Biomarkers.

Background: Inflammation is becoming increasingly recognised as a core feature of dementia and neurodegenerative processes. High-sensitivity C-reactive protein (hs-CRP) and homocysteine are blood-based markers of non-specific inflammation used in clinical settings. This study aimed to 1) investigate the associations of hs-CRP and homocysteine on neuropsychological performance (i.e. verbal memory, executive function, processing speed) in older adults attending a memory clinic; and 2) examine whether these associations differed for individuals at varying risk stages of dementia, i.e. with subjective cognitive decline (SCD) vs. mild cognitive impairment (MCI).

Method: We recruited older adults aged ≥ 50 years with new-onset cognitive concerns without dementia. A fasting blood sample was used to obtain concentrations of serum hs-CRP (mg/L) and plasma homocysteine (µmol/L). Hs-CRP levels were grouped into low <1.0mg/L, moderate 1.0-3.0mg/L, and high risk >3.0-10.0 mg/L. A standardised neuropsychological assessment was conducted by a clinical neuropsychologist, and composite scores for each neuropsychological outcome were calculated as an average of z-scores of all tests within the same domain. Classifications of MCI were determined by clinician consensus as having objective impairments in neuropsychological tests (≥1.5SDs below normative scores). Multiple regression analyses were conducted, adjusting for relevant demographic and clinical factors.

Result: The final sample consisted of 423 participants (Mean age = 67.37 years [SD = 8.15], 63.1% female, mean MMSE = 28.95 [SD = 1.35]), who were classified as either having SCD (n = 158) or MCI (n = 265). Hs-CRP and homocysteine concentrations did not differ between SCD and MCI groups. In participants with SCD, high-risk CRP concentrations were significantly associated with poorer executive function (β = -.226, 95% CI = [-0.692, -0.059], p = .020) and processing speed (β = -.212, 95% CI = [-0.584, -0.025], p = .033). There were no significant associations between CRP and neuropsychological outcomes in those with MCI, or in the total sample. Homocysteine was not associated with cognitive outcomes.

Conclusion: CRP may be involved in early disruptions to cerebral frontal-subcortical pathways. Targeting inflammation in the earliest stages of cognitive decline, where subjective complains are paramount, may be a viable strategy for prevention.