Current State of Alzheimer's Disease
Introduction
Alzheimer's disease (AD) dementia is characterized by a specific pattern of cognitive and functional decline associated with aging, ultimately leading to death. It was initially documented by Alois Alzheimer in 1906 when he presented the case of Auguste Deter, a 51-year-old woman who displayed cognitive disturbances, disorientation, delusions, and other behavioral changes when first examined in 1901. Mrs. Deter passed away 4.5 years later in 1906. Alzheimer's neuropathological examination revealed widespread brain atrophy and distinctive alterations in clusters of cortical cells. These findings were presented in a lecture on the unique disease process affecting the cerebral cortex.
The clinical diagnostic criteria for AD dementia underwent modernization in 1984 and subsequent refinements in 2011 and 2018, incorporating the use of biomarkers and the ability to identify preclinical stages of the disease. Although Alzheimer's initial description in 1906 was qualitative, the molecular characteristics of the disease's two defining pathologies—beta-amyloid peptide in plaques and hyperphosphorylated tau protein in neurofibrillary tangles (NFTs)—were not identified until the mid-1980s. As research progressed, neuropathological assessments of AD evolved to recognize multiple concurrent neuropathologies that further contribute to clinical dementia.
In the United States, AD is the most prevalent form of neurodegenerative dementia, with a higher burden on minority populations. Following the enactment of the National Alzheimer's Project Act (NAPA) in 2011 under President Obama, the U.S. national plan to address AD was established in 2012, outlining five ambitious objectives: to prevent and effectively treat AD by 2025, enhance the quality and efficiency of care, expand support for patients and caregivers, raise public awareness, and track progress while driving improvements.
National Action Plan
Following the enactment of the National Alzheimer's Project Act (NAPA) in 2011 under President Obama, the U.S. national plan to address AD was established in 2012. This plan outlined five ambitious objectives:
- Prevent and effectively treat AD by 2025.
- Optimize the quality and efficiency of care.
- Expand support for patients and caregivers.
- Enhance public awareness.
- Track progress and drive improvements19.
Diagnostic Criteria Evolution: From Clinical to Biological
The way we diagnose Alzheimer’s disease has evolved significantly over time. Initially, during the days of Alois Alzheimer (1864–1915), it was primarily based on pathological observations. However, in 1984, there was a shift toward a clinical and exclusionary approach.
The clinical diagnosis relied on criteria set by the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association. This approach combined clinical observations with some biological aspects. Subsequent efforts, including those by the International Working Group and the National Institute on Aging in collaboration with the Alzheimer’s Association, introduced biomarkers to transform Alzheimer’s disease diagnosis into a more biological categorization.
Initially, Alzheimer’s disease diagnosis was limited to the dementia stage, characterized by significant cognitive decline across multiple domains or noticeable neurobehavioral symptoms affecting daily life. Dementia marked the point where individuals were no longer fully independent, setting it apart from mild cognitive impairment.
As biomarker research progressed, Jack and colleagues introduced a framework known as the ATN framework. This framework categorized biomarkers into A (amyloid), T (phosphorylated tau), and N (neurodegeneration). It defined Alzheimer’s disease diagnosis based on the presence of amyloid β and phosphorylated tau. This research-oriented approach emphasized the significance of amyloid β and tau as key factors, suggesting that Alzheimer’s disease could be diagnosed solely based on biomarker evidence, clearly distinguishing it from dementia.
While the ATN framework had its merits, there were critiques regarding the exclusion of other significant causes of dementia, such as vascular disease. The authors argued that dementia often involves multiple underlying pathologies, with Alzheimer’s disease being just one of them. However, Alzheimer’s disease was defined by the presence of amyloid β and tau. Despite its potential, the complexity of ATN categories and the omission of other pathologies made it unsuitable for clinical practice.
Despite the growing importance of biomarkers, clinical diagnosis still relied on the criteria established by the National Institute on Aging in 2011.
The ATN framework did provide a path to diagnose Alzheimer’s disease before the onset of Alzheimer’s disease-associated dementia. It enabled personalized risk profiling for individuals with mild cognitive impairment. However, a study on doctor-patient communication in memory clinics revealed that clinicians were hesitant to share specific prognostic information with mild cognitive impairment patients. In the context of pre-dementia diagnosis, dealing with subjective cognitive decline posed even greater challenges. A recent Personal View article aimed to characterize subjective cognitive decline clinically and provide guidance to clinicians, acknowledging that it might or might not be attributed to underlying Alzheimer’s disease.
Although ATN biomarkers showed promise in predicting dementia in cases of subjective cognitive decline at a group level, creating individualized risk models remained a challenge. A Delphi study highlighted that patients and caregivers valued precise and specific information, even if it did not provide complete certainty.
Tools like ADappt are urgently needed to support decision-making and facilitate communication about Alzheimer’s disease diagnosis.
The Alzheimer’s Disease Continuum: From Silent Pathology to Dementia
Alzheimer’s disease is not a sudden onset condition but rather a gradual continuum that can span 15 to 25 years. It begins with the presence of Alzheimer’s pathology in the brain, often without any noticeable symptoms. Over time, individuals may enter a stage known as mild cognitive impairment, a phase that precedes overt dementia. This progression illustrates that dementia represents the end result of the prolonged presence of Alzheimer’s disease pathology.
It’s important to note that not every patient will follow this precise path. Between normal cognitive function and mild cognitive impairment, some individuals may experience subjective complaints. However, not all complaints indicate early signs of dementia, and it remains uncertain how predictive these complaints are for the development of dementia.
graph LR
A(Normal) ---> B(Mild Cognitive Impairment) ---> C(Dementia);
A-- Duration: 15-25 years ---CCreated: September 22, 2023