The first published data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) study supports the hypothesis that higher levels of the amyloid protein in the brain represent an early stage of Alzheimer’s disease.
Results of an analysis of participant screening data for the study, published April 6 in JAMA Neurology, also show that amyloid burden in clinically normal older adults is associated with a family history of disease, lower cognitive test scores, and reports of declines in daily cognitive function.
Major funding was provided by the National Institute on Aging (NIA), part of the National Institutes of Health; all data is now freely available to the broader research community.
With completion expected in late 2022, the A4 study is an ongoing prevention trial launched in 2014 to test whether the drug solanezumab, a monoclonal antibody, could slow cognitive decline associated with elevated brain amyloid if started before clinical symptoms appear.
Amyloid, long considered a hallmark of Alzheimer’s disease, has been the target of therapies in clinical trials in people who already show symptoms of the disease.
“A major issue for amyloid-targeting Alzheimer’s disease clinical trials, and one that is being addressed with the A4 study, is that previous trials may have been intervening too late in the disease process to be effective,” said NIA Director, Richard J. Hodes, M.D.
“A4 is pioneering in the field because it targets amyloid accumulation in older adults at risk for developing dementia before the onset of symptoms.”
The A4 study team was looking for cognitively normal participants with high levels of amyloid.
They started by pre-screening more than 15,000 people who expressed interest in the trial. Of those 15,000, the researchers brought in 6,763 clinical trial volunteers for cognitive testing, clinical assessments and genotyping.
After excluding 2,277 participants for cognitive and/or medical reasons, researchers used amyloid positron emission tomography (PET) imaging with 4,486 participants to measure amyloid accumulation in the brain.
The PET imaging revealed 1,323 with elevated amyloid levels who were eligible to continue in the A4 study.
“In 2014, A4 was a first-of-its-kind study because it used amyloid PET to identify cognitively normal people with high levels of brain amyloid,” said Laurie Ryan, Ph.D., chief of the Dementias of Aging branch in NIA’s Division of Neuroscience.
“Before the availability of amyloid PET, other amyloid-targeting clinical trials may have been testing therapies in some people who didn’t have amyloid.”
Writing for the A4 study team, lead author Reisa A. Sperling, M.D., at Brigham and Women’s Hospital and Harvard Medical School, Boston, noted in the paper that the screening data of all 4,486 participants who had PET imaging is now available to the research community. This new data will help improve efficiency of screening and enrollment of other trials designed to prevent Alzheimer’s in people without symptoms.
“A4 demonstrates that prevention trials can enroll high risk individuals — people with biomarkers for Alzheimer’s who are cognitively normal,” said Ryan, adding, “Ultimately, precision medicine approaches will be essential.”
“Alzheimer’s disease is never going to have a one-size-fits-all treatment,” she said.
“We’re likely to need different treatments, even combinations of therapies, for different individuals based on their risk factors.”
NIA’s diverse Alzheimer’s disease and related dementias research portfolio includes about 230 clinical trials.
Of these, more than 100 are focused on non-pharmacological interventions, including but not limited to diet, exercise and cognitive training.
Of the current 46 pharmacological trials supported by NIA, most investigate targets other than amyloid, such as neuroprotection and inflammation.
Funding: The research in this study is funded by NIH grants U19AG010483 and R01AG063689. Clinical trial number NCT02008357.
Neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease, and spinocerebellar ataxia, have characteristic abnormal protein aggregates in the brain.
In AD, the two neuropathological characteristics are amyloid plaques composed of amyloid β-protein (Aβ) and neurofibrillary tangles of hyperphosphorylated tau protein .
Human genetic association studies, biochemical analyses of AD plaque content, and various animal models with altered Aβ or tau expression have strongly implicated Aβ and tau in AD pathogenesis .
Furthermore, many in vivo and in vitro studies have demonstrated the neurotoxicity of these amyloidogenic proteins. However, amyloid neurotoxicity depends strongly on Aβ’s primary structure and aggregation state. For example, two predominant Aβ forms are produced in humans and are comprised of either 40 (Aβ1-40) or 42 (Aβ1-42) amino acid residues.
The relative proportion of Aβ1-42 appears to be particularly crucial for AD progression, as this longer form is more prone to aggregation and is inherently more toxic than Aβ1-40 . Aβ molecules form low molecular weight (LMW) oligomers, high molecular weight (HMW) oligomers such as protofibrils (PFs), and mature fibrils, which have been suggested to be primary agents of neuronal dysfunction in AD .
Although these Aβ aggregates may directly cause neuronal injury by acting on synapses or indirectly by activating astrocytes and microglia , evidence also supports the hypothesis that soluble oligomeric Aβ plays an important role in AD pathogenesis (i.e., the oligomer hypothesis) [1,3,4].
Many types of oligomeric Aβ species have been demonstrated in vitro, with PFs being commonly described. Aβ PFs are defined as curved linear structures >100 kDa that remain soluble upon centrifugation at 16,000–18,000× g [3,5–7].
The neurotoxicity of these Aβ PFs formed in vitro, as well as their ability to induce electrophysiological effects on neurons, has been demonstrated by several groups [8–11]. Arctic Aβ is the result of a mutation in the gene that encodes the amyloid precursor protein (APP) and leads to the production of a particular Aβ species, [Glu22Gly]Aβ, with a high propensity to form PFs .
We recently reported that PFs disturb membrane integrity by inducing reactive oxygen species’ (ROS) generation and lipid peroxidation, resulting in decreased membrane fluidity, intracellular calcium dysregulation, depolarization, and impaired long-term potentiation (LTP). In addition, the damaging effects of PFs were found to be significantly greater than those of LMW-Aβ1-42 .
Current treatments for AD are primarily aimed at mitigating symptoms, while disease-modifying approaches are aimed at halting or attenuating the progression of the disease, such as inhibiting Aβ production and aggregation or promoting Aβ1-42 clearance .
However, despite many long and expensive trials, no disease-modifying drug for AD has been approved [15,16]. A recent failure in phase 3 involved the investigation of a β secretase in patients with mild-to-moderate AD .
Other large, phase 3 trials using anti-amyloid approaches including semagacestat , bapineuzumab , and solanezumab , have yielded disappointing results. However, it has been recently reported that BAN2401 (mAb158), an antibody developed for early AD with a unique target binding profile selective for Aβ PFs, significantly slowed cognitive decline by 30%, with a concomitant reduction in amyloid plaques, compared with placebo at 18 months .
In this review, we focus on recent developments from basic and clinical studies of PFs, including research findings from our laboratory.
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