What is the pathophysiology and management of Alzheimer's disease?

Pathophysiology of Alzheimer's Disease

Alzheimer's disease results from the synergistic accumulation of amyloid-β (Aβ) plaques and hyperphosphorylated tau protein tangles in the brain, leading to synaptic dysfunction, neuronal loss, and progressive cognitive decline. 1

Core Pathological Mechanisms

Amyloid-β Cascade

• Aβ accumulation represents the upstream initiating event in Alzheimer's pathophysiology, with all autosomal dominant early-onset forms linked to alterations in amyloid precursor protein (APP) production or cleavage 1
• Aβ42 peptide accumulates with advanced aging and deposits as extracellular senile plaques, though oligomeric forms appear more synaptotoxic than fibrillar deposits 1, 2
• The APOE ε4 allele, the major genetic risk factor for late-onset disease, directly affects amyloid trafficking and plaque clearance 1
• Trisomy 21 invariably results in Alzheimer's pathology due to three intact copies of the APP coding region on chromosome 21 1

Tau Pathology and Neurodegeneration

• Intracellular hyperphosphorylated tau forms neurofibrillary tangles that correlate more strongly with clinical impairment than amyloid plaque burden 1
• Tau pathology progresses to the highest stages (Braak 5 or 6) through synergistic interactions with amyloid-β, producing the most severe cognitive decline 1
• Neurofibrillary tangles in medial temporal regions occur in almost all cognitively unimpaired individuals aged 70 years or older, representing primary age-related tauopathy 1
• Tau can progress independently of Aβ accumulation downstream of genetic risk factors and aberrant metabolic pathways 3

Downstream Pathological Cascade

• Synaptic depletion, neuronal loss, and atrophy represent the final common pathway leading to clinical symptoms 1
• Amyloidosis depresses acetylcholine synthesis and release, overactivates NMDA receptors, and increases intracellular calcium causing excitotoxic neuronal degeneration 2
• Neuroinflammation with glial activation and elevated proinflammatory cytokines contributes to progressive neuronal damage 1
• Neural dysfunction manifests as temporoparietal/precuneus hypometabolism on PET imaging and hippocampal atrophy on MRI 1

Biomarker Evidence of Pathophysiology

In Vivo Pathology Assessment

• Alzheimer's pathology is definitively assessed through biomarkers of amyloid-β (low CSF Aβ42, increased CSF Aβ40-Aβ42 ratio, positive amyloid PET) and tau pathology (increased phosphorylated tau in CSF, positive tau PET) 1
• Both amyloid and diffuse tau pathologies are found in 24% of cognitively unimpaired older individuals (mean age 71 years), far exceeding the 30% prevalence of cognitive impairment 1
• Two-thirds of individuals aged 70+ show all stages of Alzheimer's brain lesions on systematic post-mortem examination regardless of clinical status 1

Pathology-Clinical Disconnect

• Numerous cognitively unimpaired and impaired individuals demonstrate similar burdens of Alzheimer's disease brain lesions, indicating that pathology alone does not determine clinical expression 1
• In the INSIGHT study, 83% of amyloid-positive individuals (aged 77 years) showed no cognitive, behavioral, or neuroimaging changes after 5-year follow-up 1
• This disconnect highlights the critical role of modulating factors including brain reserve, cognitive reserve, and protective mechanisms 1

Modulating Factors and Risk

Genetic and Metabolic Factors

• Apolipoprotein E ε4 allele increases risk through effects on amyloid trafficking, plaque clearance, and serves as an Aβ-independent regulator of tau pathology 1, 3
• Aberrant cholesterol metabolism, endocytic system dysfunction, and microglial activation regulate tau pathology independently of amyloid accumulation 3
• Mutations in APP, PSEN1, and PSEN2 genes cause early-onset familial forms through altered APP processing 4

Vascular and Environmental Factors

• Vascular risk factors (hypertension, hypercholesterolemia, diabetes) increase dementia risk and directly contribute to Alzheimer's pathology effects on the aging brain 1
• Cognitive, physical, leisure, and social activities associate with decreased risk of mild cognitive impairment and dementia 1
• Head trauma and chronic psychological distress may influence pathophysiological progression or clinical expression 1

Reserve Mechanisms

• Brain reserve (greater synaptic density, larger neuronal populations) and cognitive reserve (alternate neural networks, compensatory strategies) allow tolerance of higher pathological burden without clinical symptoms 1
• Higher education and socioeconomic status associate with lower age-adjusted incidence of Alzheimer's diagnosis, primarily by extending the preclinical phase 1

Clinical-Pathological Staging

Preclinical to Clinical Continuum

• Approximately 30% of clinically normal individuals aged 65+ have biomarker evidence of amyloid accumulation, placing them on the Alzheimer's biological continuum 1
• The temporal lag between pathology appearance and clinical symptoms varies substantially based on reserve capacity and modulating factors 1
• Prodromal Alzheimer's disease represents the early symptomatic predementia phase with biomarker positivity 1
• Alzheimer's dementia occurs when cognitive symptoms sufficiently interfere with social functioning and instrumental activities of daily living 1

Common Clinical Phenotypes

• Amnestic presentation, logopenic variant primary progressive aphasia, and posterior cortical atrophy represent common phenotypes where Alzheimer's pathology is the primary underlying cause 1
• Behavioral/dysexecutive variants, corticobasal syndrome, and non-fluent/semantic variants of primary progressive aphasia represent uncommon phenotypes where Alzheimer's pathology is less commonly primary 1

Key Clinical Pitfalls

• Do not diagnose Alzheimer's disease based solely on biomarker positivity in cognitively unimpaired individuals, as the majority remain stable over years and current evidence cannot reliably predict progression 1
• Recognize that positive Alzheimer's biomarkers may represent copathology in other neurodegenerative diseases (α-synucleinopathies, vascular pathology, TDP-43 pathology) rather than primary Alzheimer's disease 1
• CSF biomarker changes occur in other disorders (amyloid angiopathy, dementia with Lewy bodies, prion disease), requiring consideration of the overall clinical presentation 1
• The degree of biomarker abnormality may confer different likelihoods of progression, though this remains difficult to quantify accurately for broad clinical application 1