Abstracts/Presentation Description
Colin Masters1
1The Florey, University of Melbourne
Late onset (sporadic) Alzheimer's disease: caused by defective innate immunity and treated with adaptive immunity.
The etiology of Alzheimer’s disease (AD) is best understood through the deposition of Aβ-amyloid (Aβ). There are two basic forms of AD. The common (>95%) form is sporadic, and is caused by the failure to clear Aβ (mean age at onset 80 years). The rare (< 5%) autosomal dominant familial form is caused by the over-production of Aβ42, also on a background of failure to clear (mean age at onset 45 years). In both forms, the kinetics of Aβ accumulation are similar, taking about 30 years to accumulate a total of approximately 7mg of Aβ. Thus we estimate that sporadic AD starts about the age of 50 years and the autosomal dominant form starts about 15 years of age. The first changes are seen in the Default Mode Network, a brain system that is used for high level coordination of the encoding of memories (the engram), which is the essential first step in learning. We now know that deficits of learning are more severe than memory in the early phases of AD. This may be related to the normal function of the APP molecule that gives rise to Aβ.
1The Florey, University of Melbourne
Late onset (sporadic) Alzheimer's disease: caused by defective innate immunity and treated with adaptive immunity.
The etiology of Alzheimer’s disease (AD) is best understood through the deposition of Aβ-amyloid (Aβ). There are two basic forms of AD. The common (>95%) form is sporadic, and is caused by the failure to clear Aβ (mean age at onset 80 years). The rare (< 5%) autosomal dominant familial form is caused by the over-production of Aβ42, also on a background of failure to clear (mean age at onset 45 years). In both forms, the kinetics of Aβ accumulation are similar, taking about 30 years to accumulate a total of approximately 7mg of Aβ. Thus we estimate that sporadic AD starts about the age of 50 years and the autosomal dominant form starts about 15 years of age. The first changes are seen in the Default Mode Network, a brain system that is used for high level coordination of the encoding of memories (the engram), which is the essential first step in learning. We now know that deficits of learning are more severe than memory in the early phases of AD. This may be related to the normal function of the APP molecule that gives rise to Aβ.
The advent of validated biomarkers (PET and biofluids Aβ and tau) now provides us with unprecedented opportunities for preclinical diagnosis, enabling the development of primary and secondary prevention strategies. Predictive algorithms utilizing age, biomarkers, polygenic and vascular risk scores are now being developed from longitudinal cohort studies to estimate times of onset and rates of cognitive decline. Applications of biomarker screens (blood, CSF, PET) to subjects who are about to cross the lower cutpoint thresholds will define a population who may be suitable for primary prevention clinical trials.
Therapeutic targeting the Aβ pathway remains the principal strategy for delaying onset of AD. There are many molecular targets in this pathway, and no single one is likely to prove efficacious on its own. Therefore, a combination of strategies needs to be developed and applied. The recent accelerated successes of aducanumab, Lecanemab and Donanemab , which target an epitope of Aβ, has provided a huge impetus for the development of this first-in-class disease-modifying therapy. Primary and secondary prevention trials are now underway.
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Prof Colin Masters -