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in AD depends on the phase of the disorder. In the early stages, anomalous aphasia, occasional semantic
substitutions, occur due to difficulty in finding the right words (paraphasia), but speech is preserved. Later
on, these individuals exhibit transcortical sensory aphasia, in which the patient has a clear anomic aphasia,
and comprehension is affected. During moderate and severe stages of AD, lost fluency, increased use of
wrong words, incorrect pronunciation, and poor comprehension is found. Finally, advanced stages include
echolalia and verbal stereotypes. Primary progressive aphasia, on the other hand, classifies as fluent or non-
fluent. In the fluent variant, prosody is normal, well-articulated and grammatically correct, but progressively
circumlocutory and lacking in content words. The alteration of language correlates with a degradation of
semantic memory and, therefore, the fluent variant is often mentioned as semantic dementia. In the non-
fluent variant, speech is strained and hesitant, with phonemic paraphernalia. In a study of patients with
a pathologically proven AD, PPA patients had a higher proportion of neurofibrillary tangles in language-
related neocortical areas on the entorhinal cortex compared to patients with an amnesic presentation [101] .

Apolipoprotein E
Because of its relevance in Alzheimer’s disease and cerebrovascular metabolism, Apolipoprotein E (APOE)
needs to be highlighted for its role in aphasia [102,103] . A non-memory AD phenotype appears in approximately
25% of patients with early-onset disease [104] . Compared to the memory phenotype, language AD phenotype
has different demographic characteristics, genetic profile, and course of disease. This subgroup has smaller
odds to carry at least one APOE4 allele relative to the memory subgroup, especially at an early-onset [105] .

APOE4 is over-represented in PPA, so it is likely to act as a genetic risk factor in the development of the
disease [106] . A study by Daniele et al. [107] showed that women with the APOE genotype ε2/ε4 showed an
increased risk for PPA compared to women with homozygosis ε2/ε2 or ε4/ε4, suspecting that the ε3 allele
[108]
might play a protective role in PPA and frontotemporal dementia (FTD). Interestingly, Seripa et al. showed
an association in the chromosomal region 19q13-q13.2, which included in addition to APOE, the TOMM40,
and APOC1 genes.

Presenilin-1 and GLI family zinc finger 3
Presenilin-1 (PSEN1) plays an important role in AD. Cases of visual or apraxic and language phenotypes
are more frequent, with reports of atypical presentation with speech alteration, in carriers with PSEN1
mutations. It encodes a protein that takes part in the γ-secretase complex involved in the production of beta-
amyloid. However, considering language performance certainly GLI family zinc finger 3 (GLI3) is more
remarkable. A study that associated magnetic resonance image (MRI) and GWAS showed brain atrophy in
semantic and language areas in GLI3 variants. This gene is one of the three GLI zinc finger transcription
factors that are normally implicated in pattering brain structures as an important mediator downstream
of the Sonic Hedgehog pathway. It may act as an activator or repressor in the presence or absence of Sonic
Hedgehog. GLI3 is negatively regulated in the presence of PSEN1, which ultimately leads to decreased
neuronal differentiation. Mutations in the PSEN1 gene are responsible of several autosomal dominant AD,
including mutations with an aphasic phenotype [109] .

Other genes potentially associated with aphasia
In a study of patients with clinically diagnosed FTD spectrum syndromes, genetic variations within FOXP2
do not pose a genetic risk per se but modulate the presentation of FTD. A significant and specific association
between rs1456031 TT and rs17137124 TT genotypes and verbal fluency scores occurs, with left frontal
hypoperfusion [106,110] .

Granulin (GRN) is a gene that encodes progranulin and leads to a haploinsufficiency syndrome. In these
families, affected individuals may show PPA phenotype, while others show the behavioral variant FTD
phenotype (bvFTD). A family study reported that inclusions containing the transactional response DNA-