This research was supported by BrightFocus
Longitudinal Data Needed
Reacting to the timeline of Alzheimer’s changes reported by Ossenkoppele et al, David Holtzman, MD, made the following comments to Alzforum:
“Other studies have estimated that amyloid deposition begins about 10-20 years prior to the onset of symptomatic Alzheimer’s disease or very mild dementia due to AD. The authors here argue that amyloid deposition may begin 20-30 years prior to the onset of cognitive decline due to AD. I think longitudinal studies that are ongoing will be required to determine the timeframe following amyloid deposition in which cognitive decline begins to occur. "
Holtzman is an Alzheimer’s researcher and faculty chair of neurology at Washington University in St. Louis and a member of the BrightFocus Scientific Review Committee. —MST
In two studies receiving international attention, 2013-16 BrightFocus grantee Rik Ossenkoppele, PhD, of Vrije Universiteit (VU) Medical Center, Amsterdam, and colleagues in the Netherlands have lent confidence to our understanding of how Alzheimer’s develops. Their findings help confirm that amyloid beta (Aβ) peptide levels start to build up and aggregate long before Alzheimer’s symptoms develop, and are predictive of disease.
Published in JAMA on May 19, both studies were meta-analyses, studies that are conducted by doing statistical analyses on aggregated data collected in previous research. While researchers can control for variations in data sets and other factors that might impinge upon scientific accuracy, meta-analyses, because they rely on second-hand data, cannot offer proof. However, these studies have provided a reassuring level of support for what already has been observed and hypothesized about the biologic timing and course of Alzheimer’s disease (AD).
“These reports are the largest and most detailed to date,” commented Roger N. Rosenberg, MD, a neurologists and long-time editor of JAMA Neurology. His editorial accompanied the studies in JAMA.
To conduct the studies, researchers first searched scientific literature to identify previous studies where amyloid pathology was confirmed using existing techniques (cerebrospinal fluid, CSF, biomarkers or positron emission tomography (PET) imaging. Then, thanks to cooperation from many researchers they contacted, they were able to crunch numbers on amyloid burden from shared data involving 9,500 people enrolled in 55 Alzheimer’s and/or amyloid beta (Aβ) detection studies on five continents.
One of the meta-analyses looked at the prevalence of amyloid pathology in persons without dementia (Jansen et al, 2015), while the other analyzed rates of Aβ positivity in people with Alzheimer’s disease (AD) or other dementias (Ossenkoppele et al, 2015).
Results confirmed that the ApoE4 mutation, a known Alzheimer’s risk factor, accelerates amyloid accumulation. Amyloid was two to three times more prevalent in subjects with the ApoE4 phenotype than in noncarriers, and this association went up with age and a diagnosis of cognitive dysfunction.
- There was a 20- to 30-year interval between amyloid positivity and AD dementia, as compared with a 10- to 20-year interval seen in other studies. This was one of the more surprising findings (see nearby).
- Higher levels of education were associated with a higher prevalence of amyloid positivity, yet a lower and later onset of AD-type dementia. This finding supports the “cognitive reserve” hypothesis, ie, that increased levels of learning make the brain stronger and more resilient to AD symptoms, even in the presence of amyloid-related pathology. [See Ossenkoppele's comments on cognitive reserve in the Q/A below.]
- Amyloid was detected in people with normal cognition, and increasingly so with age, from 10 percent in 50-year-olds to 23 percent in 70-year-olds, to 43 percent 90-year-olds. The researchers suspect these individuals may be resistant to AD symptoms, possibly due to variables like cognitive reserve or because their AD may have been in a “prodromal”—or asymptomatic, early stage.
Why Are These Findings Important?
While amyloid and even Aβ peptides are present in the human body throughout life, and serve some normal functions, Ossenkoppele and colleagues provide support for the idea that abnormal amyloid accumulation in the brain is an early process that drives Alzheimer’s. Early plaque formation may trigger other neurodegenerative changes, such as the misfolding of tau amyloid proteins into neurofibrillary tangles known as tau tangles; the loss of synapses, or “connection points” that transfer signals between neurons; and overall brain atrophy, or shrinkage, resulting in a measurable loss of brain volume. All these factors in combination are sometimes described as a “neurodegenerative cascade.”
With Aβ build-up as a key driver, these changes typically remain hidden in the brain for up to two decades, that is, until significant damage already is done, or in progress. Typically, it is only then that the recognizable symptoms of Alzheimer’s will prompt a diagnosis. And unfortunately, when that happens, cognition and quality of life tend to quickly decline. Currently there are no drugs to stop Alzheimer’s changes from happening, only ones that mask the symptoms. Life expectancy for the typical Alzheimer’s patient after diagnosis is about eight to 10 years, on average.
In contrast, when patients are diagnosed early—in prodromal (ie, asymptomatic) stages, or with minor cognitive impairment (MCI), a type of forgetfulness on a par with normal aging—it’s still possible to enjoy a high quality of life. People with MCI have time to plan for what’s ahead. They can also make lifestyle changes that have been shown to minimize and even delay cognition changes in some people, involving nutrition, exercise, social interaction, and mental activity.
Currently, drugs that might slow or stop Aβ build-up are being tested in clinical trials. These anti-amyloid agents belong to a new category of drugs labeled “disease-modifying treatments” because they are designed to actually slow or stop Alzheimer’s changes, not just mask symptoms. Some of these agents were tested in earlier trials, and failed. Experts believe that the reason they failed is because they were started too late—after devastating neurodegenerative changes had occurred.
So, this new evidence from the Netherlands is important because it supports the hypothesis behind a new treatment strategy. It suggests that it may, in fact, be possible to modify the course of Alzheimer’s by inhibiting amyloid buildup, as long as treatment starts early enough. That’s extremely promising.
It also underscores the value and even necessity of quantifying AB levels and plaque burden at baseline in clinical trials, particularly those involving anti-amyloid agents. A drug that attacks amyloid cannot be expected to have an impact on other potentially confounding causes of dementia, such as vascular disease, brain atrophy, and other conditions.
“Immunotherapeutics are now at a critical juncture,” Rosenberg said in his JAMA editorial, citing the three clinical trials now in progress. One of these is the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Study (“A4” for short) being co-led by Riesa Sperling, MD, of Harvard. A 2010-13 BrightFocus grantee, Sperling helped develop PET imaging for early amyloid detection.
While still other therapies are envisioned up ahead, anti-amyloid therapy now looks extremely promising despite a backdrop of earlier, failed trails. Many think it will work if used earlier, before amyloid sets in motion irreversible changes that affect cognition.
“The meta-analyses reported here provide the basis for clarifying the parameters for using anti-amyloid-β therapies among patients at risk for AD and providing impressions as to which patients are most at risk and would potentially benefit most with anti-amyloid-β therapy,” Rosenberg summarized.
Where Does Tau Fit In?
Amyloid” is a generic term for numerous different fibrous protein structures that are present naturally in the human body. While some of them have a normal function, many have been associated with disease and neurodegenerative disorders. Beta amyloid (Aβ) and tau amyloid are the two types specifically associated with Alzheimer’s disease (AD). Read more about how the tau protein is related to the development of Alzheimer's disease.
The Long View
Ultimately, researchers, clinicians, and health-conscious consumers will have to grapple with the question of whether the same tools being used in clinical trials to stratify AD risk, such as genetic subtyping and amyloid detection using imaging or biomarkers would prove useful in the general population. Today, the cost of these tests is prohibitive for most individuals outside of a clinical trial which covers those costs. Another dissuading factor is that many people would not choose to know ahead of time that they’ll develop Alzheimer’s if there is no treatment available to stop it.
All that that could change if anti-amyloid agents prove effective. There may be a move to bring down the cost of amyloid detection and make it reimbursable through Medicare and/or private health coverage. Doing so would represent a new front in the war against Alzheimer’s—a war that’s really only getting underway.
Interview with Researcher Rik Ossenkoppele, PhD
Author and driving force behind these new metaanalyses, Rik Ossenkoppele, PhD, is an Alzheimer’s researcher at Vrije Universiteit (VU) Medical Center in Amsterdam, and a 2013-16 BrightFocus grantee. These publications preceded his BrightFocus grant, where he is using PET imaging results to trace tau, Aβ and network degeneration in AD and test the amyloid cascade hypothesis.
Researcher Rik Ossenkoppele, PhD, has made it his life’s work to study Alzheimer’s—and BrightFocus is lending support.
Q. Amyloid imaging may be important for clinical treatment trials, but is it really useful in a clinical setting, given that there’s nothing yet, besides lifestyle interventions, to stop this cascade once it begins?
A. Yes, I think that this study shows that the application of amyloid imaging goes beyond clinical trial/research purposes, and can be of great value in clinical practice in certain scenarios, for example to establish a more accurate and earlier diagnosis of dementia. This could 1) reduce the uncertainty of patients and their caregivers about what is underlying the cognitive impairment; 2) optimize current treatment options (eg, certain AD medications worsen behavioral symptoms in frontotemporal dementia) and living arrangements; and 3) allow for planning for the future.
I do agree that the significance of amyloid imaging will further increase once an effective treatment becomes available.
Q. Your study supports the cognitive reserve hypothesis—that it exists and can be helpful in averting cognitive changes associated with Aβ build-up. Care to speculate?
A. Cognitive reserve is mostly a physiological phenomenon that exists by virtue of several mechanisms: 1) a greater quantity of synapses, 2) stronger connections between neurons within functional networks, 3) greater efficiency of neurons/networks, and 4) the ability to recruit alternative brain regions/networks when networks start to collapse.
The finding that cognitively normal persons with higher levels of education (which is a proxy of cognitive reserve) more often harbored amyloid pathology may reflect that they were able to longer withstand the toxic effects of amyloid-beta and/or its downstream effects. Several studies have shown that increased lifetime engagement in cognitive and physical activities may delay symptom onset, suggesting that lifestyle interventions may be useful.
Q. Do we need more research into more accessible (cheaper) Aβ imaging and/or biomarkers?
A. Yes. Quick, cheap and accessible tools to assess amyloid status are highly desirable, particularly in the prospect of disease modifying agents that would require large-scale screening in the population to intervene in a very early stage of the disease. —MST
Martha Taggart, BrightFocus Health and Science Writer
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