Stefanos N. Sampatakakis

Alzheimer’s disease (AD) is a genetically complex disorder in which inherited susceptibility is distributed across rare high-impact variants, the apolipoprotein E (APOE) locus, and a broad polygenic background of common risk alleles. Polygenic risk scores (PRSs) provide a quantitative framework for summarizing this distributed genetic liability and have become increasingly important tools for risk stratification, cohort enrichment, and biological interpretation. In this review, we synthesize evidence on AD PRSs across multiple biological and clinical scales, moving from genes and molecular pathways to biomarkers, brain structure and function, cognition, behavior, and clinical translation. Genome-wide PRSs capture aggregate inherited risk, whereas pathway-, tissue-, cell-type-, and biomarker-specific PRSs may help clarify the biological routes through which genetic susceptibility is expressed, including amyloid and tau metabolism, lipid homeostasis, endosomal trafficking, immune regulation, glial activation, proteostasis, and mitochondrial quality control. Evidence indicates that AD PRSs are most consistently associated with amyloid-related biomarkers, while associations with tau, neurodegeneration, brain atrophy, functional connectivity, cognitive decline, and neuropsychiatric manifestations are more heterogeneous and often depend on APOE, disease stage, biomarker context, and variable computation methodologies. Although PRSs show promise for research enrichment and mechanistic stratification, their individual-level clinical utility remains limited by modest predictive performance, ancestry-related transferability, calibration challenges, and ethical considerations. Future progress will require multi-ancestry cohorts, integration of common and rare variation, multi-omic annotation, longitudinal modeling, and multimodal prediction frameworks. Ultimately, PRSs are best viewed not as stand-alone diagnostic tools, but as cross-scale instruments for linking inherited susceptibility to the heterogeneous biological and clinical manifestations of AD.

Background: Research concerning the genetic risk for dementia has recently been headed towards new directions. Novel findings from genome-wide association studies have highlighted the association of Alzheimer’s disease incidence with many gene polymorphisms, apart from the Apolipoprotein-E genotype. The identification of additional genetic risk factors has led to the construction of specific genetic risk scores for dementia, considering many different genetic factors and specific biological pathways related to Alzheimer’s disease. Methods: We conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis method, summarizing existing data regarding genetic risk scores for Alzheimer’s disease and dementia, in order to improve the current understanding of the genetic underpinnings of dementia. In specific, five databases (PubMed/MEDLINE, Embase, Scopus, Web of science, and Cochrane Central) were searched using the keywords “genetic risk score”, “Alzheimer’s disease”, and “dementia” with specific inclusion and exclusion criteria. Results: From the 552 articles identified, we finally included 20 studies for the qualitative analysis. These reports were classified in three different categories of genetic scores: “polygenic risk scores (PRSs)” (including 11 studies), “pathway specific polygenic risk scores (p-PRSs)” (5 studies), and “complex genetic risk scores” (4 studies). Conclusions: Existing genetic risk scores have contributed to better dementia prediction and a better understanding of the underlying pathology. Novel approaches integrating multiple polygenic risk scores might ameliorate the accuracy of genetic risk scores. The combination of polygenic risk scores that are specific to related biological pathways or relevant biomarkers is of utmost importance to achieve a better predictive ability.

In the present study, we investigated the association of genetic predisposition with specific dimensions of dementia pathophysiology for global and domain-specific cognitive decline in older adults. The sample was drawn from the Hellenic Longitudinal Investigation of Aging and Diet (HELIAD) study, comprising 512 cognitively normal individuals over 64 years of age, with a mean follow-up of 2.9 years. Cognitive function was evaluated through a neuropsychological test battery, while genetic predisposition was assessed based on two distinct Polygenic Risk Scores (PRS) for amyloid-beta 42 (Aβ₄₂) and white matter hyperintensities (WMH). The association of each PRS with the cognitive decline rate was examined using generalized estimating equation models. In the whole sample, higher PRSs Aβ₄₂ (β = −0.042) and WMH (β =−0.029) were associated with a higher rate of global cognitive decline per year, an association which remained significant in age, sex, and education subgroups. Moreover, higher PRSs Aβ₄₂ and WMH were related to significant memory decline only in females, older, and highly educated participants. Thus, while the association of both PRSs with global cognitive decline over time was independent of age, sex, or education, the relationship of the specific PRSs with the memory decline rate appeared to vary depending on these factors.

Background: There is a paucity of evidence on the association between genetic propensity for hippocampal atrophy with cognitive outcomes. Therefore, we examined the relationship of the polygenic risk score for hippocampal atrophy (PRShp) with the incidence of amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease (AD) as well as the rates of cognitive decline. Methods: Participants were drawn from the population-based HELIAD cohort. Comprehensive neuropsychological assessments were performed at baseline and at follow-up. PRShp was derived from the summary statistics of a large genome-wide association study for hippocampal volume. Cox proportional hazards models as well as generalized estimating equations (GEEs) were used to evaluate the association of PRShp with the combined incidence of aMCI/AD and cognitive changes over time, respectively. All models were adjusted for age, sex, education, and apolipoprotein E (APOE) genotype. Results: Our analysis included 618 older adults, among whom 73 developed aMCI/AD after an average follow-up of 2.96 ± 0.8 years. Each additional SD of PRShp elevated the relative hazard for incident aMCI/AD by 46%. Participants at the top quartile of PRShp had an almost three times higher risk of converting to aMCI/AD compared to the lowest quartile group. Higher PRShp scores were also linked to steeper global cognitive and memory decline. The impact of PRShp was greater among women and younger adults. Conclusions: Our findings support the association of PRShp with aMCI/AD incidence and with global cognitive and memory decline over time. The PRS association was sex- and age-dependent, suggesting that these factors should be considered in genetic modelling for AD.

As sleep appears to be closely related to cognitive status, we aimed to explore the association between the percentage of deep sleep, cognitive state, and the cerebrospinal fluid (CSF) biomarker amyloid-beta 42 in non-demented individuals. In this cross-sectional study, 90 non-demented participants from the Aiginition Longitudinal Biomarker Investigation of Neurodegeneration cohort underwent a one-night WatchPAT sleep evaluation. Participants were categorized by cognitive status (patients with mild cognitive impairment [MCI] or cognitively normal [CN] individuals) and CSF Aβ42 status (Aβ42 ≤ 1,030 pg/mL [A+] or Ab42 > 1,030 pg/mL [A−]). After controlling for age, sex, and years of education, a significant inverse association was found between the percentage of deep sleep and the odds of being classified as MCI compared to CN (OR = 0.86, 95% CI [0.76–0.97], p = 0.012). However, a non-significant trend for an inverse association between the percentage of deep sleep and the odds of being classified as A+ was observed (OR = 0.92, 95% CI [0.84–1.01], p = 0.092). This study demonstrates a significant link between deep sleep and MCI. Although more longitudinal studies are needed, deep sleep could potentially serve as a novel biomarker of cognitive decline and an intervention target for dementia prevention.

Background: There is paucity of evidence on the association of genetic propensity for hippocampal atrophy with cognitive outcomes. Therefore, we examined the relationship of a Polygenic Risk Score for hippocampal atrophy (PRShp) with the incidence of amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease (AD) as well as the rates of cognitive decline. Methods: Participants were drawn from the population based HELIAD cohort. Comprehensive neuropsychological assessments were performed at baseline and follow-up. PRShp was derived from the summary statistics of a large GWAS for hippocampal volume. Cox proportional hazards models as well as generalized estimating equations (GEEs) were used to evaluate the association of PRShp with the combined incidence of aMCI/AD and cognitive changes over time, respectively. All models were adjusted for age, sex, education, and Apolipoprotein E (APOE) genotype. Results: Our analysis included 618 older adults, among whom 73 developed aMCI/AD after an average follow-up of 2.96±0.8 years. Each additional SD of PRShp elevated the relative hazard for incident aMCI/AD by 46%. Participants at the top quartile of PRShp had almost three times higher risk of converting to aMCI/AD compared to the lowest quartile group. Higher PRShp scores were also linked to steeper global cognitive and memory decline. The impact of PRShp was greater among women and younger adults. Conclusions: Our findings support the association of PRShp with aMCI/AD incidence and with global cognitive and memory decline over time. PRS association was sex and age dependent, suggesting that these factors should be considered in genetic modelling for AD.

The possible relationship between Subjective Cognitive Decline (SCD) and dementia needs further investigation. In the present study, we explored the association between specific biomarkers of Alzheimer’s Disease (AD), amyloid-beta 42 (Aβ₄₂) and Tau with the odds of SCD using data from two ongoing studies. In total, 849 cognitively normal (CN) individuals were included in our analyses. Among the participants, 107 had available results regarding cerebrospinal fluid (CSF) Aβ₄₂ and Tau, while 742 had available genetic data to construct polygenic risk scores (PRSs) reflecting their genetic predisposition for CSF Aβ₄₂ and plasma total Tau levels. The associations between AD biomarkers and SCD were tested using logistic regression models adjusted for possible confounders such as age, sex, education, depression, and baseline cognitive test scores. Abnormal values of CSF Aβ₄₂ were related to 2.5-fold higher odds of SCD, while higher polygenic loading for Aβ₄₂ was associated with 1.6-fold higher odds of SCD. CSF Tau, as well as polygenic loading for total Tau, were not associated with SCD. Thus, only cerebral amyloidosis appears to be related to SCD status, either in the form of polygenic risk or actual CSF measurements. The temporal sequence of amyloidosis being followed by tauopathy may partially explain our findings.

Subjective cognitive decline (SCD) has been described as a probable early stage of dementia, as it has consistently appeared to precede the onset of objective cognitive impairment. SCD is related to many risk factors, including genetic predisposition for dementia. The Apolipoprotein (APOE) ε4 allele, which has been thoroughly studied, seems to explain genetic risk for SCD only partially. Therefore, we aimed to summarize existing data regarding genetic factors related to SCD, beyond APOE ε4, in order to improve our current understanding of SCD. We conducted a PRISMA systematic search in PubMed/MEDLINE and Embase databases using the keywords “subjective cognitive decline” and “genetic predisposition” with specific inclusion and exclusion criteria. From the 270 articles identified, 16 were finally included for the qualitative analysis. Family history of Alzheimer’s disease (AD) in regard to SCD was explored in eight studies, with conflicting results. Other genes implicated in SCD, beyond APOE ε4, were investigated in six studies, which were not strong enough to provide clear conclusions. Very few data have been published regarding the association of polygenic risk for AD and SCD. Thus, many more genes related to AD must be studied, with polygenic risk scores appearing to be really promising for future investigation.

The present study investigated the association of genetic predisposition for white matter hyperintensities (WMHs) with incident amnestic mild cognitive impairment (aMCI) or Alzheimer’s disease (AD), as well as whether such an association was influenced by age, sex, and cognitive reserve. Overall, 537 individuals without aMCI or dementia at baseline were included. Among them, 62 individuals developed aMCI/AD at follow up. Genetic propensity to WMH was estimated using a polygenic risk score for WMHs (PRS WMH). The association of PRS WMH with aMCI/AD incidence was examined using COX models. A higher PRS WMH was associated with a 47.2% higher aMCI/AD incidence (p = 0.015) in the fully adjusted model. Subgroup analyses showed significant results in the older age group, in which individuals with a higher genetic predisposition for WMHs had a 3.4-fold higher risk for developing aMCI/AD at follow up (p < 0.001), as well as in the lower cognitive reserve (CR, proxied by education years) group, in which individuals with a higher genetic predisposition for WMHs had an over 2-fold higher risk (p = 0.013). Genetic predisposition for WMHs was associated with aMCI/AD incidence, particularly in the group of participants with a low CR. Thus, CR might be a modifier in the relationship between genetic predisposition for WMHs and incident aMCI/AD.

Cognitive and physical decline, both indicators of aging, seem to be associated with each other. The aim of the present study was to investigate whether physical function parameters (walking time and handgrip strength) are related to cerebrospinal fluid (CSF) biomarkers (amyloid-beta Aβ₄₂, Tau, PhTau) in individuals in the Alzheimer’s disease (AD) continuum. The sample was drawn from the Aiginition Longitudinal Biomarker Investigation of Neurodegeneration study, comprising 163 individuals aged 40–75 years: 112 cognitively normal (CN) and 51 with mild cognitive impairment (MCI). Physical function parameters were measured at baseline, a lumbar puncture was performed the same day and CSF biomarkers were analyzed using automated methods. The association between walking time, handgrip strength and CSF biomarkers was evaluated by linear correlation, followed by multivariate linear regression models adjusted for age, sex, education and APOEe4 genotype. Walking time was inversely related to CSF Aβ₄₂ (lower CSF values correspond to increased brain deposition) in all participants (p < 0.05). Subgroup analysis showed that this association was stronger in individuals with MCI and participants older than 60 years old, a result which remained statistically significant after adjustment for the aforementioned confounding factors. These findings may open new perspectives regarding the role of mobility in the AD continuum.