To date, there is no effective treatment that can prevent progression of Alzheimer’s disease; available drugs can only delay worsening of symptoms. Therefore there is urgent need for therapies that alter the progression of Alzheimer’s disease. The Aβ hypothesis posits that increased steady-state levels and consequent Aβ assembly is the primary event driving Alzheimer’s disease pathogenesis (). The rest of the disease process is believed to result from this aberrant assembly. A number of different anti-amyloid therapies are under development; two examples are discussed and illustrated in : decreasing the production of soluble Aβ monomer and removing soluble and deposited Aβ.
The Aβ hypothesis: an increase in the concentration of Aβ, especially the 42–amino acid form, is the underlying cause for the pathological features of Alzheimer’s disease.
Reduction of Aβ levels is particularly attractive because it may be possible to titrate Aβ down to concentrations that will not support oligomerization. It would be anticipated that cell-penetrant agents that could reduce intracellular and/or extracellular monomer levels below the critical concentration needed for oligomerization would thus prevent Aβ from assembling into toxic structures. The development of potent highly selective inhibitors of β- and γ-secretases that can readily enter the brain and lower Aβ production () is being actively pursued. Similarly, efforts are also ongoing to develop small molecules that can upregulate the enzymes that control Aβ degradation and thus lower Aβ levels by increasing Aβ catabolism.
Anti-Aβ immunotherapy employs antibodies that recognize multiple different toxic Aβ assemblies by both directly neutralizing them and preventing their toxic effect, by promoting microglial clearance, and/or by redistributing Aβ from the brain to the systemic circulation. This approach has already been shown to reduce cerebral Aβ levels, decrease amyloid-associated gliosis and neuritic dystrophy, and alleviate memory impairment in transgenic mouse models of Alzheimer’s disease (80
). More importantly, Alzheimer’s disease patients that were immunized with aggregated Aβ showed diminished cognitive decline and slowed disease progression compared with patients that received placebo (81
). Unfortunately, this phase IIa trial had to be stopped prematurely because 18 of the 298 patients who had been immunized developed meningoencephalitis. Notably, in four cases that have since come to autopsy (two affected with encephalitis and two not), all showed evidence of clearance of amyloid deposits. Thus in the first clinical test of the Aβ hypothesis it appears that (as in preclinical studies of mouse models) targeted removal of cortical Aβ beneficially modifies Alzheimer’s disease progression. Efforts are ongoing to develop an equally effective immunization protocol that avoids induction of encephalitis. Thus there is good reason to believe that therapies directed at preventing the generation of toxic Aβ assemblies will soon come to the clinic and that, unlike current therapies, they will actually halt further deterioration and offer the potential of restoring normal cognitive function.
With the advancement of potentially disease-modifying therapies, there is an urgent need to develop methods for use in early ante mortem
diagnosis. This is required, not only from a clinical standpoint, but also because it affects the integrity of clinical trials and epidemiological research. Currently there are at least four methods that have evolved from our better understanding of the disease process: analysis of Aβ species in CSF (82
); visualization of amyloid plaques by PET as discussed above (15
); measurement of Aβ in peripheral blood (84
); and measurement of total tau and/or phosphotau in CSF (85
Given the genetic evidence supporting a prominent role for Aβ42
in disease, many studies have investigated the diagnostic utility of measuring Aβ42
in CSF. For Alzheimer’s disease patients, Aβ42
levels in CSF are typically reduced to around 50% of the level found in controls. The mean sensitivity and specificity to discriminate between Alzheimer’s disease and normal aging are both >85% (87
). However, decreased CSF Aβ42
is found in certain patients with frontotemporal dementia and vascular dementia, and measurement of CSF Aβ42
alone is insufficient to discriminate between Alzheimer’s disease and these dementias (88
). CSF Aβ40
is unchanged or slightly increased in Alzheimer’s disease (89
); consequently a decrease in the ratio of Aβ42
in CSF has been found in Alzheimer’s disease, and this decrease seems more pronounced than the reduction of CSF Aβ42
). Alzheimer’s disease is also associated with a significant increase in CSF tau and phospho-tau levels (85
), and combining measurement of total tau, Aβ42
, and phospho-tau identifies incipient Alzheimer’s disease in patients with mild cognitive impairment with very high accuracy (90
The reduced level of CSF Aβ42
in Alzheimer’s disease is believed to be caused by deposition of Aβ42
in senile plaques, hence leaving lower levels of Aβ42
to diffuse into CSF. Accordingly, studies have found a strong correlation between low Aβ42
in CSF and high retention of PIB (83
). Factors that may contribute to reduced Aβ42
levels, in addition to deposition in senile plaques, include formation of Aβ42
oligomers that escape ELISA detection and binding of Aβ42
to other proteins that block the antibody recognition of Aβ. For instance, ELISA measurements of plasma Aβ levels in Alzheimer’s disease have yielded conflicting data and this could, in part, reflect an inability to measure Aβ oligomers. This possible confounder might differ for antibodies used in different ELISA protocols and could explain some of the contradictory results. Development of anti-Aβ dimer/ oligomer-specific antibodies should obviate concerns about epitope masking due to Aβ self-association and may provide a useful system to measure Aβ dimer/ oligomer levels in both CSF and plasma. Indeed, a small number of preliminary studies suggests that measurement of Aβ oligomers will be of benefit (63
). If this holds true in larger studies, one would anticipate that combining measurement of disease-linked assembly forms (oligomers) of Aβ together with measurement of tau in CSF and PIB binding in brain will provide a highly specific and sensitive means of measuring both early and incipient Alzheimer’s disease.