Alzheimer Disease

Progressive neurodegenerative disorder and the most common cause of dementia (~60–70% of cases), characterized pathologically by extracellular amyloid-β plaques and intracellular neurofibrillary tangles (hyperphosphorylated tau), leading to synaptic loss and neuronal death, predominantly affecting the hippocampus and temporoparietal cortex initially.

Classified by:

• Early-onset (EOAD): <65y, ~5–10% of cases, higher likelihood of autosomal dominant genetic mutations (APP, PSEN1, PSEN2 — near-100% penetrance)

• Late-onset (LOAD): ≥65y, majority of cases, polygenic/sporadic: strongest genetic risk factor is APOE ε4 allele (dose-dependent risk increase, does not guarantee disease)

• Staged clinically: preclinical (biomarker positive, asymptomatic) → mild cognitive impairment (MCI) due to AD → mild → moderate → severe dementia

• Insidious onset, gradual progressive decline (distinguishes from vascular dementia's stepwise course)

• Earliest and most prominent: short-term episodic memory impairment (repeating questions, misplacing items, forgetting recent conversations) — anterograde memory affected before remote memory

• Progression through domains:

• Language: word-finding difficulty, anomia, progressing to fluent aphasia

• Visuospatial: getting lost in familiar places, difficulty with tasks requiring spatial orientation

• Executive function: impaired planning, judgment, problem-solving

• Behavioral/psychiatric (variable, often later): apathy, depression, agitation, psychosis (delusions, hallucinations), sleep disturbance, wandering

• Late-stage: loss of ADLs (dressing, bathing, feeding), mutism, incontinence, motor rigidity, immobility, increased mortality from aspiration pneumonia/infections

• Preserved early: motor function, level of consciousness (helps distinguish from delirium)

• Red flags against typical AD (consider alternative diagnosis): rapid progression (weeks–months — think CJD), early prominent motor signs (parkinsonism — think DLB/PSP), early hallucinations with fluctuating cognition (DLB), young onset with strong family history (genetic testing indicated), stepwise decline with vascular risk factors (vascular dementia)

Clinical diagnosis of "probable AD dementia" per NIA-AA criteria: insidious onset, clear history of worsening cognition, initial and most prominent deficit in one of — amnestic presentation (most common) or non-amnestic (language, visuospatial, executive) — with exclusion of other causes.

Cognitive screening tools:

• MMSE (Mini-Mental State Exam): <24/30 suggestive of dementia (education/language-adjusted)

• MoCA (Montreal Cognitive Assessment): more sensitive for MCI/early disease, <26/30 abnormal

Labs/workup to exclude reversible causes (mandatory in all dementia workups):

• FBC, U&E/creatinine, LFTs, TSH, B12/folate, calcium, glucose

• Consider syphilis serology (RPR/VDRL), HIV testing if risk factors

Neuroimaging (mandatory to exclude structural/vascular/other causes):

• MRI brain (preferred): hippocampal and medial temporal lobe atrophy; excludes tumor, normal pressure hydrocephalus (ventriculomegaly, gait apraxia, urinary incontinence triad), subdural hematoma, significant vascular disease

• CT if MRI unavailable/contraindicated

Advanced/specialist biomarkers (research and specialist dementia clinics, not routine primary care):

• CSF analysis: ↓Aβ42, ↑total tau, ↑phospho-tau — supports AD pathology

• Amyloid PET or tau PET imaging

• Blood-based biomarkers (plasma p-tau217, Aβ42/40 ratio) — emerging, increasingly used for triage

• Genetic testing: APOE genotyping (risk stratification, not diagnostic), APP/PSEN1/PSEN2 testing if strong family history/early onset

Differentials: vascular dementia, dementia with Lewy bodies (DLB), frontotemporal dementia, Parkinson's disease dementia, normal pressure hydrocephalus, depression ("pseudodementia" — subacute onset, prominent mood symptoms, "don't know" answers vs. confabulation), delirium, chronic subdural hematoma, hypothyroidism, B12 deficiency.

No cure; goals are symptomatic control, functional preservation, and slowing progression.

Pharmacological — symptomatic (mild–moderate disease):

• Cholinesterase inhibitors (first-line): donepezil 5mg od, titrate to 10mg od after 4–6 weeks; or rivastigmine (oral 1.5mg bd titrated to 6mg bd, or transdermal patch 4.6mg/24h titrated to 9.5–13.3mg/24h); or galantamine 8mg od titrated to 16–24mg/day

• Side effects: GI upset (nausea, diarrhea), bradycardia (caution in cardiac conduction disease), vivid dreams

• Moderate–severe disease: add memantine (NMDA receptor antagonist) 5mg od, titrate weekly by 5mg to target 10mg bd — renal dose adjustment needed

• Combination donepezil + memantine used in moderate–severe stages

Disease-modifying therapies (emerging, specialist-initiated):

• Anti-amyloid monoclonal antibodies: lecanemab, donanemab — IV infusion, target early symptomatic AD with confirmed amyloid pathology; modest slowing of decline; major risk: ARIA (amyloid-related imaging abnormalities — edema/effusion or hemorrhage), requires baseline and serial MRI monitoring, APOE ε4 carriers at higher ARIA risk

Behavioral/psychiatric symptoms:

• Non-pharmacological first-line: environmental modification, structured routine, caregiver education, redirect rather than confront

• Pharmacological only if non-drug measures fail and symptoms distressing/dangerous: SSRIs (citalopram, sertraline) for depression/agitation; avoid benzodiazepines (worsen cognition, fall risk); antipsychotics (risperidone low dose) only for severe agitation/psychosis with risk to self/others — carries black box warning for increased mortality/stroke risk in dementia patients, use lowest dose shortest duration

Non-pharmacological (all stages):

• Cognitive stimulation therapy, physical exercise, social engagement

• Caregiver support and education — caregiver burnout is a major driver of institutionalization

• Advance care planning, power of attorney, safety assessment (driving, falls, wandering, medication management)

• Nutrition support in later stages (risk of weight loss, dysphagia — consider speech/swallow assessment before feeding tube discussions; feeding tubes do NOT improve survival in advanced dementia and are generally not recommended)

Referral: neurology/geriatric psychiatry for diagnostic uncertainty, young-onset disease, or consideration of disease-modifying therapy; social work/occupational therapy for functional and safety assessment.