What is the pathophysiology of dementia?

Pathophysiology of Dementia

Core Pathological Mechanisms

Dementia results from the synergistic accumulation of misfolded proteins—primarily amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles—leading to synaptic dysfunction, neuronal loss, and progressive cognitive decline. 1

Amyloid-β Pathology

• Aβ accumulation represents the upstream initiating event in Alzheimer's disease pathophysiology, with all autosomal dominant early-onset forms linked to alterations in amyloid precursor protein (APP) production or cleavage 1
• Biomarkers of brain Aβ deposition include low CSF Aβ42, increased CSF Aβ40-Aβ42 ratio, and positive PET amyloid imaging 2
• Aβ accumulation becomes abnormal first and a substantial load accumulates before clinical symptoms appear, with a lag phase potentially exceeding a decade 2
• Trisomy 21 (Down syndrome) invariably results in Alzheimer's pathology due to three intact copies of the APP coding region on chromosome 21 1
• The APOE ε4 allele, the major genetic risk factor for late-onset disease, directly affects amyloid trafficking and plaque clearance 1

Tau Pathology and Neurofibrillary Tangles

• 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 2, 1
• Two main protein kinases are involved in anomalous tau phosphorylations: cyclin-dependent kinase Cdk5 and glycogen synthase kinase GSK3β 3
• Neurofibrillary tangles in medial temporal regions occur in almost all cognitively unimpaired individuals aged 70 years or older, representing primary age-related tauopathy 1

Downstream Neurodegeneration

• Synaptic depletion, neuronal loss, and atrophy represent the final common pathway leading to clinical symptoms 1
• Biomarkers of synaptic dysfunction include decreased FDG uptake on PET in temporoparietal cortex, which may demonstrate abnormalities very early, particularly in APOE ε4 carriers 2
• Structural MRI showing disproportionate atrophy in medial, basal, and lateral temporal lobe and medial parietal cortex becomes abnormal later as a marker of neuronal loss 2
• Neuroinflammation with glial activation and elevated proinflammatory cytokines contributes to progressive neuronal damage 1

Temporal Sequence of Pathophysiological Events

The biomarker model demonstrates that pathological changes follow an ordered sequence:

1. Aβ accumulation occurs first and is necessary but not sufficient to produce clinical symptoms 2
2. Synaptic dysfunction markers (FDG-PET, fMRI) may show abnormalities very early, especially in APOE ε4 carriers, potentially before detectable Aβ deposition 2
3. Elevated CSF tau (total and phosphorylated) appears as a biomarker of neuronal injury, though not specific to AD 2
4. Structural brain atrophy develops later, maintaining close relationship with cognitive performance through MCI and dementia stages 2
5. None of the biomarkers is static; rates of change follow a nonlinear, sigmoid-shaped time course 2

Neurotransmitter Dysfunction

• Current theories attribute cognitive symptoms partly to deficiency of cholinergic neurotransmission 4
• Persistent activation of NMDA receptors by glutamate has been hypothesized to contribute to symptomatology 5
• Available medications (cholinesterase inhibitors like donepezil and NMDA antagonists like memantine) temporarily alleviate symptoms but do not prevent or reverse the underlying disease course 4, 5, 6

Prevalence of Pathology in Asymptomatic Individuals

A critical pitfall: pathology does not equal disease.

• Approximately 20-40% of clinically normal older individuals demonstrate evidence of Aβ accumulation, depending on age and genetic background 2
• 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

Modulating Factors and Reserve Capacity

The temporal lag between pathology appearance and clinical symptoms varies substantially based on:

• Brain reserve (greater synaptic density, larger neuronal populations) allows tolerance of higher pathological burden without clinical symptoms 1, 7
• Cognitive reserve (alternate neural networks, compensatory strategies) enables individuals to cope with encroaching pathology 7
• After a "tipping point" is reached, compensatory mechanisms begin to fail, potentially leading to rapid decline 2, 7

Risk and Protective Factors

• Vascular risk factors (hypertension, hypercholesterolemia, diabetes) increase dementia risk and directly contribute to Alzheimer's pathology effects 1
• Cognitive, physical, leisure, and social activities associate with decreased risk of mild cognitive impairment and dementia 1
• Oxidative stress constitutes a main factor in modification of normal signaling pathways, leading to biochemical and structural abnormalities 3

Mixed Pathologies

Most dementia cases involve multiple pathologies:

• Dementia is commonly associated with more than one neuropathology, usually Alzheimer disease with cerebrovascular pathology 8, 9
• Mixed neuropathologies are frequently detected in brains of older people with dementia and have important clinical implications 9
• 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

Critical 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 2, 1

• CSF biomarker changes occur in other disorders (amyloid angiopathy, dementia with Lewy bodies, prion disease), requiring consideration of the overall clinical presentation 1
• Brain Aβ accumulation is necessary but not sufficient to produce clinical symptoms of MCI and dementia 2
• Current evidence about the natural history of asymptomatic biomarker-positive individuals is insufficient to predict subsequent cognitive decline and dementia 2