Biomarkers of Cognitive Decline 

Biomarkers of cognitive decline are biological indicators that can predict or track changes in cognitive function over time.

Cerebrospinal Fluid (CSF) Biomarkers

  1. Amyloid-β 42 (Aβ42): Lower levels of CSF Aβ42 are associated with cognitive decline and progression to Alzheimer’s disease (AD).
  2. Tau proteins: Higher levels of tau proteins in CSF correlate with cognitive decline.
  3. Total tau (t-tau)
  4. Phosphorylated tau (p-tau)

Blood-Based Biomarkers

  1. Plasma phosphorylated tau (p-tau): Elevated levels, particularly p-tau181, p-tau217, and p-tau231, are associated with future cognitive decline.
  2. Plasma amyloid-β (Aβ) ratio: A lower Aβ42/40 ratio is linked to faster cognitive decline.
  3. Neurofilament light (NfL): Higher plasma levels predict faster cognitive decline.
  4. Glial fibrillary acidic protein (GFAP): Elevated plasma levels are associated with steeper cognitive decline.

Neuroimaging Biomarkers

  1. Amyloid PET imaging: Detects amyloid plaques in the brain.
  2. FDG-PET: Shows characteristic patterns of hypometabolism in AD.
  3. Structural MRI: Measures brain atrophy, particularly in the hippocampus and cortical regions.

Other Biomarkers

  1. Plasma triglyceride/HDL cholesterol (TG/HDL-C) ratio: Higher ratios are associated with faster cognitive decline in mild cognitive impairment (MCI) and dementia.
  2. Apolipoprotein A1 (ApoA1): Higher plasma levels are linked to faster cognitive decline in MCI, while higher CSF levels are associated with slower decline.

These biomarkers can be used individually or in combination to predict cognitive decline, particularly in the context of AD and MCI. They offer potential for early detection and monitoring of cognitive changes, which could be crucial for timely interventions and treatment strategies.

Role of Inflammation in Cognitive Decline 

Inflammation plays a significant role in cognitive decline and is reflected in several biomarkers associated with cognitive impairment and dementia.

Inflammatory Processes and Cognitive Decline

Recent research has linked inflammation to cognitive decline and increased risk of dementia. While inflammation is normally a protective response, prolonged inflammation can cause tissue damage, including in the brain. Normal aging is associated with heightened and prolonged inflammation throughout the body and brain.

Inflammatory Biomarkers associated with cognitive decline and dementia risk

  1. C-reactive protein (CRP): Chronic peripheral inflammation, as measured by CRP, is associated with an increased risk of dementia, including Alzheimer’s disease (AD) dementia.
  2. Cytokines: Proinflammatory cytokines like interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) have been consistently linked to cognitive impairment.
  3. Neutrophil-lymphocyte ratio (NLR): This ratio is considered a marker of systemic inflammation and has been associated with cognitive outcomes.
  4. Albumin: Lower levels of albumin have been negatively associated with cognitive impairment4.

Specific Inflammatory Biomarkers in Studies

  1. TWEAK, TNFB, and CDCP1: Higher levels of these proteins were associated with higher risks of incident all-cause and AD dementia.
  2. IL-10, LIF-R, CCL19, IL-17C, MCP-4, and TGF-alpha: These proteins were found to be associated with cognitive function.
  3. IL-8, MMP7, and TIMP-4: These markers, associated with vascular injury and neuroinflammation, were part of a model that could distinguish between individuals with mild cognitive impairment (MCI) who progressed to dementia and those who remained stable.

Mechanisms of Inflammatory Impact

  1. Inflammation within the brain can have far-reaching acute and long-term effects:
  2. Neuroinflammation over time is associated with risk of dementia and cardiovascular pathology.
  3. Activation of microglia and cytokines in the brain produces proinflammatory factors harmful to brain cells.
  4. Inflammatory processes can destroy brain tissue, particularly in limbic and associated structures like the hippocampi and basal ganglia, which are crucial for cognitive processes.

Implications for Biomarker Development

Inflammatory biomarkers could be used for early detection and monitoring of cognitive changes. A combination of inflammatory biomarkers with other types of biomarkers (e.g., amyloid and tau markers) may improve the accuracy of predicting cognitive decline and dementia risk. Developing plasma biomarker profiles that include inflammatory markers could aid in prognostic deliberations and identify individuals at higher risk of dementia in clinical practice.

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