RARE MISSENSE VARIANTS IN TREM2 AND ABCA7 IN A PATIENT WITH SPORADIC EARLY-ONSET ALZHEIMERS DISEASE

ITZCOVICH, TATIANA; CHREM MENDEZ, PATRICIO; VAZQUEZ, SILVIA; BARBIERI-KENNEDY, MICAELA; NIIKADO, MATÍAS; MARTINETTO, HORACIO; ALLEGRI, RICARDO; SEVLEVER, GUSTAVO; SURACE, EZEQUIEL I.

Los Angeles

Conferencia; Alzheimer's Association International Conference; 2019

Alzheimer's Association

Background: Alzheimers disease (AD) is a clinically heterogeneousneurodegenerative disease. Presentations of symptoms in individualsbefore the age of 65 years are classified as early-onsetAlzheimer?s disease (EOAD). According to the family history,cases can be divided into early-onset familial AD (EOFAD) andsporadic (sEOAD). The latter are thought to be predominantlypolygenic. The accumulation of variants which independently increasethe risk of late-onset Alzheimer?s disease (LOAD) maylead to sEOAD at an earlier stage of life (Barber et al., 2017;Wingoet al., 2012). Here, we present an Argentine patient who began withmemory deficits at the age of 49. Magnetic resonance imaging(MRI), single photon emission computed tomography (SPECT)and neurocognitive testing results were compatible with a dementiaof the Alzheimer type. Also, the patient did not have family historyof the disease. Methods: Patient underwent positron emission tomographyusing F-18-2-fluoro-2-deoxy-D-glucose and Pittsburgh Compound B. Exome sequencing was performed on genomicDNA from leukocytes in a NovaSeq 6000 platform (Illumina).MLPA (MRC-Holland) was performed to determine the presenceof copy number variation in the genes PSEN1, PSEN2 and APP. Results:Neuroimaging analysis revealed retention of PiB in thefollowing brain regions: frontal, parietal, precuneus, posteriorcingulate, lateral temporal and bilaterally striatum. FDG-PETshowed moderate to severe bilateral cortical hypometabolism.This pattern is similar to that observed in patients with autosomaldominant AD mutations (Villemagne et al., 2009). Exomesequencing and MLPA analysis revealed neither variants norcopy number variations in PSEN1, PSEN2, APP genes. Interestingly,two rare heterozygous missense variants in TREM2(p.His157Tyr) and ABCA7 (p.Thr575Ser) genes were found. Bothvariants had minor allele frequency less than 0.01 (gnomaAD)and showed a CADD phred score greater than 20. Several variantsin both genes have been associated with AD suggesting an importantrole in the disease pathogenesis. Conclusions: Data presentedhere contribute further evidence to the notion that the combinationof rare variants in AD-associated genes may be responsible for asubgroup of early onset cases.