Alzheimer’s disease progresses through several distinct stages, each defined by the extent of brain damage and the corresponding cognitive and functional decline. These stages are commonly called preclinical, early, and late. This post summarizes Katie Peek's Scientific American article, "Alzheimer's impact on the brain."
Alzheimer's Progression
Preclinical Stage
The preclinical stage of Alzheimer’s represents the earliest phase of the disease, occurring long before any noticeable symptoms manifest. During this stage, pathological changes silently unfold within the brain, primarily in the form of beta-amyloid plaques and tau tangles.
Brain regions affected
The damage begins in the entorhinal cortex and hippocampus, areas critical for memory formation and spatial navigation. Beta-amyloid plaques begin to accumulate between neurons, while tau tangles form inside neurons, disrupting normal cellular function. Beta-amyloid graphic © Juan Gaertner/shutterstock.com.
Despite these changes, individuals typically do not exhibit any cognitive or functional impairments, as the brain can compensate for the early neuronal damage. Hippocampus graphic by 7mike5000, CC BY-SA 3.0 via Wikimedia Commons
Characteristics
No outward symptoms: The preclinical stage is asymptomatic. Cognitive functions such as memory, attention, and reasoning remain intact.
Biomarkers detectable: While there are no observable signs, advanced imaging (e.g., PET scans) and cerebrospinal fluid tests can detect abnormal levels of amyloid or tau proteins, signaling the onset of the disease.
Early interventions possible
The preclinical period is critical for future research into early interventions, such as lifestyle modifications or medication to prevent further neuronal damage.
Early Stage
The early stage of Alzheimer’s, also known as mild Alzheimer’s, marks the period where clinical symptoms begin to appear. At this point, the disease has caused enough neuronal loss and brain tissue shrinkage to affect cognition and daily activities. Lecanemab (Leqembi) may be administered to slow cognitive decline in patients at this stage.
Brain Regions Affected
The damage has spread from the hippocampus to other parts of the temporal and parietal lobes. The hippocampus continues to deteriorate, leading to memory problems. The frontal lobe also begins to experience dysfunction, impairing decision-making and planning. Cortex graphic © Vasilisa Tsoy/shutterstock.com.
Characteristics
Memory loss: Short-term memory begins to fade. Patients may forget recent events, repeat questions, or struggle to remember appointments or conversations.
Disorientation: Damage to the parietal lobe makes spatial tasks, such as navigating familiar places, more difficult.
Executive dysfunction: Patients may have trouble organizing thoughts, making decisions, or solving problems. Tasks that involve planning or completing multiple steps become harder.
Language issues: Word-finding difficulties can arise as damage spreads into brain regions involved in language production.
Mood changes: Emotional disturbances, including anxiety, irritability, or mild depression, may become noticeable as the frontal lobe begins to deteriorate.
While patients may still live independently at this stage, they require more help managing complex tasks such as finances or medication schedules.
Late Stage
The late stage of Alzheimer’s, also referred to as severe Alzheimer’s, is marked by profound and widespread brain atrophy, causing severe cognitive and functional impairments. This stage is associated with a near-total loss of independence and the need for full-time care.
Brain Regions Affected
By this stage, the damage has extended throughout the cerebral cortex, affecting the frontal, temporal, parietal, and occipital lobes. The hippocampus has experienced extensive neuronal loss, and the motor cortex and brainstem may also be affected, leading to loss of motor control and basic bodily functions.
Characteristics
Severe memory loss: Patients lose the ability to recognize loved ones, recall personal history, or even remember basic information about their surroundings. Long-term memories may also erode.
Inability to communicate: Language abilities are severely impaired. Patients may struggle to speak coherently or may stop speaking altogether.
Loss of physical function: As motor skills deteriorate, patients may lose the ability to walk, sit up, or even swallow. Incontinence becomes common.
Behavioral changes: Personality shifts, such as aggression, paranoia, or apathy, often occur. Patients may also experience hallucinations or delusions.
Complete dependency: At this stage, individuals rely entirely on caregivers for all aspects of daily living, including eating, dressing, bathing, and moving. Most will eventually require round-the-clock supervision.
The late stage of Alzheimer’s ultimately results in death, usually from complications such as infections (e.g., pneumonia) or failure of basic body systems, as the brain can no longer control essential functions like swallowing and breathing.
Alzheimer's progression graphic © Designua/shutterstock.com.
Conclusion
Each stage of Alzheimer’s disease correlates with specific regions of the brain being affected. The temporal (with the amygdala and hippocampus) and parietal lobes are the earliest affected, and the frontal and occipital lobes are the latest. As these regions progressively degrade, the symptoms evolve from subtle memory problems to complete cognitive and functional incapacitation. The destruction of neurons and the disruption of brain networks explain the stepwise decline observed in patients.
Open-Access Article
Peek, K. (2024). Alzheimer's impact on the brain. Scientific American Custom Media in collaboration with the Davos Alzheimer's Collaborative.
Glossary
atrophy: the shrinkage of tissue, particularly brain tissue, due to the degeneration of neurons, which is characteristic of Alzheimer’s disease.
beta-amyloid: a protein fragment that accumulates in the brains of Alzheimer’s patients, forming plaques that disrupt cell function and contribute to the death of neurons.
brainstem: the lower part of the brain that connects to the spinal cord, responsible for regulating essential functions such as breathing, heart rate, and sleep. It remains relatively unaffected in the early stages of Alzheimer's.
cerebral cortex: the outer layer of the brain involved in higher cognitive functions such as memory, thought, and language. Alzheimer’s disease leads to the thinning and degeneration of the cerebral cortex.
entorhinal cortex: a brain region located near the hippocampus, playing a critical role in memory, navigation, and the initial stages of Alzheimer’s disease. It is one of the first areas to be affected.
early stage: the beginning phase of Alzheimer’s, where memory lapses and mild cognitive impairments begin to appear, although the patient may still function relatively independently.
hippocampus: a structure located in the brain's temporal lobe, crucial for memory formation and spatial navigation. In Alzheimer’s, it is one of the first areas to be damaged, leading to memory loss.
late stage: the advanced phase of Alzheimer’s, where severe cognitive decline, loss of independence, and significant brain atrophy occur, often resulting in the patient being bedridden and unable to communicate.
lecanemab (Leqembi): an FDA-approved monoclonal antibody treatment for Alzheimer’s disease, designed to reduce beta-amyloid plaques in the brain. Lecanemab binds to beta-amyloid and helps to clear the toxic accumulation of this protein, which is believed to slow the progression of cognitive decline in patients with early-stage Alzheimer’s. It is part of a new generation of disease-modifying therapies aimed at addressing the underlying biology of Alzheimer’s, rather than just alleviating symptoms.
neurons: the primary cells of the brain that transmit information through electrical and chemical signals. In Alzheimer’s disease, neurons are progressively destroyed, impairing communication among brain regions.
parietal lobe: a brain region that integrates sensory information, including spatial sense and navigation. Alzheimer’s disease can lead to difficulties in interpreting spatial relationships due to damage to this region.
preclinical stage: the phase before the onset of noticeable symptoms of Alzheimer’s, where pathological changes such as the buildup of beta-amyloid and tau proteins begin to occur silently in the brain.
synapse: the junction between two neurons where communication occurs via neurotransmitters. Alzheimer’s disrupts synaptic function, leading to impaired neuronal communication.
tau protein: a protein that stabilizes microtubules in neurons. In Alzheimer’s disease, tau proteins become abnormally twisted, forming tangles inside neurons, which contributes to cell death and the progression of the disease.
temporal lobe: a brain region involved in processing sensory input and encoding memory. In Alzheimer’s, this region degenerates, contributing to difficulties with memory and recognition.
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