Abstract Details

The HTT gene contains a key region of CAG repeats. When expanded beyond 39 repeats, Huntington disease develops. CAG expansions ranging from 27 to 35 repeats are termed as intermediate alleles (IAs). Previous studies reported a higher frequency of IAs in AD patients.

To assess the effect of intermediate alleles (IAs) of Huntington's disease (HTT) gene on progression from SCD to MCI.

106 patients diagnosed with SCD underwent extensive neuropsychological assessments and blood sample collections at baseline. Patients were followed-up for a mean time of 14.72 (4.75). We tested APOE and HTT alleles genotyping at the end of the follow-up.

Eleven out of 106 patients (10.38% [95%C.I.=4.57-16.18]) were carriers of intermediate alleles (IA⁺) During the follow-up, 44 out of 106 patients (41.51% [95%C.I.=32.13-50.89]) progressed to MCI (p-SCD), while 62 patients (58.49% [95% C.I.=49.11-67.87]) did not (np-SCD). IAs, age at baseline, and APOE ?4 had effect on progression from SCD to MCI. We dichotomized age at baseline (<60 = younger patients [YP], >60 = older patients [OP]) and classified patients into four groups: YP/IAs^–, YP/IAs⁺, OP/IAs^– and OP/IAs⁺. OP/IAs⁺ had a higher proportion of progression from SCD to MCI (85.71% [95%C.I.=59.79-100]) as compared to YP/IAs^– (28.57% [95%C.I.=13.60-43.54], χ²=13.91, p<0.001) and OP/IAs^– (45.00% [95%C.I.=32.41-57.59], χ²=10.12, p=0.001). We classified patients according to APOE and IA status as: ?4^–/IA^–, ?4^–/IA⁺, ?4⁺/IA^–, ?4⁺/IA⁺. Proportion of progression in ?4⁺/IA⁺ group (100%) was higher as compared to ?4^–/IA^– (33.33% [95%C.I. =21.96-44.71]) and ?4⁺/IA^– (55.56% [95%C.I.=36.81-74.30], χ² = 4.60, p=0.032).

IAs interact with age and APOE ?4, two well-recognized risk factors for cognitive decline, increasing the risk of progression to MCI in SCD patients. Our results may suggest a role of HTT IAs in the continuum from SCD to MCI, adding an important piece to the puzzle of genetic factors involved in cognitive decline.