Paper Review — verify claims with raw data

What this review does well

• Comprehensive synthesis of blood and ocular biomarkers and detection technologies (SIMOA, IP‑MS, PEA, RT‑qPCR, OCT) with well-referenced examples and cohort mentions (BioFINDER, ADNI, AIBL) Klyucherev et al. — coverage
• Balanced critique — explicitly notes assay/platform variability, small cohorts, and overlapping pathology that reduce specificity (retina changes occur in AMD, glaucoma) Klyucherev et al. — limitations

Critical appraisal — top issues and blindspots

1. Over-reliance on heterogeneous secondary literature: the review correctly compiles diverse studies but cannot resolve cross-platform discordance; this is a limitation inherent to narrative reviews (authors note need for standardization) Klyucherev et al. — assay variability
2. Specificity vs sensitivity tradeoffs under-emphasised for panels: while panels are recommended, the review could quantify false-positive risk in low-prevalence screening populations — an important epidemiological consideration not deeply modelled here.
3. Limited discussion of population diversity: the review cites BioFINDER/ADNI predominantly; it notes the need for population studies but could have more forcefully highlighted ethnicity/sex/age effects on plasma biomarkers (a growing literature) and how cutoffs may shift across groups.
4. Ocular biomarkers are promising but inconsistent: retinal thinning, RNFL, and vascular metrics sometimes fail to replicate; review presents both sides but the field needs standardized imaging pipelines and large prospective cohorts to test predictive value.

Representative claims from the review with supporting context

• Plasma p‑Tau (181/217/231) is repeatedly emphasised as the most disease‑specific blood marker and predicts conversion when combined with cognitive testing and APOE genotype — but the effect sizes and thresholds vary by assay platform Klyucherev et al. — p‑Tau summary
• Plasma Aβ42/Aβ40 ratio measured by IP‑MS shows good concordance with amyloid PET in several cohorts but remains sensitive to pre‑analytical conditions and peripheral Aβ sources (platelets, muscle) Klyucherev et al. — plasma Aβ
• Circulating miRNA panels are promising (high theoretical sensitivity) but suffer from reproducibility problems due to preanalytical and sequencing biases — the review calls for standardized pipelines and validation in large cohorts before clinical use Klyucherev et al. — miRNA concerns

Bottom-line, practical recommendations (from review + critical lens)

1. Do not adopt single plasma biomarkers as standalone screening tools yet — prefer validated panels and risk-stratified algorithms that combine plasma p‑Tau, Aβ42/40, NfL, GFAP/YKL‑40 and clinical/APOE data.
2. Standardize pre-analytical variables and cross-validate assays (SIMOA, IP‑MS, Lumipulse) in multi-centre cohorts before setting universal cutoffs — the review highlights this imperative Klyucherev et al. — standardization
3. For ocular markers: pursue multi-modal retinal imaging studies with harmonized OCT/OCTA/hyperspectral protocols and deeply phenotyped cohorts to resolve specificity vs comorbidity (AMD, glaucoma).
4. Invest in large, longitudinal, population-based validation studies that prospectively evaluate predictive value and false-positive rates in primary-care screening settings.