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.

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).

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).

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

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).