inputs from the olfactory bulb, anterior olfactory nucleus, and the pyriform cortex [171] . Damage to the olfactory bulb and the olfactory tracts and system are also early characteristic features of AD [172, 173] . Anosmia/olfactory impairment are early and predictive signs of mild cognitive impairment and progression to AD [174] and A␤ deposition and tau pathology can be observed in the nasal epithelium in the majority of AD cases [175] .