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Key points
- Alzheimer's drugs have had a 99% fail rate over the last several decades.
- The leading theory of causation is challenged by the heterogeneity and age-related nature of Alzheimer's disease.
- Despite drug failures, dementia rates are declining in the U.S. and other Western countries due to effective public health measures.
Since the 1970s, a cure for Alzheimer’s has always been right around the proverbial corner.
The dominant story pushed by advocacy organizations, the pharmaceutical industry, and academic experts has been that Alzheimer’s is a disease separate from brain aging that will be defeated by “attacking” specific molecules. For the last two decades, the primary target has been beta-amyloid protein—one of the features of the neuritic plaques noted by German psychiatrist Alois Alzheimer and others in the early 20th-century.
While billions have been spent in drug development over the last two decades, the lion’s share on anti-amyloid approaches, efforts have consistently failed. The FDA’s much-maligned June approval of the anti-amyloid biologic aducanumab, which also failed to adequately demonstrate clinical efficacy while raising major concerns about safety and cost, has again stirred up questions about the very premise that we can “cure” Alzheimer’s.
What is confounding this decades-long molecular “war”?
Amyloid is complicated and pathology is not destiny
While Alzheimer’s has often rhetorically been compared to polio in fundraising efforts, the role of amyloid in the brain is more complex than a virus. Amyloid-related components have been shown to have antioxidant properties, to be crucial to growth of cells, synapses, and learning, and involved in stress and immune responses. While its appearance may be indicative that something’s “not quite right” in the brain, reducing amyloid to a specific pathogenetic factor via analogy to poliovirus has been misguided.
Importantly, research has not strongly established that levels of amyloid clearly correlate with cognitive symptoms. Amyloid deposition frequently occurs in the cognitively intact, with up to 40% of nondemented elderly reaching neuropathologic criteria for Alzheimer’s based on amyloid burden alone. Similarly confounding is that 25-30% of people clinically diagnosed with Alzheimer’s are, upon postmortem-analysis, observed to lack neuropathological criteria for the illness. Cognitive symptoms correlate more strongly with presence of tau tangles (the other hallmark of the “disease” first described by Dr. Alzheimer). Despite beliefs that tangles follow plaques in pathogenic cascades, the interrelationships between amyloid and tau are unclear.
Such complexities raise foundational questions. Have we mistakenly regarded disease-associated proteins like amyloid as “toxic”? Is amyloid’s appearance merely an effect of earlier damage rather than causative? Are anti-amyloid therapies attacking a process associated with normal brain aging that may be protective?
The strongest case for amyloid has been the relationships between various autosomal dominant mutations in early-onset disease and amyloid processing. But the rare early-onset illness is not the same as the more common late onset.
Moreover, our thinking about the role of genes in disease has changed dramatically from earlier simplistic models. Linear cascades of genes-->proteins-->specific molecular derangements that can be treated by targeting drugs and biologic treatments are no longer seen as realistic conceptual approaches. Molecular biologists have made simple, often fame-and-fortune-seeking, claims about impending breakthroughs, but we have gradually learned we need to apply a more systems-based approach to complex neurodegenerative diseases. As we study genomics, we are becoming increasingly confused about what a gene actually is. It is not just an inherited strand of DNA, but rather a network of genetic and environmental relationships that change over time.
Epigenetics is just the tip of the intellectual iceberg with respect to how limited our thinking about molecular cures have become.
Alzheimer’s isn’t one thing
While Alzheimer’s is conventionally regarded as a singular “disease,” it is in reality highly heterogeneous. This heterogeneity applies to genetics, risk factors, age of onset, clinical presentation, progression, response to drugs, and—perhaps most importantly—brain pathology.
When neuropathologists examine the brains of people diagnosed with Alzheimer’s at the molecular/cellular levels, “it” appears to be the outcome of multiple overlapping pathological abnormalities. In fact, a majority of so-called AD cases show signs of mixed dementia. This means they encompass not only plaques and tangles, but also pathologies like vascular lesions, accumulation of alpha-synuclein (the abnormal protein in Lewy bodies), abnormal proteins called TDP-43, hippocampal sclerosis, and white matter disease. Even in cases with classic plaques and tangles, distributions of lesions vary in the brain and bear unclear relationships to patterns of neuronal death and other less common pathological features. The 2018 NIA-AA Research Framework illustrates the variability of patterns of pathologies and the unclear relationships among them.
What this well-established phenomenon means is that there are multiple pathways to neurodegeneration in persons clinically diagnosed with AD that frequently overlap.
It would be much more appropriate to speak of Alzheimer’s diseases (plural) or Alzheimer’s syndrome than perpetuate the misapprehension we are dealing with a singular condition that can be instrumentally fixed via single-mechanism drugs. Indeed, given the reality of underlying heterogeneity, it is perhaps unsurprising that drugs like aducanumab targeting isolated aspects of this diffuse syndrome have almost universally failed to provide clinical benefit. While current therapies are organized around the theory (and business plan) that all Alzheimer’s can be effectively treated via pathways that converge on amyloid, this has left untreated a significant proportion of associated conditions in the AD phenotype that are unrelated to plaque-and-tangle pathology (e.g., vascular damage).
As researcher John Hardy stated about the heterogeneity of Alzheimer’s in Margaret Lock's book The Alzheimer's Conundrum: “I wouldn’t say it’s a dirty little secret. Everybody knows about it. But we don’t know what to do about it.”
But if we can’t properly define the condition, how can we realistically posit a cure?
Alzheimer’s is entangled with aging
Despite billions of dollars flowing into the pursuit of diagnostics and cure, there remains no definitive way to distinguish Alzheimer’s from severe brain aging. Most scientists would at least privately concede that the notion of brain aging and Alzheimer’s arising from clearly differentiated physiological processes—a distinction first made in the '70s when the National Institute on Aging came into existence and made Alzheimer’s its cause célèbre—is simply unproven.
Given what we’ve since learned about intimate entanglements of Alzheimer’s and aging, this appears far more defensible as a political stratagem than a scientific thesis. Cambridge researcher Carol Brayne and colleagues have referred to the “dis-entangling” of Alzheimer’s and aging as the “great Alzheimer’s mistake,” as age remains far and away the strongest risk factor for dementia.
Curing Alzheimer’s may entail curing aging
Let’s allow ourselves to dream: we eventually “cure” Alzheimer’s. What does this practically mean? Would a cure allow patients to return to an earlier brain state (for example, their brains before age 60)? Would they still experience aging in their brains and could that become severe, causing forgetfulness? How would that condition be different from Alzheimer’s? Would we be confronting a new challenge—that of curing brain aging?
Finding hope in prevention and care
At present, the prospect of “curing Alzheimer’s” is more innovation fantasy than reality. It is important to be honest about the challenges we face and sensitive to the dangers of creating false hope for those living with dementia and their families. We should be skeptical of the long-standing belief that there is a causal relationship between money spent on Alzheimer’s research and finding cures, which is functionally a form of superstition.
The good news is this: when we approach the challenge more systemically, there is genuine reason for hope.
Focusing on prevention rather than cure is perhaps where we can make genuine progress. Once again, drugs fail the task, but current research suggests up to 40% of dementia risk may actually be amenable to prevention/delay by focusing on social determinants of brain aging. Rates of dementia have been falling in the U.S. and Western Europe due largely to public policies initiated in the mid-20th century (expanding public education, building national health care systems that have effectively treated vascular risk factors, successful smoking cessation programs, de-leading gasoline, etc.) that have improved brain health at the population level.
Arguably, achieving universal health care, supporting lifelong learning (e.g., universal free college/vocational training), reducing pollution exposure, and addressing the nation’s aging water pipe infrastructure (which has yielded a modern-day lead crisis) could be expected to exponentially contribute to brain health across decades. Of course, we can also substantially improve the systems that care for persons living with dementia and their families.
Ultimately, absent a cure for Alzheimer’s, there remains much we can do for one another.
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This post has been adapted from the forthcoming book American Dementia: Brain Health in an Unhealthy Society (Johns Hopkins University Press). Learn more at americandementia.com.
