From the Guidelines
Alzheimer's disease (AD) is a progressive neurological disorder with a long preclinical phase, followed by a prodromal stage of mild cognitive impairment (MCI), and ultimately leading to dementia. The natural history of AD is characterized by the accumulation of amyloid beta (Aβ) plaques and neurofibrillary tangles, leading to neuronal degeneration and cognitive decline 1.
Preclinical Phase
The preclinical phase of AD can last for decades, during which time individuals may be asymptomatic, but biomarker evidence of AD pathology, such as Aβ accumulation, may be present 1.
Prodromal Stage
The prodromal stage of AD is characterized by MCI, which is a clinical syndrome defined by mild cognitive deterioration, but with preserved activities of daily living 1. Individuals with MCI and biomarker evidence of AD have an increased risk of developing dementia, with up to 90% progressing to dementia within 5 years 1.
Clinical Phase
The clinical phase of AD is characterized by dementia, which is defined by significant cognitive decline, impaired daily functioning, and behavioral changes 1. The diagnosis of probable AD dementia can be made based on clinical criteria, including insidious onset, clear-cut history of worsening cognition, and prominent cognitive deficits in one or more domains, such as memory, language, visuospatial, or executive function 1.
Biomarkers
Biomarkers, such as Aβ and tau, can be used to support the diagnosis of AD and predict progression to dementia 1. However, the use of biomarkers in clinical practice is still evolving, and there is a need for standardized recommendations for counseling and disclosure of biomarker results 1.
Modulating Factors
The natural history of AD can be influenced by various modulating factors, such as vascular risk factors, depressive symptomatology, and cognitive reserve, which can alter the pace of clinical expression of AD 1.
Clinical Implications
Understanding the natural history of AD is essential for the development of effective prevention and treatment strategies, as well as for providing accurate diagnosis, counseling, and care for individuals with AD and their families 1.
From the Research
Natural History of Alzheimer's Disease
The natural history of Alzheimer's disease (AD) is a complex and multifaceted process that spans several years, from preclinical stages to severe impairment [(2,3,4)]. The disease is characterized by a seamless continuum, with pathophysiological changes beginning many years prior to clinical manifestations 2.
Preclinical Stages
The preclinical stages of AD are marked by an insidious impairment of memory, which may progress to mild cognitive impairment (MCI) 4. Before MCI, there is a prodromal, ill-defined presymptomatic period of disease ('pre-MCI") 4.
Clinical Stages
The clinical stages of AD are characterized by:
- Deficits in the ability to encode and store new memories 3
- Progressive changes in cognition and behavior 3
- Problems with naming and word-finding, verbal and written comprehension and expression 4
- Visuospatial, analytic and abstract reasoning abilities, judgment, and insight become affected 4
- Behavioral changes, such as delusions, hallucinations, irritability, agitation, verbal or physical aggression, wandering, and disinhibition 4
Disease Progression
The disease progression of AD is influenced by various factors, including:
- Metabolic, vascular, and inflammatory changes 3
- Comorbid pathologies 3
- Amyloid precursor protein (APP) cleavage and production of the APP fragment beta-amyloid (Aβ) 3
- Hyperphosphorylated tau protein aggregation 3
Survival and Mortality
The survival and mortality rates of AD patients are sensitive to modeling assumptions concerning mortality 5. Patients with fronto-temporal dementia (FTD) may experience poorer survival than those with AD 6.
Key Features
The key features of the natural history of AD include:
- A seamless continuum from preclinical to clinical stages 2
- A multifaceted process involving pathophysiological, biomarker, and clinical perspectives 2
- A complex interplay of genetic, environmental, and lifestyle factors [(3,4)]
- A need for disease-modifying therapies to effectively manage the disease [(2,3,4)]