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Background  The co-occurrence of the c.709-1G>A  GRN  mutation and the p.A152T  MAPT  variant has been identified in 18 Basque families affected by frontotemporal dementia (FTD). We aimed to investigate the influence of the p.A152T  MAPT  variant on the clinical and neuropathological features of these Basque  GRN  families.    Methods and findings  We compared clinical characteristics of 14 patients who carried the c.709-1G>A  GRN  mutation ( GRN +/A152T-) with 21 patients who carried both the c.709-1G>A  GRN  mutation and the p.A152T  MAPT  variant ( GRN +/A152T+). Neuropsychological data (n = 17) and plasma progranulin levels (n = 23) were compared between groups, and 7 subjects underwent neuropathological studies. We genotyped six short tandem repeat markers in the two largest families. By the analysis of linkage disequilibrium decay in the haplotype block we estimated the time when the first ancestor to carry both genetic variants emerged.   GRN +/A152T+ and  GRN +/A152T- patients shared similar clinical and neuropsychological features and plasma progranulin levels. All were diagnosed with an FTD disorder, including behavioral variant FTD or non fluent / agrammatic variant primary progressive aphasia, and shared a similar pattern of neuropsychological deficits, predominantly in executive function, memory, and language. All seven participants with available brain autopsies (6  GRN +/A152T+, 1  GRN +/A152T-) showed frontotemporal lobar degeneration with TDP-43 inclusions (type A classification), which is characteristic of  GRN  carriers. Additionally, all seven showed mild to moderate tau inclusion burden: five cases lacked β-amyloid pathology and two cases had Alzheimer’s pathology. The co-occurrence of both genes within one individual is recent, with the birth of the first  GRN +/A152T+ individual estimated to be within the last 50 generations (95% probability).    Conclusions  In our sample, the p.A152T  MAPT  variant does not appear to show a discernible influence on the clinical phenotype of  GRN  carriers. Whether p.A152T confers a greater than expected propensity for tau pathology in these  GRN  carriers remains an open question.

The unexpected co-occurrence of GRN and MAPT p.A152T in Basque families: Clinical and pathological characteristics