Clinical Manifestations, Pharmacological Treatment, and Preventive Measures for Cognitive Impairment (Dementia) Due to Alzheimer's Disease

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized primarily by memory impairment, language dysfunction, and other cognitive deficits. It can lead to reduced ability to perform activities of daily living and the emergence of behavioral and psychological symptoms, imposing a heavy burden on individuals, families, and society. AD has an insidious onset and progresses slowly; even before typical symptoms appear, a series of pathophysiological changes may already be occurring in brain tissue. Mild cognitive impairment (MCI) is an early stage of AD and represents an important window for early detection, diagnosis, and intervention. The incidence of dementia before age 50 is less than 1 in 4,000.

I. Clinical Stages

Preclinical AD: In this stage, patients have no obvious cognitive symptoms but already exhibit ADrelated biomarker abnormalities, including decreased cerebrospinal fluid (CSF) Aβ levels and positive cerebral Aβ deposition on PET imaging.

MCI Stage: This is an early stage of AD, generally considered an intermediate state between normal aging and AD dementia. Patients show mild but measurable cognitive decline, particularly noticeable memory impairment, yet they remain capable of independent activities of daily living.

Mild AD Dementia Stage: Still part of the early phase of ADrelated cognitive impairment, patients experience further decline in cognitive function, especially in memory, planning, and performing everyday tasks. These symptoms affect the ability to handle complex tasks such as paying bills and managing finances, though patients can usually still perform basic daily activities.

Moderate AD Dementia Stage: Cognitive and behavioral function worsens; patients are unable to independently complete complex daily tasks and typically require assistance. They may exhibit anxiety, agitation, hallucinations, delusions, and other behavioral and psychiatric symptoms, including aggression.

Severe AD Dementia Stage: Patients experience substantial deterioration of cognitive and physical function, lose the ability to care for themselves, and become completely dependent on others.

II. Clinical Manifestations

The clinical manifestations of ADrelated cognitive impairment are divided into three stages and seven periods:

Stage 1 – Preclinical AD: Biological evidence of AD pathology is present but no clinical symptoms. Includes Periods 0 and 1.

Stage 2 – Early Clinical AD (MCI due to AD): Individuals show abnormal or impaired cognitive test scores but do not meet dementia criteria; work function and independence in daily life are mildly affected. Includes Periods 2 and 3.

Stage 3 – Late Clinical Stage (Dementia): Divided into Period 4 (mild dementia), Period 5 (moderate dementia), and Period 6 (severe dementia).

1. Preclinical Period

Period 0: No subjective cognitive complaints, no neurological symptoms, no cognitive decline, and no behavioral or psychiatric symptoms.

Period 1: Subjective cognitive decline – the individual complains or reports deterioration in memory or other cognitive functions, but objective cognitive tests remain within normal range.

2. Early Clinical Period

Period 2: Transitional decline – subtle changes are detected, with minimal impact on daily function.

Period 3: Together with Period 2, corresponds to clinical MCI. Common psychiatric symptoms include apathy, depression, and anxiety. Based on the presence or absence of memory impairment, MCI is typically divided into amnestic MCI and nonamnestic MCI.

Amnestic MCI: Main clinical features are pronounced memory impairment, such as reduced learning ability, recent memory loss, frequent forgetting of events, repetitive questioning or verbosity, and difficulty remembering appointment times or events.

Nonamnestic MCI: Main clinical features are impairments in other cognitive domains, such as inattention, difficulty repeating phrases, disorientation, object recognition difficulties, repetitive actions, and restlessness.

3. Late Clinical Stage (Dementia)

Period 4 (Mild Dementia): Daily life is significantly affected; instrumental activities are notably impaired. The individual cannot live completely independently and may need occasional help. Psychiatric symptoms include apathy, irritability, emotional lability, depression, and dysthymia.

Period 5 (Moderate Dementia): Progressive cognitive impairment and behavioral changes have a widespread impact on daily life. Basic functions are partially impaired; the individual cannot live independently and often requires help. Patients are prone to psychotic behaviors such as anxiety, delusions, and hallucinations.

Period 6 (Severe Dementia): Patients are unable to undergo clinical interviews. Daily life is severely affected; they cannot care for themselves and are completely dependent on help. Sleep and nighttime behavioral disturbances, as well as increased irritability and aggressive behaviors, may occur.

 

III. Pharmacological Treatment

1.Cholinesterase Inhibitors (e.g., donepezil, rivastigmine, galantamine): Indicated for mildtomoderate AD. These drugs inhibit cholinesterase activity, raising acetylcholine levels and thereby improving cognitive function.

2.N- Methyl- D- Aspartate (NMDA) Receptor Antagonist (memantine): For moderate- to- severe AD, memantine blocks NMDA receptors, reduces excitotoxic effects of glutamate, alleviates neuronal damage, and helps improve cognitive abilities including memory, thinking, and language.

3.Aβ- Targeted Therapy – Lecanemab: Binds to soluble amyloidbeta protofibrils, promoting their clearance and reducing amyloid plaque formation. It is used for early AD, particularly in patients with positive amyloid biomarkers.

4.Drugs Based on the Brain- Gut Axis to Suppress Neuroinflammation (e.g., sodium oligomannate/GV- 971): By modulating gut microbiota composition, it lowers neuroinflammation and aims to slow AD progression, suitable for mild- to- moderate AD.

5.Antidepressants: For depressive symptoms, drugs such as fluoxetine may be used as symptomatic treatment.

IV. Primary Prevention

1.Lifestyle Interventions: Including smoking cessation, moderate alcohol consumption, and increased leisure activities such as intellectual, physical, and social activities.

2.Healthy Diet: The MIND diet (MediterraneanDASH Intervention for Neurodegenerative Delay) is a dietary approach that may reduce AD risk. Recommendations include high consumption of green leafy vegetables, berries, nuts, legumes, whole grains, fish, poultry, olive oil, and moderate alcohol (preferably red wine), while avoiding red meat, butter, cheese, pastries, sweets, and fried foods.

3.Education Level and Cognitive Training: Higher educational attainment and cognitive training can increase cognitive reserve.

4.Mental Health: Manage negative symptoms such as depression; improve sleep quality.

5.Blood Pressure Control: Prevent and manage diabetes, cerebrovascular disease, atrial fibrillation, and other conditions.

6.Appropriate Exercise: Moderateintensity aerobic exercise, such as jumping rope, swimming, dumbbell exercises, calisthenics, and Tai Chi.

 

 

 

Yuhui LIU,Xianle BU, Xin MA, Gang WANG, et al. Guidelines for drug treatment of Alzheimer's disease. WANFANG DATA. 2025,8(1) 2096-5516.

https://www.alzcn.com/EN/10.3969/j.issn.2096-5516.2025.01.002