Clearing amyloid-β from the brain has failed to reverse Alzheimer's disease in patients, and this unfortunate outcome is slowly - all too slowly - producing a change in direction in the mainstream of Alzheimer's research. One possible conclusion is that amyloid-β is simply the wrong target, and this has led to a great deal of alternative theorizing in recent years. Even so, the consensus remains that amyloid-β does play a significant role in the condition, albeit not enough of a role in the later stages of Alzheimer's to allow anti-amyloid therapies to work. The jury remains out on whether early reduction in amyloid-β aggregation can postpone Alzheimer's - i.e. whether this aggregation actually a causative mechanism or whether it is a side-effect of the actual cause, such as chronic inflammation driven by persistent infection.
A currently popular view is that the mechanistic evidence continues to suggest that amyloid-β is important, and thus it should be targeted - but not in isolation, as the past decade or two of failed trials amply demonstrate that removal of only amyloid-β is not sufficient. The conclusion is that there must also be reductions in tau aggregation, perhaps treatment of cerebrovascular dysfunction, suppression of inflammation in the brain, and so forth. Along these lines, today's open access research is a demonstration of a combination immunotherapy in mice that targets both amyloid-β and tau. Absent stunning success in some of the more radical new directions in Alzheimer's research, such as restoring drainage of cerebrospinal fluid, we will likely see such combination immunotherapies tested in humans in the near future.
Alzheimer's disease (AD) is a complex and multifactorial disease involving genetic and environmental risk factors that together lead to the progressive accumulation of two hallmark pathologies: β-amyloid plaques and neurofibrillary tangles (NFTs). Although many clinical trials have aimed to reduce β-amyloid and, more recently, to target the accumulation of tau that drives NFT formation, debate remains regarding which of these pathologies represents the most tractable target, and the precise timing for these potential treatments.
Recent longitudinal analyses demonstrated evidence of synergism between Aβ and phosphorylated tau (p-tau) suggesting these pathologies may interact to trigger the progression from amnestic mild cognitive impairment (MCI) subjects to AD dementia. PET imaging studies suggest that Aβ deposits start decades before dementia onset, and may or may not precede tau pathology, with the latter correlating better with symptom onset and the degree of dementia.
According to the modified amyloid cascade model, primary age-related tauopathy (PART) develops universally as a function of aging and, by itself, produces no or only mild cognitive symptoms. Aβ deposition occurs independently in the neocortex and induces or facilitates the spread of pathological tau, perhaps by promoting the production of pathological tau strains. Pathological tau is directly associated with neurodegeneration, which in turn drives cognitive decline. In this model of AD, Aβ does not directly cause cognitive symptoms but is still central to disease pathogenesis as a dominant driver of downstream pathological processes including tau pathology.
This synergistic model suggests that combinatorial/multi-target therapies directed at the accumulation of both amyloid and tau pathologies may be more effective in the treatment of AD than previously tested unimodal approaches. Recently, we demonstrated that the combination of AV-1959R and AV-1980R vaccines targeting Aβ and tau, respectively, induced robust antibody responses against various forms of both Aβ and tau pathological molecules in wildtype mice.
Here, we tested the therapeutic efficacy of co-formulated vaccines targeting Aβ and tau administered simultaneously in combination with AdvaxCpG adjuvant in the Tau22/5xFAD (T5x) mouse model of AD that develops highly aggressive Aβ and tau pathology. T5x mice immunized with a mixture of Aβ- and tau-targeting vaccines generated high Aβ- and tau-specific antibody titers that recognized senile plaques and neurofibrillary tangles in human AD brain sections. Production of these antibodies in turn led to significant reductions in the levels of soluble and insoluble total tau, and hyperphosphorylated tau as well as insoluble Aβ42, within the brains of T5x mice.