With regards to the blood-brain barrier, they only report that it does cross it. Other amyloid antibodies will bind amyloid precursor protein (which is cut to form the main component of amyloid plaques) on the surface of epithelial cells to help localize them to the brain. I can't find any discussion of the mechanism at play with this one though.

The primary publication you can access via sci-hub. In case you meant this linked article:

An antibody therapy markedly reduces aggregates of amyloid-β, the hallmark protein of Alzheimer's disease, and might slow cognitive decline in patients. Confirmation of a cognitive benefit would be a game-changer. See Article p.50

Subject terms: Alzheimer's disease Therapeutics

It is 25 years1 since the amyloid-β (Aβ) protein was proposed as the trigger for a cascade of events in the brain that lead to Alzheimer's disease. A growing number of anti-Aβ treatments have been developed to short-circuit this cascade — and several are currently being evaluated in people who have already developed or are at risk of developing symptoms of Alzheimer's (www.alzforum.org/therapeutics). On page 50, Sevigny et al.2 report findings from an initial 12-month, placebo-controlled trial of the antibody aducanumab, which selectively binds to potentially harmful soluble and insoluble Aβ aggregates, respectively called Aβ oligomers and fibrils.

The trial was primarily intended to clarify the Aβ-fibril-reducing effects and safety of different aducanumab doses administered intravenously once a month. It involved people who had been diagnosed with mild cognitive impairment (non-disabling memory and thinking problems) or mild dementia (which did have a slightly disabling effect) due to Alzheimer's disease. Each of the participants also tested positive for Aβ in a positron emission tomography (PET) scan, indicating moderate to frequent build-up of fibril-containing plaques — a cardinal feature of the disease. The study was not designed to definitively address aducanumab's effect on cognitive decline.

Aducanumab treatment was associated with unusually striking, progressive, dose-dependent reductions in PET measurements of Aβ-plaque burden. Aducanumab was also presumed to bind to and remove harder-to-measure Aβ oligomers, which seem to accumulate at or near plaques and may be the more damaging of the two aggregates3. What's more, despite the relatively small number of study participants and the substantial extent to which the disease has progressed by the time people with Alzheimer's develop memory and thinking problems, exploratory analyses suggested that higher antibody doses and greater Aβ-plaque reductions were associated with slower cognitive decline. If these preliminary cognitive findings are confirmed in larger and more-definitive clinical trials, which are now under way, it would provide a shot in the arm in the fight against Alzheimer's disease and compelling support for the amyloid hypothesis.

The amyloid hypothesis contends that a 42-amino-acid form of Aβ (Aβ42) becomes harmful when, owing to its overproduction or reduced clearance from the brain, individual Aβ42 monomers come together in various numbers and conformations to form oligomers and fibrils. These Aβ42 aggregates trigger a cascade of neurobiological events, including: certain inflammatory responses; aggregation, phosphorylation and propagation of a protein called tau; and other neuronal changes. These events contribute to the formation of Aβ plaques and tau-containing tangles, loss of neurons and the synaptic connections between them, cognitive decline and disability, and other features of Alzheimer's disease (Fig. 1).

Proponents of the amyloid hypothesis cite an abundance of supporting evidence1. Others note that the evidence is largely circumstantial, and that questions remain about the offending Aβ species and its effects. As such, they wonder whether Aβ42 accumulation is a consequence rather than an initiator of disease, and worry that anti-Aβ drug development might lead to a dead end. What will it take to confirm or refute the amyloid hypothesis once and for all?

Confirmation of this hypothesis will require definitive evidence that an anti-Aβ treatment can reduce cognitive decline in people affected by or at risk of developing Alzheimer's disease. Sevigny and colleagues' trial provides convincing evidence that aducanumab can enter the brain, target Aβ fibrils and substantially reverse plaque deposition — a major advance. But although the authors' additional cognitive findings are encouraging, they are not definitive. It would be prudent to withhold judgement about aducanumab's cognitive benefit until results from the larger trials are in. It will also be useful to see what can be learnt from large trials of other anti-Aβ treatments in the coming months and years.

Conversely, refutation of the amyloid hypothesis will require failure of anti-Aβ treatments to reduce cognitive decline in sufficiently large and suitably designed trials — not only in people with cognitive impairment due to Alzheimer's disease, but also in people without such impairment who have evidence of Aβ plaques, and even people without impairment who are at genetic risk of developing Alzheimer's but have little or no Aβ deposition. Several prevention trials using anti-Aβ treatments have started4, and more are on the way. Because abnormal Aβ build-up can begin more than two decades before the onset of memory and thinking problems5, having a drug such as aducanumab that substantially reverses pre-existing Aβ deposition might increase the chances of extinguishing the disease even after it has set in.

What accounts for aducanumab's unusually pronounced plaque-busting effects, even in small doses and despite the fact that only one to two antibody molecules out of every thousand are thought6 to cross the blood–brain barrier? It might be a combination of three things: the drug's unusually high selectivity for Aβ42 fibrils and oligomers, which minimizes the number of antibody molecules that bind to the abundant Aβ monomers in the blood and so maximizes the number of unbound antibodies that can enter the brain; its unusually high affinity for Aβ42 fibrils and oligomers; and the mechanism by which it enlists microglia, the brain's principal immune cells, to engulf and clear Aβ fibrils.

On the one hand, aducanumab's microglia-mediated activity could account for the antibody's ability to remove plaques, rather than just to slow further Aβ accumulation (which would be valuable in its own right). On the other hand, this activity might increase the chance of people developing amyloid-related imaging abnormalities (ARIA) — defects characterized by evidence of brain-fluid accumulation in magnetic resonance imaging scans. Like certain other anti-Aβ antibody treatments7, Sevigny and colleagues' study found that aducanumab was more likely to cause ARIA in higher doses and in people who carry the APOE type 4 gene, which is the major genetic risk factor for Alzheimer's disease.

The authors observed that ARIA were sometimes associated with transient headaches, visual disturbances or confusion, but were often associated with no symptoms, and that symptoms typically resolved within one to three months. Nonetheless, the frequency of ARIA caused the researchers to limit the maximum dose studied. It will be important to establish a sweet spot: a dose that is sufficiently safe and well tolerated, but also effective.

In addition to confirming the amyloid hypothesis, finding that the effects of treatments such as aducanumab on Aβ or other biological measurements of Alzheimer's disease are associated with a cognitive benefit might help to accelerate the evaluation and regulatory approval of promising Alzheimer's-prevention therapies that are based on reducing the biological measurements alone4. Indeed, confirmation that an anti-Aβ treatment slows cognitive decline would be a game-changer for how we understand, treat and prevent Alzheimer's disease. Now is the time to find out.

1. Selkoe, D. J. & Hardy, J. EMBO Mol. Med. 8, 595–608 (2016).

2. Sevigny, J. et al. Nature 537, 50–56 (2016).

3. Haass, C. & Selkoe, D. J. Nature Rev. Mol. Cell Biol. 8, 101–112 (2007).

4. Reiman, E. M. et al. Nature Rev. Neurol. 12, 56–61 (2016).

5. Fleisher, A. S. et al. JAMA Neurol. 72, 316–324 (2015).

6. Yu, J. Y. & Watts, R. J. Neurotherapeutics 10, 459–472 (2013).

7. Sperling, R. A. et al. Alzheimer's Dement. 7, 367–385 (2011).