Alzheimer's & Dementia Pharmacotherapy

Alzheimer's & Dementia Pharmacotherapy

1. Definition, disease overview & clinical staging

• Alzheimer's disease (AD) is a progressive, irreversible neurodegenerative disorder in which loss of hippocampal and cortical neurons leads to impairment of memory and cognitive ability; it is the prototypical neurodegenerative cause of dementia (G&G 14e Ch.21, p.413).
• The brain region most vulnerable to neuronal dysfunction and cell loss in AD is the medial temporal lobe, including the entorhinal cortex and hippocampus (G&G 14e Ch.21, p.419).
• Two proteins accumulate in AD: amyloid β (Aβ) in extracellular amyloid plaques and the microtubule-associated protein tau in intracellular neurofibrillary tangles (G&G 14e Ch.21, p.419).
• AD has three major stages (G&G 14e Ch.21, p.419): 1. An asymptomatic "preclinical" stage during which accumulation of Aβ and tau begins. 2. A mild cognitive impairment (MCI) stage — episodic memory loss (repeated questions, misplaced items) not yet severe enough to impair daily function. 3. A dementia stage — progressive loss of functional abilities.
• Prognosis: death usually ensues within 6 to 12 years of onset, most often from a complication of immobility such as pneumonia or pulmonary embolism (G&G 14e Ch.21, p.420).
• Diagnosis has traditionally been clinical — memory impairment plus other cognitive impairments that are insidious, progressive, and not explained by another disorder — with steady recent movement toward biomarker inclusion (G&G 14e Ch.21, p.420).
• Two biomarker classes are used (G&G 14e Ch.21, p.420):
  • Fluid biomarkers — changes in Aβ and tau in CSF or plasma.
  • Imaging biomarkers — hippocampal atrophy on structural MRI; cortical hypometabolism on fluorodeoxyglucose (FDG) PET; amyloid or tau deposition on PET.
• Amyloid-PET tracers approved to detect Aβ deposition in cognitively impaired individuals: florbetapir, flutemetamol, florbetaben; flortaucipir is approved for tau PET imaging (G&G 14e Ch.21, p.420).
• The 2018 NIA-AA research framework classifies individuals by "ATN" status — Amyloid, Tau, and Neurodegeneration biomarkers — with amyloid biomarkers required for a diagnosis of AD [Jack et al., 2018] (G&G 14e Ch.21, p.420).
• Common feature across neurodegenerative disorders: AD is one of several proteinopathies (each defined by aggregation of a particular protein — Aβ and tau in AD; α-synuclein in PD; TDP-43 in ALS; huntingtin in HD); it shows selective vulnerability (injury most severe in hippocampus/neocortex, non-uniform even within cortex) (G&G 14e Ch.21, pp.413–414).