These data demonstrate that CSF-AI is a stable characteristic of patients with mild to moderate AD and is increased in an important minority of such patients. The functional significance of BBB integrity in AD is suggested by correlations with CSF/plasma IgG ratio and with rates of disease progression. We did not find a relationship between vascular risk and BBB impairment as others have reported, perhaps because this group of patients was selected to minimize the presence of cerebrovascular disease by virtue of a diagnosis of probable AD and a Hachinski ischemia score of ≤4. The imaging data provide further evidence against the hypothesis that BBB impairment in these patients is due to occult vascular disease. The available brain pathology also fails to find significant cerebrovascular disease in this subject population, regardless of BBB status. Although BBB impairment may indeed be more common in vascular dementia than in AD,4
the relatively high prevalence of BBB impairment in these AD patients raises the possibility that BBB dysfunction may be more common in AD than is generally believed. If that is so, then the causes and consequences of BBB dysfunction in AD are of interest.
The cause remains speculative, although an effect of amyloid angiopathy on the BBB may be the most obvious candidate. None of these patients had clinically evident hemorrhages during follow-up. Brain MRI failed to disclose vascular complications of amyloid angiopathy, although MRI sequences appropriate for detecting remote microhemorrhages were not included. The subset of available neuropathology reports on this population further supports absence of significant hemorrhagic complications of amyloid angiopathy, although vascular amyloid was a common finding, as expected in most cases of AD. Amyloid angiopathy therefore remains a viable explanation for the BBB impairment seen in these patients, although the variation in BBB integrity was not obviously associated with variation in vascular amyloid.
A less obvious (but equally plausible) contributor to BBB impairment in AD is high plasma homocysteine. Whereas the relationships between hyperhomocysteinemia and dementia are well established, a relationship between homocysteine and BBB impairment is less well known. One recent study of 30 patients with hyperhomocysteinemia and amnestic mild cognitive impairment demonstrated a significant elevation of CSF-AI in patients compared with 35 healthy control subjects.18
As homocysteine is known to be toxic to vascular endothelial cells, the authors speculate that elevated homocysteine levels directly promote BBB impairment and tested this possibility by lowering hyperhomocysteinemia in the patients and then reassessing BBB status. Reducing homocysteine concentrations with B-vitamin therapy by approximately 50% significantly reduced CSF-AI by 11% over 9 months.18
This report therefore suggests that hyperhomocysteinemia may perturb BBB integrity in AD.
The consequences of BBB dysfunction are also not entirely clear, and aside from these data, one could even construct scenarios under which BBB permeability might actually be beneficial for patients with AD. For example, BBB permeability might provide a pathway for β-amyloid clearance or might permit endogenous anti-amyloid antibody to enter the CNS. However, the data here argue that BBB impairment in AD is associated with adverse consequences, as increased degrees of BBB impairment are associated with increased rates of neurodegeneration. Whether this is a causal association or noncausal correlation cannot be determined from these data, but it is clear that the data do not show any clinical benefit from increased BBB permeability in AD.
In addition to effects on the natural history of AD, BBB dysfunction may also potentially modify responses to treatment with large molecules like immune globulin. Previous trials of active immunization were halted because of encephalitis in a small but significant minority of patients,19
leading to current trials of passive immunization, which may be intrinsically safer. However, preliminary findings of MRI changes in AD patients receiving passive immunization show that even passive immunization may be risky.20
Furthermore, if the complication of CNS inflammation in immune therapy trials could be linked to BBB integrity at baseline, then it might be possible to diminish this very serious risk of immunotherapy by screening patients with the CSF-AI and foregoing immunotherapy in patients with BBB impairment.