Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease.

Objective To investigate whether neurofilament light polypeptide (NfL) level in cerebrospinal fluid (CSF), currently a prognostic biomarker of neurodegeneration in patients with multiple sclerosis (MS), may be a potential biomarker of cognitive dysfunction in MS. Methods This observational case–control study included patients with MS. CSF levels of NfL were determined using enzyme-linked immunosorbent assay. Cognitive function was measured with the Brief International Cognitive Assessment for MS (BICAMS) battery and Paced Auditory Serial Addition Test (PASAT3), standardized to the Greek population. Results Of 39 patients enrolled (aged 42.7 ± 13.6 years), 36% were classified as cognitively impaired according to BICAMS z-scores (–0.34 ± 1.13). Relapsing MS was significantly better than progressive forms regarding BICAMS z-score (mean difference [MD] 1.39; 95% confidence interval [CI] 0.54, 2.24), Symbol Digit Modality Test score (MD 1.73; 95% CI 0.46, 3.0) and Greek Verbal Learning Test (MD 1.77; 95% CI 0.82, 2.72). An inversely proportional association between CSF NfL levels and BICAMS z-scores was found in progressive forms of MS (rp = –0.944). Conclusions This study provides preliminary evidence for an association between CSF NfL levels and cognition in progressive forms of MS, which requires validation in larger samples.

Multiple Sclerosis (MS) is an autoimmune disease of the Central Nervous System (CNS), mainly appeared in young adults, characterized by neuroinflammation, demyelination, neurodegeneration and remyelination and with a variety of CNS-related symptoms. The prevalence of cognitive decline in MS patients has been reported to range widely, from 13% to 72%, occurring in all stages of the disease, and can lead to mental disability, social impairment, and an impoverished quality of life. The pathogenetic mechanism of the cognitive decline in MS has yet to be revealed, and, thus, we are still unable to predict which patients are more likely to manifest such a decline and at what stage of the disease. Clinical factors, including the type and the course of the disease, but also fatigue and emotional disturbances, can impact the degree of MSrelated cognitive impairment. It has been reported that almost 40% of the MS patients demonstrate a significant deficit in recognizing and recalling verbal and visual memories, either at the onset of the disease or at its later stages, whereas short-term memory remains almost intact. Many patients also demonstrate deficits in complex attention, a slower efficiency in information processing, a declined ability of problemsolving, planning, and prioritization tasks or even visual agnosia and aphasia. Most of the MS-specific disease-modifying treatments seem to reduce the rate of MS attacks and slower the progression; however, their impact on cognitive impairment remains unclear. We propose that cognitive function evaluations should be incorporated in the regular assessment and monitoring of MS patients since they seem to be well correlated with the progression of the disease. Even if the effect of the neuropsychological batteries used for diagnostic and therapeutic purposes still remains very much limited, especially due to the validation and standardization issues, specific cognitive functions treatment strategies should be implemented in the therapeutic scheme of MS patients.

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