Peripheral Markers of Inflammation in Patients With Alzheimer's Disease Compared to Cognitively Normal Elderly

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by the loss of cognitive brain functions and functional decline. One of the pathological features of this condition is the progressive deposition in the brain of amyloid beta-peptide (A-beta) (1). Once deposited in the brain, the peptide exerts a toxic effect by triggering a chronic inflammation that interferes initially with normal brain function and results eventually in neuronal death (2). It is currently postulated that at a certain threshold of A-beta accumulation compensatory mechanisms in the brain are no longer sufficient to cope with A-beta toxicity, and the clinical syndrome of AD develops. It is possible that A-beta may accumulate in the brain over a period of up to 10-15 years before clinical symptoms become significant. The question has been raised whether the accumulation of A-beta is possibly a normal process of aging, suggesting that all people may be susceptible to the disease if they live long enough - of note is that the prevalence of Alzheimer's disease rises to over 40% above the age of 85 years.

Among the many possible ageing-related factors involved in the development of AD, senescence of the immune system may significantly enhance changes in the brain and intensify the neurological decline in patients with this disease. A direct consequence of immunosenescence is the increased frequency of systemic infections and, in fact, many who die with AD have previously suffered from a severe infection. Since patients with AD have an ongoing chronic inflammatory response in the brain, associated with the activation of glial cells and a partially disrupted blood brain barrier, systemic inflammation may intensify this process in the brain and increase the overall neuronal damage.

In contrast to the damage caused by immune activation, A-beta vaccination studies have shown very promising effects in mouse models of the disease, particularly with regard to the clearance of amyloid plaques by A-beta antibodies (3). When tested in patients with AD, 6% of the vaccinated patients developed severe inflammatory reactions in the brain (4). Nonetheless, a cohort of patients showed improved cognitive tests where specific antibodies were induced (5). In a recent study we demonstrated that such brain inflammation may be due to increased levels of IFN-γ in the brain (6), possibly as a result of sub-clinical systemic infection and the specific immune responses observed in humans.

While the chronic inflammation progresses throughout the disease, the specific arm of the immune system, i.e., brain-specific lymphocytes, may also be stimulated to play a role. In contrast to previous assumptions, our findings in human subjects with AD demonstrate that a specific immune response to A-beta is indeed significantly induced in both elderly individuals and patients with AD as compared to middle-aged individuals (7). The nature and role of this immune response to A-beta in man is yet to be investigated, and may lead to the characterization of pathways associated with neuronal cell death, and result in new diagnostic modalities and immunotherapeutic approaches.

The purpose of this study is to determine whether peripheral markers possibly related to A-beta induced inflammation of the brain are increased in patients with clinical AD.