Alzheimer's Disease — Causes, Stages, Symptoms & Treatment Guide — Symptoms, Causes & Treatment | MyMedicPlus

Alzheimer's disease (AD) is the most common cause of dementia, accounting for 60–70% of all dementia cases and affecting approximately 55 million people worldwide. It is a progressive neurodegenerative disorder characterised pathologically by extracellular amyloid-beta plaques and intraneuronal neurofibrillary tangles (aggregated hyperphosphorylated tau protein), leading to synaptic dysfunction, neuronal loss, and progressive cortical atrophy. Clinically, it produces a characteristic pattern of episodic memory impairment followed by progressive decline in language, visuospatial function, and executive function, ultimately leading to complete functional dependency. The disease course spans 8–10 years from diagnosis to death, though ranges from 3 to 20 years. Late-onset Alzheimer's disease (after age 65) represents 95% of cases; early-onset AD (before 65) is rarer and more commonly familial. Lecanemab and donanemab (anti-amyloid antibodies) received FDA approval in 2023-2024 for early-stage AD, slowing cognitive decline by approximately 25-35% in trials — the first treatments to modify disease progression.

The amyloid cascade hypothesis proposes that abnormal accumulation and aggregation of amyloid-beta (Abeta-42) is the initiating event in AD pathogenesis, triggering tau hyperphosphorylation, neuroinflammation, and neuronal death. The APOE epsilon4 allele is the strongest genetic risk factor for late-onset AD — increasing risk 3-fold (heterozygous) to 8–12-fold (homozygous) compared to epsilon3 carriers. Rare autosomal dominant mutations in APP, PSEN1, and PSEN2 genes cause early-onset familial AD. Non-genetic risk factors: age (risk doubles every 5 years after 65), female sex, low educational attainment, midlife hypertension, obesity and diabetes, depression, hearing loss, physical inactivity, heavy alcohol use, smoking, traumatic brain injury, and social isolation — the Lancet Commission identified 12 modifiable risk factors contributing 40% of dementia risk.

Early stage (mild AD): prominent short-term episodic memory impairment (forgetting recent conversations, appointments, repeating questions), difficulty learning new information, mild word-finding difficulty (anomia), getting lost in familiar places, and subtle changes in personality or mood (anxiety, depression, social withdrawal). Middle stage (moderate AD): significant language impairment, disorientation in time and place, difficulty with ADLs (dressing, bathing, cooking), personality changes (agitation, suspiciousness, wandering), and sleep disturbances. Late stage (severe AD): severe global cognitive impairment, complete dependence on carers for all activities, loss of ambulatory function, swallowing difficulties (dysphagia), mutism, and incontinence. Behavioural and psychological symptoms of dementia (BPSD) — agitation, aggression, hallucinations, delusions — occur in 80–90% of patients at some point.

Cognitive assessment: Mini-Mental State Examination (MMSE) — score below 24/30 suggests cognitive impairment; Montreal Cognitive Assessment (MoCA) — more sensitive for early AD and mild cognitive impairment (MCI). Informant history is essential — reliable account of symptom onset, progression, and functional impact. Blood tests: FBC, B12, folate, TFTs, calcium, renal and liver function, glucose, and syphilis serology — to exclude reversible causes of cognitive impairment. Brain imaging: CT or MRI showing medial temporal lobe (hippocampal) atrophy, excluding vascular or structural lesions. Definitive biomarker diagnosis: CSF analysis (low Abeta-42, elevated tau and phospho-tau — high sensitivity and specificity); amyloid PET scan (detects amyloid plaques in living patients); and plasma phospho-tau 217 (pTau217) — emerging highly accurate blood biomarker. Genetic testing: APOE genotyping in selected cases; PSEN1/PSEN2/APP sequencing in early-onset familial AD. The 2024 NIA-AA revised criteria allow biological diagnosis of AD based on biomarkers rather than solely clinical features.

Symptomatic pharmacotherapy: acetylcholinesterase inhibitors (AChEIs) — donepezil (Aricept) 5–10 mg daily; rivastigmine (Exelon) 6–12 mg daily (also available as transdermal patch); galantamine (Reminyl) 16–24 mg daily — modest but consistent benefits on cognition, function, and behaviour in mild-to-moderate AD (MMSE 10–26). Memantine (Namenda/Ebixa) 20 mg daily — NMDA receptor antagonist, used in moderate-to-severe AD (MMSE below 20), particularly for agitation and global function. Disease-modifying therapy: lecanemab (Leqembi) — anti-amyloid monoclonal antibody FDA-approved in 2023 for early AD (MCI or mild AD with confirmed amyloid pathology), reducing amyloid plaques and slowing clinical decline by approximately 27% over 18 months; donanemab is under regulatory review with similar profile. Non-pharmacological: cognitive stimulation therapy, music therapy, reminiscence therapy, structured daily routines, and caregiver education programmes. Agitation management: low-dose risperidone or quetiapine (with close monitoring), mirtazapine, or trazodone in preference to benzodiazepines. Carer support: dementia caregiver support programmes, respite care, community nursing, and advance care planning.

Advanced Alzheimer's disease causes complete loss of all cognitive domains — patients eventually cannot recognise family members, communicate, dress, eat, or maintain continence. Dysphagia (swallowing difficulty) in late-stage disease causes aspiration pneumonia — the most common direct cause of death. Urinary and faecal incontinence require full nursing care. Wandering behaviour causes injuries and exposure. Severe behavioural and psychological symptoms of dementia (agitation, psychosis, aggression) impose enormous carer burden. Malnutrition and pressure injuries occur in bed-bound patients. Average survival from diagnosis is 8-10 years. Caregiver burnout and depression affect 40-75% of family members — carer support services are essential components of dementia care.

Population-level strategies targeting modifiable risk factors could prevent or delay up to 40% of dementia cases globally (Lancet Commission, 2024). Key modifiable factors: maintain blood pressure control throughout life (target systolic below 130 mmHg in midlife); achieve and maintain healthy BMI; manage type 2 diabetes rigorously; treat hearing loss with hearing aids; engage in regular aerobic exercise (150 minutes per week); maintain social engagement; participate in cognitively stimulating activities; achieve 7–9 hours of quality sleep (slow-wave sleep facilitates amyloid clearance via the glymphatic system); limit alcohol; quit smoking; wear helmets to prevent traumatic brain injury. Mediterranean and MIND diets (rich in leafy greens, berries, whole grains, fish, and olive oil) are associated with reduced cognitive decline. There is currently no proven pharmacological preventive strategy, though trials of anti-amyloid therapies in preclinical AD are ongoing.

Seek medical assessment if a person repeatedly forgets recent events or conversations, becomes confused in familiar surroundings, struggles with familiar tasks like cooking or handling finances, or shows personality changes that are uncharacteristic. Early diagnosis allows treatment initiation at the most beneficial stage and enables advanced care planning. A GP referral to a memory clinic or neurologist is appropriate. Urgent assessment is needed if a person with known dementia develops sudden behavioural change, acute confusion worse than baseline (may indicate delirium from an intercurrent illness such as UTI or pneumonia), or becomes aggressive or poses a safety risk. Family members and caregivers experiencing burnout, depression, or safety concerns should seek support from dementia organisations and social services.