Alzheimer’s Disease

Neurology

Description

Alzheimer’s disease is a progressive, neurodegenerative disorder that destroys cortical and limbic neurons, leading to a characteristic syndrome of gradually worsening episodic memory loss followed by impairments in executive function, language, visuospatial skills, and ultimately basic activities of daily living. It is the most common cause of dementia worldwide, accounting for sixty to eighty percent of cases, and its incidence doubles every five years beyond age sixty-five. Neuropathologically it is defined by extracellular β-amyloid plaques, intracellular neurofibrillary tangles composed of hyper-phosphorylated tau, and widespread synaptic and neuronal loss that culminate in global cerebral atrophy.

Symptoms

Insidious onset of anterograde episodic memory impairment manifests as repetitive questioning, misplacement of objects and reliance on memory aids; subtle word-finding pauses, impaired route navigation and slowed executive processing follow. As disease advances over years, patients develop prominent aphasia, apraxia, agnosia, disinhibition, apathy, agitation, delusions, sleep–wake cycle inversion, wandering and eventual loss of gait and sphincter control. Late-stage sufferers are mute, bed-bound and vulnerable to aspiration and infection.

Risk Factors

Advanced age, APOE-ε4 carrier status, first-degree family history, female sex, low educational attainment, traumatic brain injury, midlife hypertension, diabetes mellitus, obesity, dyslipidemia, smoking, chronic sleep deprivation, depression, social isolation, hearing loss and air-pollution exposure increase vulnerability, whereas lifelong cognitive stimulation, physical exercise, Mediterranean-style diet, adequate sleep, sustained social engagement and controlled vascular risk factors confer relative protection. Down syndrome invariably leads to early amyloid deposition due to trisomy 21 gene dosage of APP.

Diagnosis

Diagnosis is clinical, integrating a history of cognitive and functional decline corroborated by an informant, neuropsychological testing showing amnestic multidomain deficits, and exclusion of alternative etiologies by physical examination, routine chemistries, thyroid-stimulating hormone, vitamin B12 level and syphilis or HIV tests when indicated. Structural MRI or CT demonstrates disproportionate medial temporal and parietal atrophy; FDG-PET reveals posterior cingulate and temporoparietal hypometabolism. Disease-specific biomarkers include cerebrospinal-fluid profile of reduced Aβ-42, elevated total and phosphorylated tau, or amyloid PET positivity combined with tau PET or MRI atrophy, which satisfy research and appropriate use criteria. Blood-based assays for phosphorylated tau-181 and amyloid ratio are emerging but remain adjunctive. The National Institute on Aging–Alzheimer’s Association diagnostic framework classifies dementia due to Alzheimer’s pathologic change when biomarker evidence supports the phenotype.

Treatment

Current symptomatic therapy targets neurotransmitter deficits. Acetylcholinesterase inhibitors—donepezil 5–10 mg nightly, rivastigmine 6–12 mg daily oral or 9.5–13.3 mg/24 h transdermal, or galantamine 16–24 mg daily—modestly improve cognition and daily function in mild to moderate disease and delay nursing-home placement. The NMDA-receptor antagonist memantine 10 mg twice daily provides additional benefit in moderate to severe stages and is synergistic with donepezil. Adverse effects include gastrointestinal upset, bradycardia and syncope for cholinesterase inhibitors, and dizziness or hallucinations for memantine. Disease-modifying monoclonal antibodies targeting aggregated amyloid—aducanumab and lecanemab—reduce cerebral amyloid burden and slow cognitive decline in selected early-stage patients with confirmed amyloid pathology but carry risks of amyloid-related imaging abnormalities requiring MRI surveillance. Non-pharmacologic interventions—structured aerobic and resistance exercise, cognitive stimulation therapy, occupational therapy home-safety assessments, caregiver skills training and music or reminiscence therapy—improve function and delay institutionalization. Neuropsychiatric symptoms respond to environmental modification, trazodone or SSRIs for depression and agitation; antipsychotics are reserved for severe psychosis or aggression after weighing cerebrovascular and mortality risks. Advance-care planning, driving evaluation, legal and financial counseling are integral components of management.

Outlook

Median survival after diagnosis is eight to ten years but ranges from three to twenty years depending on age at onset, sex, frailty and comorbidities. Progressive dependence culminates in aspiration pneumonia, sepsis or cachexia. Early detection, aggressive vascular risk-factor control, initiation of cognitive-enhancing medications, enrollment in structured activity programs and caregiver respite delay functional decline and improve quality of life.

Complications

Progressive dysphagia leads to aspiration pneumonia, immobility precipitates deep-vein thrombosis, pressure ulcers and sarcopenia, incontinence increases urinary infection risk, neuropsychiatric symptoms cause caregiver stress and injury, malnutrition and dehydration worsen frailty, wandering and impaired judgment elevate risk of falls, hypothermia or financial exploitation, and antipsychotic exposure increases stroke and sudden-death risk.

Prevention

Primary prevention focuses on modifiable vascular and lifestyle risk factors: maintaining systolic blood pressure below 130 mm Hg, treating diabetes and dyslipidemia, achieving a body-mass index 18.5–25, abstaining from tobacco, limiting alcohol to low-risk levels, engaging in at least 150 minutes of moderate aerobic exercise weekly, lifelong cognitive engagement through education, bilingualism, reading, musical training or social interaction, and adhering to Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet patterns. Multidomain trials such as FINGER show cognitive benefit from combined lifestyle interventions.

Support

Patients and caregivers should maintain regular medical follow-up every three to six months, adhere to prescribed medications, establish safe home layouts free of tripping hazards, use labeled pillboxes and calendars, engage in mentally stimulating and physical activities at least three times weekly, follow a diet rich in fruits, vegetables, whole grains and omega-3 fatty acids, ensure adequate hydration and seven to eight hours of sleep, and participate in community resources such as Alzheimer’s Association support groups, respite care services and adult-day programs. Caregivers must monitor for medication side effects, inexorable weight loss, dehydration and caregiver burnout, obtain durable power of attorney and advance directives early, and consider safety technologies like GPS tracking for wandering.