Pharmacological Treatment of Alzheimer's Disease

I. Pathogenesis

The pathogenesis of Alzheimer's disease (AD) is extremely complex, involving multiple factors and hypotheses. Currently, the most widely accepted theory is the amyloid cascade hypothesis, which posits that aggregation of amyloid-beta (Aβ) is central to AD pathology. However, inflammation, oxidative stress, autophagy, the cholinergic hypothesis, and the tau hypothesis also play significant roles in the disease process. In the brains of AD patients, the main pathological features are senile plaques (composed primarily of Aβ) and neurofibrillary tangles (composed mainly of hyperphosphorylated tau protein), accompanied by oxidative stress, inflammatory responses, and synaptic damage. Ultimately, these lead to synaptic loss, degeneration and death of cholinergic neurons, brain atrophy, and impairments in learning, memory, and cognition.

Treatment Principles
The treatment principles for AD include early diagnosis, timely intervention, and lifelong management. Although current anti-AD drugs cannot reverse or halt the disease, they can effectively improve symptoms. Recent clinical studies have shown that anti-Aβ immunotherapy can effectively slow cognitive decline; therefore, long-term treatment should be maintained whenever possible. For behavioral and psychological symptoms of dementia (BPSD), nonpharmacological interventions are preferred on the basis of antidementia therapy. When necessary, antipsychotic medications may be added, but their efficacy and side effects should be regularly evaluated. Education, psychological support, and practical assistance for caregivers can reduce the incidence of complications in AD patients, thereby improving quality of life and longterm prognosis.

II. Current Status of Pharmacological Treatment
In clinical practice, pharmacotherapy for AD mainly includes the following options.
(A) Conventional Medications
Currently, the primary drugs used clinically for AD are cholinesterase inhibitors, memantine, and other agents.
1.Cholinesterase Inhibitors(e.g., donepezil, rivastigmine, galantamine): These drugs improve symptoms in patients with mildtomoderate AD by increasing acetylcholine levels in the synaptic cleft.
Donepezil:Initial dose 5 mg once daily, taken after dinner. If tolerated, the dose may be increased to 10 mg once daily after one month for maintenance.
Common side effects:Gastrointestinal reactions (anorexia, nausea, abdominal pain, diarrhea, and in severe cases vomiting – these usually resolve within 12 weeks; or starting with a low dose titration can reduce GI effects), insomnia due to brain overstimulation (for patients with insomnia, the drug may be taken in the morning), and more serious side effects include bradycardia (contraindicated if heart rate <40 bpm; low doses are generally safe).
Rivastigmine:Initial dose 1.5 mg twice daily, taken with breakfast and dinner to reduce GI effects. If tolerated, the dose may be increased to 3 mg twice daily after 4 weeks.
2.Excitatory Amino Acid Receptor Antagonist – Memantine:It improves neurotransmission by modulating glutamate levels in the brain and is used for moderatetosevere AD to reduce symptoms and improve quality of life.
Dosage regimen:Week 1 – 5 mg (half a tablet) once daily in the morning; Week 2 – 10 mg once daily; Week 3 – 15 mg once daily in the morning; Week 4 – 20 mg once daily in the morning. For patients with a confirmed diagnosis of moderatetosevere AD, memantine alone or in combination with donepezil or rivastigmine may be used. For severe AD patients with pronounced BPSD, combination of a cholinesterase inhibitor and memantine is recommended.
3.Other Agents: Nootropics (e.g., huperzine A, oxiracetam), antidepressants (e.g., selective serotonin reuptake inhibitors), mood stabilizers (e.g., carbamazepine), anxiolytics/hypnotics, and drugs that improve cerebral blood circulation (e.g., ginkgo biloba extract, cerebroprotein hydrolysate) are used symptomatically but do not address the underlying neuronal degeneration and death.
Sodium oligomannate (GV971): Conditionally approved by China's National Medical Products Administration for mildtomoderate AD to improve cognitive function. Production is currently suspended.
(B) Monoclonal Antibody Therapy
The advent of monoclonal antibodies has made it possible to shift AD treatment from symptomatic to diseasemodifying therapy. Taking lecanemab as an example: it mediates microglial phagocytosis via Fcγ receptors, primarily clearing Aβ oligomers and protofibrils, and also recognizes and wraps oligomers and protofibrils, blocking fibril and protofibril formation pathways, thereby reducing the amyloid burden.

Diseasemodifying drugs are indicated only for mild cognitive impairment due to AD and mild AD dementia; they are not for dementia caused by nonAD conditions (e.g., vascular dementia, dementia with Lewy bodies, frontotemporal dementia). Before use, the presence of Aβ plaque deposition in the patient's brain must be confirmed by PETCT or CSF analysis. Regarding efficacy, both donanemab and lecanemab have placebocontrolled pivotal studies showing slowing of disease progression, but no headtohead direct comparison studies exist between the two drugs.
1.Lecanemab:Targets soluble Aβ oligomers and protofibrils. By binding to their Nterminus, it promotes clearance of abnormally aggregated Aβ protein and reduces amyloid plaque formation, thereby delaying disease progression. Its action is more focused on earlystage soluble Aβ aggregates.
2.Donanemab:Targets already deposited amyloid plaques, especially the N3pG subtype of Aβ plaques. By binding to Aβ in plaques, it activates immune clearance mechanisms. Its action is more focused on clearing already formed plaques.

III. Pharmacological Treatment of Behavioral and Psychological Symptoms of Dementia (BPSD)
For atypical antipsychotic treatment of BPSD, an individualized strategy is recommended. Treatment should be initiated with informed consent, starting at a low dose, with regular assessment of benefits and risks to minimize potential adverse effects. Among atypical antipsychotics, risperidone, aripiprazole, olanzapine, and quetiapine are recommended for BPSD symptoms, but adverse drug reactions must be closely monitored. For agitation symptoms, brexpiprazole is preferred to control symptoms and improve quality of life.
1.Antipsychotics: Mainly used to control severe hallucinations, delusions, agitation, and impulsivity. Use should follow the principle of "start low, go slow" – initiate at a low dose, titrate slowly based on treatment response, and after symptom control, slowly reduce the dose to discontinuation. Common drugs include olanzapine, risperidone, and quetiapine. For very elderly patients (typically >85 years old), half of the recommended starting dose may be used.
Olanzapine: Starting dose 1.25–2.5 mg/day, maximum dose 10 mg/day, once daily or divided into 1–2 doses.
Risperidone: Starting dose 0.25–0.5 mg/day, maximum dose 2 mg/day, divided into 1–2 doses.
Quetiapine: Starting dose 12.5 mg/day, maximum dose 200 mg/day, divided into 1–3 doses.
Brexpiprazole: Starting dose 0.5 mg/day on days 17, increase to 1 mg/day on days 814, then adjust to 2 mg/day on day 15.
2.Antidepressants and Anxiolytics: Commonly used drugs include sertraline (25–100 mg), trazodone (25–100 mg), citalopram (10–20 mg, caution for QT prolongation), mirtazapine (7.5–30 mg), and paroxetine (5–40 mg).
Dosage and titration guidelines:
Sertraline: Start with ¼ tablet (12.5 mg) once daily, taken half an hour after breakfast with a full glass of warm water. Increase by ¼ tablet every 4 days until symptoms resolve, then maintain at that dose. Maximum daily dose 100 mg once daily. For elderly patients, 50 mg once daily is typical. Individualize based on tolerance and clinical response.

Paroxetine: Start with ¼ tablet (5 mg) once daily, taken half an hour after breakfast with a full glass of warm water. Increase by ¼ tablet every 4 days until symptom resolution. Maximum daily dose 40 mg once daily. For elderly patients, 20 mg once daily is typical.
Mirtazapine: Start with ¼ tablet (7.5 mg) once daily, taken half an hour after dinner with a full glass of warm water. Increase by ¼ tablet every 4 days until symptom resolution. Maximum daily dose 30 mg once daily at night. For elderly patients, 15 mg once daily is typical.

For all medications, final dosing should be individualized based on the patient's condition and under a physician's guidance.

Yuhui LIU, Xianle BU, Xin MA, Gang WANG, et al. Guidelines for drug treatment of Alzheimer's disease. Chinese Journal of Alzheimer's Disease and Related Disorders. 2025, Vol. 8 ›› Issue (1) : 8-16.
https://www.alzcn.com/EN/10.3969/j.issn.2096-5516.2025.01.002