What are the biological and clinical stages of Alzheimer's disease?

From the Guidelines

Alzheimer's disease progresses through distinct biological and clinical stages, including preclinical, mild cognitive impairment, and dementia, with the most recent evidence suggesting that the biological process starts with the evidence of AD neuropathological changes, irrespective of clinical symptoms 1. The biological stages of Alzheimer's disease are characterized by amyloid beta protein accumulation forming plaques, followed by tau protein tangles, neuronal damage, and brain atrophy.

• The preclinical phase of AD (stage 2) comprises the condition of subjective cognitive decline (SCD), in which healthy adults subjectively experience cognitive decline, while performance on neuropsychological testing is within normal limits and activities of daily living are preserved 1.
• The prodromal phase of AD is characterized by the stage of mild cognitive impairment (MCI), which is an at-risk condition for dementia and is defined as a clinical syndrome, in which mild cognitive deterioration is present but activities of daily living are preserved 1. The clinical stages of Alzheimer's disease advance from preclinical (no symptoms but biological changes present), to mild cognitive impairment (subtle memory problems), to mild dementia (noticeable memory loss, confusion), moderate dementia (significant memory loss, personality changes, difficulty with daily activities), and severe dementia (complete dependence, loss of communication abilities, physical decline) 1.
• Early detection is crucial as medications like cholinesterase inhibitors and memantine can temporarily slow symptom progression when started early 1.
• The disease reflects a gradual breakdown in brain function, with each stage representing increasing neuronal damage and corresponding cognitive and functional decline. The most recent study on the topic, published in 2024, highlights the importance of distinguishing between the biological and clinical disease staging, and suggests that the biological process starts with the evidence of AD neuropathological changes, irrespective of clinical symptoms 1.
• This study also emphasizes the need for a joint consensus regarding recommendations and guidance for the use of predictive diagnoses in AD, considering the effects of the paradigm shift toward predictive medicine and the shift from research to clinical contexts for implementing less invasive biomarkers 1.

From the Research

Biological Stages of Alzheimer's Disease

• The biological process of Alzheimer's disease begins with the appearance of AD neuropathologic change (ADNPC) while people are asymptomatic 2
• The progression of the neuropathologic burden leads to the later appearance and progression of clinical symptoms 2
• Early-changing Core 1 biomarkers, such as amyloid positron emission tomography (PET), approved cerebrospinal fluid biomarkers, and accurate plasma biomarkers, map onto either the amyloid beta or AD tauopathy pathway 2
• These biomarkers reflect the presence of ADNPC more generally, including both neuritic plaques and tangles 2

Clinical Stages of Alzheimer's Disease

• Three clinical phases of Alzheimer's disease may be defined:
  • Pre-symptomatic (or pre-clinical) AD, which may last for several years or decades until the overproduction and accumulation of Aβ in the brain reaches a critical level that triggers the amyloid cascade 3
  • Pre-dementia phase of AD, in which early-stage pathology is present, ranging from mild neuronal dystrophy to early-stage Braak pathology, and may last for several years according to individual resilience and brain reserve 3
  • Clinically defined dementia phase of AD, in which cognitive and functional impairment is severe enough to surmount the dementia threshold 3
• An abnormal Core 1 biomarker result is sufficient to establish a diagnosis of AD and to inform clinical decision making throughout the disease continuum 2
• Later-changing Core 2 biomarkers can provide prognostic information, and when abnormal, will increase confidence that AD is contributing to symptoms 2

Relationship Between Biological and Clinical Stages

• The characterization of pathogenic Aβ by means of biochemical analysis of biological fluids or by molecular neuroimaging are presented as diagnostic tools to help identify AD cases at the earliest stages of the disease process 3
• The cumulative knowledge on the pathogenesis of AD derived from basic science models will hopefully be translated into clinical practice in the forthcoming years 3
• An integrated biological and clinical staging scheme is described that accommodates the fact that common copathologies, cognitive reserve, and resistance may modify relationships between clinical and biological AD stages 2