Central to our understanding of AD and its treatment are the pathological features of neuritic plaques (NPs) and neurofibrillary tangles (NFTs) (
9), the most important components of which are β-amyloid (
1,
10–
11) (Aβ1-40 and Aβ1-42 or Aβ) and hyperphosphorylated tau (
12–
15), respectively. For some years the field was split between those who believed that β-amyloid (amyloid hypothesis) was the trigger that was responsible for the neurodegeneration and those who believed that the trigger was abnormal tau (tau hypothesis). The findings that genetically dominant early-onset forms of AD resulted from mutations in APP, presenilin 1, and presenilin 2 substantially altered the debate. Mutations in all three genes could be shown to lead to variations in the processing of APP, resulting in increased concentrations of Aβ1-40 and Aβ1-42 and/or a shift in their ratio favoring the formation of Aβ1-42. Aβ1-42 was demonstrated to have greater toxic potential because of its greater propensity to form oligomers and fibrilized forms (
16). However, it is yet to be determined which of the various combination of products and aggregates of the APP processing pathway as well as their location, i.e., intracellular or extracellular, are the chemical moieties and pathways that most directly affect neuronal damage in AD (
17–
21).
DOES THE IMMUNE SYSTEM CONTRIBUTE TO AD PATHOLOGY?
There is increasing evidence that the mere accumulation of β-amyloid (Aβ1-40 and Aβ1-42 and all their forms including diffuse amyloid plaques and NPs) may not be sufficient to induce the cognitive findings of AD and that the immune system may play a critical role in the clinical symptoms. Activated microglia and astrocytes, cellular components of the brain's immune network, are found in close proximity to senile plaques (
22–
25). Elevated levels of both pro- and anti-inflammatory cytokines, e.g., interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and C-reactive protein are found in the plasma and/or cerebrospinal fluid of patients with AD (
26–
29). Evidence of complement activation is also found in the AD brain (
30) together with increased numbers of brain T cells, primarily of the CD8
+ type (
6,
7).
Despite the fact that the above findings were reported some time ago, the absence of a leukocyte infiltration diminished interest in the role of the immune system and neuroinflammation in AD. It was not until findings from several epidemiological studies suggested that anti-inflammatory drugs, particularly nonsteroidal anti-inflammatory drugs, reduce the risk of developing AD that interest developed in the possible causative role of neuroinflammation in the clinical symptoms of AD (
31–
34). Subsequent support for the importance of the immune system in AD pathology derives from the findings that polymorphisms in genes that are part of inflammatory pathways are associated with altered risk of AD (
35–
41) and from neuroimaging studies using labeled PK1195 (1-[2-chlorphenyl]-
N-methyl-
N-[1-methyl-propyl-]-3-isoquinoline carboxamide) (
42,
43). PK1195 is a tracer that binds to the peripheral benzodiazepine receptor, a receptor found on activated microglia cells, cells normally present in very small numbers in the brain. An increased accumulation of the tracer has been found in entorhinal and temporoparietal cortices and the posterior cingulate of even mildly affected patients with AD. Unfortunately, however, trials of anti-inflammatory agents in AD have not shown efficacy (
33,
34).
If the toxic products of APP processing are what results in AD, what are the possible mechanisms for immune system modification of clinical symptoms? Postmortem findings have suggested that clinical manifestations of AD are most closely tied to regional accumulation of NFTs rather than NPs and loss of synapses even more than NFTs (
44–
48). Studies of neuronal damage reveal that inflammation can modify or accelerate APP production and tau phosphorylation (
49–
54). Further, individuals known to be healthy before their death can have substantial amounts of β-amyloid found at postmortem (
55–
61), but these brains usually do not display the typical neuroinflammatory markers of AD (
62). In addition, subjects with possible as well as early AD at postmortem show substantial numbers of activated microglia (
63–
65), suggesting that neuroinflammation can occur early in the disease process.
Further, Toll-like receptors (TLRs) have been linked to the pathogenesis of AD and TLRs 1, 2, 4, 5, 7, and 9 and CD14 are up-regulated in the aging mouse brain (
66,
67). Both TLRs and CD14 are membrane proteins found on cells that are part of the immune system. In this context, it is of some significance to note that the immune system consists of two networks, the innate and the adaptive. Initiation of the innate network response occurs through the recognition of “pathogen-associated molecular patterns” that are produced by microorganisms. In general, recognition relies on interaction with TLRs and inflammation on downstream signaling to activate the transcriptional factor nuclear factor-κB that leads to increased transcription of proinflammatory genes.
Recent studies with positron emission tomography using amyloid tracers have shown that some 10%–15% of older healthy individuals have amyloid tracer accumulations that overlap with those of patients with AD and that even a higher percentage was seen in those with mild cognitive impairment (
68–
72). Thus, the amyloid tracer data are consistent with other neuroimaging and cognitive data, suggesting that changes in brain physiology in individuals at risk for AD may begin decades earlier than the expected clinical manifestation of the disorder (
73–
81) and that β-amyloid accumulation is not always immediately toxic.