Alzheimer's & Dementia Pharmacotherapy

Introduction & pathophysiology

• Alzheimer's disease (AD) is a progressive, irreversible neurodegenerative disorder — loss of hippocampal and cortical neurons (most vulnerable: entorhinal cortex & hippocampus) causing memory and cognitive decline; it is the prototypical cause of dementia. Death usually follows within 6–12 years, often from an immobility complication (pneumonia, pulmonary embolism).
• Two pathological hallmarks — extracellular amyloid plaques (aggregated amyloid β, Aβ) and intracellular neurofibrillary tangles (hyperphosphorylated tau in paired helical filaments). Plaques deposit first; tangle burden accrues over time and correlates more closely with cognitive impairment.
• Amyloid hypothesis — the early-onset autosomal-dominant genes APP, PSEN1, PSEN2 all drive Aβ production (presenilins form the catalytic core of γ-secretase); soluble Aβ oligomers (perhaps dimers) are more pathogenic than mature fibrils — the rationale for anti-amyloid therapy. APOE ε4 is the dominant risk allele (≥3-fold risk; ε4 carriers are <¼ of people yet >½ of AD cases).
• Three clinical stages — asymptomatic preclinical (Aβ/tau begin accumulating) → mild cognitive impairment (MCI) (episodic memory loss, function preserved) → dementia (progressive loss of functional ability). Modern diagnosis adds biomarkers — amyloid/tau PET (florbetapir, flutemetamol, florbetaben; flortaucipir for tau), CSF/plasma Aβ-tau, and the 2018 NIA-AA ATN framework (amyloid biomarker required for an AD diagnosis).
• Mechanisms of neuronal injury — Aβ and tau impair synaptic transmission/plasticity and drive excitotoxicity (excess glutamate via NMDA receptors — the basis for memantine), oxidative stress and neuroinflammation.