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The polygenic risk score (PRS), together with the <i>ɛ4</i> allele of the <i>APOE</i> gene (<i>APOE-ɛ4</i>), has shown high potential for Alzheimer’s disease (AD) risk prediction. The aim of this study was to validate the model of polygenic risk in Russian patients with dementia. A microarray-based assay was developed to identify 21 markers of polygenic risk and <i>ɛ</i> alleles of the <i>APOE</i> gene. This case–control study included 348 dementia patients and 519 cognitively normal volunteers. Cerebrospinal fluid (CSF) amyloid-β (Aβ) and tau protein levels were assessed in 57 dementia patients. PRS and <i>APOE-ɛ4</i> were significant genetic risk factors for dementia. Adjusted for <i>APOE-ɛ4</i>, individuals with PRS corresponding to the fourth quartile had an increased risk of dementia compared to the first quartile (OR 1.85; <i>p</i>-value 0.002). The area under the curve (AUC) was 0.559 for the PRS model only, and the inclusion of <i>APOE-ɛ4</i> improved the AUC to 0.604. PRS was positively correlated with tTau and pTau181 and inversely correlated with Aβ42/Aβ40 ratio. Carriers of <i>APOE-ɛ4</i> had higher levels of tTau and pTau181 and lower levels of Aβ42 and Aβ42/Aβ40. The developed assay can be part of a strategy for assessing individuals for AD risk, with the purpose of assisting primary preventive interventions.