A diagnosis of Alzheimer’s Disease (AD) often comes late, typically when cognitive impairment is perceptible by the affected or their family. In addition to neuropsychological testing, current diagnostic options comprise brain imaging and body fluid analysis (‘biomarkers’). After excluding other causes of cognitive decline, the initial diagnosis ‘probable’ AD could be the outcome. Decades ago, AD was safely confirmed by post-mortem analysis, by detecting amyloid plaques and tau tangles in the brain. The advance of biomarker and brain imaging research today is a promise to diagnose AD early. But should AD be diagnosed in the absence of clinical symptoms?
I assume the majority of neurodegeneration researchers would agree that AD is still not satisfyingly defined. For many, it is still an ill-defined multifactorial condition with age as a major risk factor. It is a condition that comes in various facets, caused by individual genetic and non-genetic risk factors. Is such an open definition reasonable? Is it reasonable to accept that AD represents a ‘syndrome’ rather than a clearly defined ‘disease’? Yes, I think it is!
The label “Alzheimer’sche Krankheit” (German for ‘Alzheimer’s Disease’) was introduced about 110 years ago, based on a single case. At that time, the brains Alois Alzheimer and colleagues analyzed under the microscope very likely came from familial early-onset cases (genetic cases, presenile dementia). In the 1970s, the term ‘AD’ was expanded to also include age-related forms (multifactorial sporadic cases, senile dementia). In my opinion, this was a grave and central error in AD research1. With that expansion, AD became an umbrella term combining very rare genetic and very frequent age-related sporadic dementia. Subsequently, under this umbrella, the different AD forms were defined simply as a ‘plaques-and-tangles disease’. This insinuated that all AD forms have the same cause and, therefore, should be treatable by a one-size-fits-all approach. Based on the amyloid-cascade hypothesis of the 1990s, the prime therapeutic target became the amyloid beta peptide1. Considering all the failed anti-amyloid clinical trials and the moderate clinical effects of the newly approved anti-amyloid antibodies (aducanumab, lecanemab, and donanenamb; all FDA approved), it appears almost obsessive to force a multi-faceted, multifactorial, and—in the majority of cases—age-related disease, into one very limited pathogenetic framework. With that, of course, biomarker research has also been predetermined.
Prioritization of AT over cognitive decline
In 2011, National Institute on Aging/Alzheimer’s Association (NIA-AA) workgroups agreed on recommendations for AD diagnostics/evaluation in different stages of the disease (preclinical, mild cognitive impairment, dementia). In 2018, these guidelines were updated and called a ‘research framework’2. The 2018 guidelines used a so-called AT(N) classification system, which, defined by the amyloid cascade (hypothesis), relied on the presence of amyloid (A) and tau (T), detectable in CSF and with PET imaging. This classification system also considered neurodegeneration (via detection of neurofilament, N), and, therefore, neuron loss as the prerequisite of cognitive impairment. Just recently, an Alzheimer’s Association Workgroup published a reworked proposal3 that reinforces the established diagnostic classification system, however, now prioritized AT biomarkers over neurodegeneration and cognitive decline in AD diagnosis. These recent diagnostic criteria rely exclusively on defined biological hallmarks, clinical symptoms are no longer needed for an AD diagnosis. As expected, this proposal caused quite some disapproval in the neurodegeneration community. Above all, the criticism and concerns highlighted the potential of a significant overdiagnosis of clinically asymptomatic individuals in the future.
Is AD diagnosis without symptoms appropriate?
As one voice out of many, the American Geriatrics Society (AGS) called this new approach inconsistent and commented that diagnosing asymptomatic patients through positive biomarker testing alone poses a risk for harm (financial, psychological, or social) while lacking any benefit. The AGS rather advocated for categorizing asymptomatic biomarker-positive individuals as “at elevated risk” instead of assigning them a clinical AD diagnosis. Further questions addressed how reliable biomarkers are in principle, or who exactly should decide about the redefinition of a disease diagnosis.
Another question that comes to mind: AT-positive/asymptomatic AD and then what? Consequently, if these redefined criteria become the new norm, with AD biomarker testing becoming more readily available, many more individuals will test “positive for AD” and—accepting the results as outcome determined—be somewhat left without effective treatment options for asymptomatic individuals. The approved anti-amyloid antibodies so far were only tested in patients at an early symptomatic disease stage, with limitations regarding gender and genetic background, and only moderately curbing cognitive decline while posing possible severe side effects.
Back to amyloid only again?
As pointed out before1, for many, the decades-long focus of AD research on amyloid beta alone has been a path too narrow and misleading. After all, it has not created any breakthrough therapy or cure. The ‘revised criteria for diagnosis and staging of Alzheimer’s disease’ reinforces the definition of AD as a ‘plaques-and-tangles disease’ and further promotes the focus on amyloid. Thirty years after the advent of the amyloid-cascade concept we know that 30-40% of the elderly do have plaques and tangles but no cognitive impairments. In addition, based on the recent diagnosis proposal, about 20% of individuals 50 years of age or above are estimated to be defined as having AD. Interestingly, this new idea of diagnosing and staging AD has appeared amidst a growing acceptance of AD as an age-related neurodegenerative diseases with multifactorial and multigenetic origins. Dozens of risk genes impacting on various biological pathways (e.g. inflammation, metabolism, protein clearance) have been discovered and need to be included into a more integrative framework of age-related neurodegeneration. Again, despite other announcements from parts of the AD field, the exact causes of this disease are not known yet. The recently shown effects of lecanemab and donanemab effectively removing amyloid from the brain, with only minor clinical effects, is not a proof of a causal role of amyloid in AD.
In my opinion, AD research should concentrate more on amyloid-independent pathways and the power of prevention. In addition, it does not help to put all the different types of age-related neurodegeneration into individual research drawers and investigate them separately. I am convinced that future success in uncovering the exact causes of neurodegeneration and finding therapies is only possible when we leave these research silos, better now than later.
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