To begin with, FH of AD was studied using first-degree relatives of patients with AD as a composite risk factor for dementia, as shown previously [55]. FH studies have yielded conflicting results regarding the association of FH of AD and SMC. On the one hand, the longitudinal study of Nicholas et al. [38] as well as the case–control study of Heun et al. [39] showed that SMC were not associated with FH of AD. On the other hand, Tsai et al. [41] as well as Haussman et al. [42] found that SMC were related to FH of AD in all participants and in the CN group, respectively. The most recent multicenter study of Heser et al. [40] showed a strong association between SMC and FH of AD (p = 0.008), as well as increased all-type dementia risk (p = 0.002). In that study, the authors considered a negative participant’s answer valid regarding FH only if the respective maternal age or age of death was at least 75 years (or paternal age at least 70 years), resulting in a very high missing data rating for FH (approximately 60%). Additionally, the mean age of participants was approximately 80 years old; hence, the results may not apply to younger cohorts.

Selection bias is the most important limitation of FH studies, as some participants were excluded due to absence of living relatives [40], while self-selection may have resulted in a healthier sample with fewer memory complaints than the general population [41]. In any case, the generalizability of results is limited. Moreover, SCD estimation in most family studies was made using simple questions, either via in-person or telephone interviews, except for one study [38], in which a structured SMC questionnaire was used. Thus, the SMC assessment raises questions concerning the reliability of the results, as simple questions are likely to be vague and, therefore, hide useful information, leading to an increased risk of misclassification. Last but not least, an important concern regarding FH studies, compared to single genetic variants such as APOE ε4, is the possible contribution of the psychological distress caused by the knowledge of being at increased risk of SCD. There is an ongoing debate about whether disclosing genetic dementia risk information has negative psychological consequences on relatives of patients with AD [56].

All twin studies [43,44,45] concluded that there was no association between SCD and genetic background. However, questions arise regarding the generalizability of these results in different populations, as the ethnic background of participants was limited, and all studies included community-dwelling populations, while one study included only male individuals [44]. The twin study design itself offers an advantage, allowing researchers to differentiate between the contributions of genetic and environmental factors [43]; thus, the conduction of multi-ethnic, larger twin studies in the future is essential.

As far as other alleles beyond APOE ε4 are concerned, only PSEN1 280A mutation carriers were cross-sectionally related to SCD [34]. PSEN1 280A mutation, which is recognized as the most common cause of familial early-onset AD with complete penetrance, meaning that eventually all carriers will develop AD until their fifth decade of age, appears to be associated with SCD as well. Prospectively, KIBRA T allele [46], which is involved in cell migration and synaptogenesis, as well as PER2 G carriership [36], which is involved in sleep–wake cycle alterations and neurodegeneration, were related to increased longitudinal cognitive decline in subjects with SCD; however, the number of events was relatively small. Among the rest of the gene variants studied [35,47], neither the APOE ε7 allele nor the PSEN-1 Glu318Gly mutation were directly associated with SCD and longitudinal cognitive decline, even though these were found only in the SMC groups. The 50 genes related to vascular damage [48] were not associated with cognitive decline in subjects with SMC receiving anti-hypertensive treatment, similarly to inflammatory genes studied in the past [57].

The aforementioned studies offered indications rather than conclusions concerning the genetic profile of individuals with SMC, presenting remarkable limitations, such as the generalizability of the findings due to the specific features and characteristics of the population samples and the statistical power being limited by the relatively short sample sizes. Additionally, each study used a different questionnaire to evaluate SMC, enhancing the heterogeneity of participants’ answers. A recent study aimed to link questionnaire data from international aging studies and was able to differentiate items that made the greatest contribution to measurement precision, opening new perspectives of developing new self-perceived cognitive functioning questionnaires [58]. In any case, many more genes need to be investigated, such as the bridging integrator 1 (BIN₁), clusterin (CLU), and phosphatidylinositol-binding clathrin assembly protein (PICALM), which have been previously shown to be associated with increased risk for late onset AD [54] and also predict objective verbal memory (p < 0.05) [59].

4. Polygenic Risk