Understanding Alzheimer’s Disease Progression
Alzheimer’s disease is the most common cause of dementia and is a chronic progressively debilitating and eventually fatal condition. The disease evolves clinically over eight to fifteen years. The underlying biology however can predate the onset of dementia symptoms by decades. Multiple purported disease hypotheses such as inflammation, oxidative stress, glutamate excitotoxicity, cholinergic failure, autophagocytic dysregulation, brain/gut microbiome dysfunction, and the tau and amyloid hypotheses have been proposed.
Other Types of Proposed Disease Mechanisms
The amyloid cascade hypothesis is the most accepted, but the reality is probably an implication of several different mechanisms to a variable degree.
Amyloid Beta Accumulation and Plaque Formation
The amyloid cascade hypothesis suggests that the protein amyloid beta accumulates in the extracellular space either from an overproduction and/or deficient clearance of the protein. Amyloid is produced throughout the body and can move from the periphery to the brain and from the brain to the periphery. One of the proteins involved in amyloid transport is ApoE.
Amyloid beta can exist in soluble protofibril forms before accumulating into insoluble plaques in the extracellular space. These plaques can interact with cell receptors and activate downstream mechanisms which lead to inflammation, oxidative stress and hyperphosphorylation of the tau protein, a component of the cell’s microtubules.
Tau Propagation and Network Failure
The intracellular accumulation of phosphorylated tau results in cellular microtubular dysfunction and eventually cell death. Amyloid accumulation leads to pathological hyperconnectivity between different neuronal networks which drives the spreading of the tau protein through different connected brain regions.
The tau protein can be propagated from one neuron to the next within a neuronal network through synapses. Eventually sufficient neurons within a network succumb, which then leads to a cascading network failure. The initial spreading within a given neuronal network underlies the many different clinical presentations of the disease.
Biomarkers, Memory Loss and Other Symptoms
Biomarkers are now available as diagnostic tools to help diagnose Alzheimer’s disease, monitor the disease progression and identify its different biological stages. These tests may include cerebrospinal fluid levels of amyloid beta 42/40, involving fluid around the brain and spinal cord, serum p-tau217, amyloid and tau PET scans, serum NfL and GFAP. Clinical stages may not follow the underlying biological stages depending on the presence of other conditions affecting cognitive functions, and brain health.
Clinical Trials Supporting New Treatment Options
Two therapies, lecanemab (Leqembi) and donanemab (Kisunla), have shown in the clinical trials Clarity-AD and TRAILBLAZER-ALZ 2 respectively the ability to slow down, compared to placebo, Alzheimer disease progression in people diagnosed with biologically proven Alzheimer’s disease with mild cognitive impairment or mild dementia.
Lecanemab and the Clarity-AD Trial
Lecanemab showed over the 18-month study compared to placebo, a substantial reduction in amyloid deposition on PET scan and a significant reduction compared to the placebo group in clinical progression as measured by the various clinical scales used, including CDR-SB, ADAS-Cog14, ADCS MCI-ADL, HRQoL and the caretaker burden scale. These results were further supported by extension data extending to 36 months.
Starting Treatment Earlier and Long-Term Impact
The Clarity AD study included an optional tau PET sub study and used the tau PET probe MK6240 to identify patients with no tau or a low accumulation of tau in the brain. As tau begins to accumulate in the brain, cognition and thinking skills start to decline; therefore, patients with no tau or low tau in the brain represent an early stage of Alzheimer disease. After three years of lecanemab treatment, 59% of these patients (24/41) showed improvement or no decline from baseline on the CDR-SB. This suggests that starting treatment with lecanemab earlier may have a greater positive impact on disease progression and may provide continued benefits to patients with early AD over the long-term.
Donanemab and the Trailblazer-Alz 2 Trial
Donanemab showed similar results, with greater clinical impact in participants at an earlier stage of the Alzheimer disease process. Participants treated with donanemab had 40% less decline in ability to perform activities of daily living, including daily activities, at 18 months. In the low/medium tau population, 47% of participants treated with donanemab showed no decline on CDR-SB, a key measure of disease severity, after one year vs. 29% of those on placebo. Participants in the donanemab group also experienced a 39% lower risk of progressing to the next stage of disease vs. placebo.
Treatment Access in Canada
These therapies have been approved in multiple countries in recent years. Health Canada approved lecanemab in January 2026 for adult patients with a clinical diagnosis of mild cognitive impairment or mild dementia due to Alzheimer’s disease, who are ApoE ε4 noncarriers or heterozygotes and who have confirmed biologically amyloid pathology. Donanemab was approved by Health Canada in May 2026 for adult patients with a clinical diagnosis of mild cognitive impairment or mild dementia due to Alzheimer’s disease, who are ApoE ε4 heterozygotes or non-carriers and who have confirmed amyloid pathology.
Risk Factors, ARIA and MRI Monitoring
People who are ApoE ε4 homozygotes or receiving ongoing anticoagulant medications should not use these therapies. These therapies are associated with an increased risk of focal brain swelling called ARIA-E or focal brain hemorrhage called ARIA-H. The risk is greatest in people who are ApoE ε4 homozygote carriers, and the risk is generally highest early in treatment. Frequent magnetic resonance imaging monitoring, with MRI scans, is therefore required according to product-specific monitoring schedules.
Treatment With Experienced Clinique Neuro Outaouais
Early identification, selection, evaluation and monitoring during treatment should be done by neurologists and experienced healthcare providers familiar with these therapies. Clinique Neuro-Outaouais provides Alzheimer’s disease evaluation, biomarker-based diagnosis and treatment support through its cognitive neurology clinic and infusion clinic. For more information, visit our Alzheimer’s research page.
References
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