Alzheimer’s disease
What is Alzheimer’s Disease?
Disease definition & pathophysiology
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, behavioral changes, and impaired daily functioning.
Pathologically, it is defined by extracellular amyloid-beta plaques, intracellular neurofibrillary tangles (composed of hyperphosphorylated tau protein), and widespread neuronal loss, particularly in the hippocampus and cortex.
Inflammation, oxidative stress, and cholinergic deficits also significantly contribute to disease pathology.
Commonly used Pharmacodynamic (PD) Models
- Disease progression models describing cognitive decline (e.g., using ADAS-Cog scores).
- Indirect-response or turnover models describing amyloid-beta accumulation or clearance.
- Target engagement models for anti-amyloid antibodies or tau-targeted therapies.
Patient characteristics
Typical patient population
Primarily affects individuals aged 65 and older, with prevalence sharply rising with advancing age.
Early-onset Alzheimer’s (<65 years) accounts for less than 5% of all cases.
Incidence and prevalence slightly higher in females.
Risk factors & disease progression indicators
Risk factors include advanced age, genetic predisposition (ApoE4 allele), family history, cardiovascular disease, diabetes, traumatic brain injury, and lifestyle factors (low physical and cognitive activity).
Disease progression indicated by cognitive decline severity, impairment of daily activities, behavioral disturbances, and biomarker changes (amyloid and tau biomarkers in CSF or imaging).
Diagnosis & biomarkers
Key Clinical Biomarkers
Diagnosis combines clinical assessment (cognitive tests) with biomarker evaluation.
CSF biomarkers include decreased amyloid-beta (Aβ42), increased total tau (t-tau), and increased phosphorylated tau (p-tau).
Neuroimaging biomarkers (PET imaging) detect amyloid plaques, tau accumulation, and structural brain atrophy (MRI).
Disease Severity Classification
Severity commonly assessed using clinical scales like Mini-Mental State Examination (MMSE):
- Mild AD: MMSE ~20–26 (mild cognitive impairment, memory loss, preserved basic activities)
- Moderate AD: MMSE ~10–19 (significant cognitive deficits, daily function impaired)
- Severe AD: MMSE <10 (severe cognitive dysfunction, completely dependent)
Clinical Dementia Rating (CDR) also frequently used (scale from 0–3).
How can Alzheimer’s Disease be treated?
Treatment aim (PD-targets)
Current treatments primarily target cognitive symptoms through modulation of neurotransmitter systems, particularly cholinergic and glutamatergic pathways.
Emerging therapies target disease modification by reducing amyloid-beta plaques or tau protein accumulation.
Common Drug Classes & Regimens
Cholinesterase inhibitors (first-line treatment for mild-to-moderate AD)
- Donepezil, Rivastigmine, Galantamine:
- MoA: Enhance cholinergic neurotransmission by inhibiting acetylcholinesterase, temporarily stabilizing cognitive function.
NMDA receptor antagonists (moderate-to-severe AD)
- Memantine:
- MoA: Modulates glutamate activity, reducing excitotoxicity and neuronal damage; often combined with cholinesterase inhibitors in advanced disease.
Disease-modifying biologics (emerging treatments)
- Anti-amyloid antibodies: Aducanumab, Lecanemab, Donanemab
- MoA: Target amyloid-beta, promoting clearance or reducing plaque formation.
Dose Adjustments
Dose titration required due to gastrointestinal or neurological side effects (cholinesterase inhibitors).
Renal impairment necessitates dose adjustment for memantine.
Elderly patients may require slower dose titration.
Commonly used PK-models
- Population PK models capturing variability due to age, renal function, genetic factors, or disease severity.
- One- or two-compartment models for cholinesterase inhibitors and memantine.
- PK-PD models linking drug exposure to cognitive outcomes (e.g., MMSE or ADAS-Cog scores) or biomarker responses (amyloid PET imaging).