SNCA, which encodes α-syn, was the first gene discovered in a patient with PD [
70]. Most
SNCA mutations are associated with PD pathology, and the involvement of AD-related genes as a genetic risk factor is limited. Interestingly,
SNCA polymorphism of the GG frequency (rs10516846) was significantly increased in patients with AD compared to healthy control (HC) [
71]. In addition, α-syn levels in CSF of patients with early-onset AD (EOAD) were higher in GG (rs10516846) carriers than in AA carriers [
71], suggesting an association between
SNCA gene polymorphisms and elevated α-syn levels in AD pathophysiology. Peripheral leukocytes in patients with AD showed elevated mRNA expression of
SNCA with a reduced methylation rate in the intron 1 part of
SNCA, one of the methylation regulatory regions of
SNCA [
72].
Previous studies have suggested associations between α-syn and representative genes in AD, such as amyloid precursor protein (
APP), presenilin 1 (
PSEN1), and apolipoprotein E (
APOE). α-Syn and phosphorylated α-syn-positive dystrophic neurites have been observed in the brains of APP transgenic mice [
73]. Additional overexpression of mutated
PSEN1 in
APP transgenic mice accelerated Aβ-induced synucleinopathies and further promoted phosphorylation of α-syn [
73]. Human studies also showed a high frequency (50–60%) of Lewy body pathology in familial AD groups, supporting an association between AD-related genes and α-syn [
6,
74]. Intriguingly, α-syn pathology has been observed in the amygdala in over 90% of patients with autosomal dominant AD in
PSEN1 [
75]. Direct interactions of α-syn with the presenilin 1 protein were identified in the brain tissues of cognitively normal individuals. They were significantly increased in the tissues of patients with AD and DLB with
PSEN1 mutations [
76]. Increased interactions of the presenilin 1 protein with α-syn in
PSEN1-mutated cell lines were associated with increased membrane binding and α-syn accumulation [
76]. Additionally, a study revealed that cells with
PSEN1 mutations associated with AD and DLB had exacerbated phosphorylation and accumulation of α-syn [
77]. In a recent CSF biomarker study, the tau/α-syn ratio was altered in patients with AD, and in particular, changes in EOAD were statistically higher than those in late-onset AD [
63]. Furthermore, CSF α-syn levels were higher in symptomatic autosomal dominant AD mutation carriers than in non-mutation carriers [
78]. Considering the high contribution of genetic factors in EOAD, changes in CSF α-syn levels could be influenced by AD-related genes, resulting in greater changes in autosomal dominant AD.
APOE encodes the apolipoprotein E protein, an important lipid-binding protein for intercellular lipid redistribution in the CNS, which is a major risk factor for late-onset AD (after the age of 65 years). The possible pathophysiological roles of
APOE and α-syn have been investigated, mainly in relation to PD. The apolipoprotein E protein level was elevated by over fourfold in transgenic mice with the α-syn A30P mutation, and
APOE knockout in α-syn A30P transgenic mice increased the survival rate, delayed behavioral symptoms, and decreased neuronal degeneration and Aβ aggregates [
79]. In particular, the APOEε4-expressing PD mouse model, but not ε2 and ε3, showed increased α-syn pathology and astrogliosis and impaired behavioral ability with worsened neuronal and synaptic loss [
80]. In patients with PD, apolipoprotein E was elevated in the CSF with an abundance in dopaminergic neurons of the substantia nigra from postmortem brain tissues [
81]. Although the association between the apolipoprotein E protein and α-syn has been focused on in patients with PD, it may be involved in AD pathophysiological conditions. For instance, laboratory studies have shown elevated CSF α-syn levels in APOEε4-carrier patients with AD [
63,
78]. Additionally, elevated CSF α-syn levels were significantly associated with Aβ plaque burdens in APOEε4-positive individuals with autosomal dominant AD [
78]. Thus, these studies described the associations of the APOEε4 risk allele with CSF α-syn levels and Aβ deposition in AD. Although the exact mechanism has not been clearly elucidated, accumulating evidence suggests that α-syn is strongly associated with AD-related genes and contributes to disease progression at the genetic level.