BACKGROUND: Alzheimer's disease (AD) pathophysiology is mostly (>95%) not 
inherited in a Mendelian fashion. Such sporadic AD (sAD) forms do not exhibit 
familial aggregation and are characterized by complex genetic inheritance. 
Growing evidence indicates that multiple genes contribute to sAD-characteristic 
endophenotypes, molecular mechanisms, signaling pathways and biomarker 
signatures either individually or through complex gene-gene interactions, 
lifestyle and the environment.
DISCUSSION: Under the hypothesis that low-prevalence variants showing 
moderate-to-high effect size may be associated with risk for sAD, two 
independent research groups have demonstrated that a rare variant (rs75932628, 
encoding a substitution of arginine by histidine at residue 47 (R47H), in the 
TREM2 gene, which encodes the triggering receptor expressed on myeloid cells 2) 
is significantly associated with an increased susceptibility to sAD. Another 
study has provided intriguing evidence that a low-frequency variant (rs63750847) 
in the APP gene is associated with a reduced risk of developing AD and a lower 
likelihood of age-related cognitive decline in elderly subjects without AD.
SUMMARY: Recent years have witnessed tremendous development in genetics 
technology that has allowed full individualized genome-wide or genomic screening 
embracing all of the risk and protective variants for sAD, both across 
populations and within individuals. Hopefully, the integration of neurogenetics 
with systems biology and high-throughput genotyping will further pave the way to 
decipher all of the related causes, mechanisms, and biomarkers across the 
spectrum of distinct AD forms. After an almost lost apprentice decade in AD 
therapy development, the epoch of individualized asymptomatic screening and 
progress in primary and secondary prevention of sAD is probably at its dawn. 
Even though we are more at the beginning than at the end of sAD genetics, there 
is some reason for optimism given the recent identification of novel risk or 
protective variants (such as rare TREM2 and APP mutations) showing strong 
statistical associations with sAD.