Early onset Alzheimer's disease in a South American pedigree from Argentina

Abstract

We report the clinical, SPET, immunohistochemical and DNA features of an early-onset familial Alzheimer's disease (FAD) in an Argentine pedigree of South American indian ethnic background. Pedigree spans 5 generations comprising more than 110 biological relatives. Clinical data supported the diagnosis of early onset FAD (mean age at onset 38.9 years) in 10 family members, including 3 with pathological confirmation (mean age at death 48.5). The pattern of transmission suggested autosomal dominant inheritance. Prominent features were mood changes, early language impairment, myoclonus, seizures and cerebellar signs. SPET displayed bilateral frontal, temporo-parietal and cerebellar hypoperfusion in early stages and in an asymptomatic member at risk, suggesting that SPET may have predictive value in this family. Immunohistochemistry showed beta amyloid deposits within neuritic plaques and vessel walls and no anti-PrP immunoreactivity. DNA analysis showed no abnormalities in the beta amyloid precursor protein gene. The identification of additional genetic defects in well characterized independent FAD pedigrees will contribute to the understanding of the pathogenesis of Alzheimer's disease.

Dedifferentiation and neuronal repression define familial Alzheimer’s disease

“…Further, the comparative enrichment for top transcriptional regulators and gene sets belonging to these endotypes across the EOFAD mutations may give insight into the documented severity of each; for example, there is evidence that the PSEN1 M146L and PSEN1 A431E mutants causes a particularly early onset (an average of 39 and 40 years, respectively) (59,60) along with an accelerated progression of the disease, while PSEN1 H163R and PSEN1 A246E mutants may have a relatively delayed onset (an average of 45 and 53 years, respectively) (61). Our analysis revealed that PSEN1 M146L mutants have the most severe repression of neuronal lineage and synaptic function, whereas PSEN1 H163R and PSEN1 A246E mutants have the most significant up-regulation of EMT-like dedifferentiation and nonectoderm lineage, and PSEN1 A431E is particularly enriched for cell cycle reactivation.…”

Is there a familial overlap between dementia and other psychiatric disorders?

“…schizophrenia) increase susceptibility for AD+P, an increased morbid risk for idiopathic psychoses could be expected among relatives of AD+P probands. Studies by Rubin et al (1993) and Mangone et al (1995) reported that EOAD patients exhibit prominent psychiatric features, with nearly 40% of patients experiencing mild EOAD also manifesting psychiatric symptoms.…”

A Comparison of Family History of Psychiatric Disorders Among Patients With Early- and Late-Onset Alzheimer’s Disease

“…5,7,8 Some EOAD patients exhibit prominent psychiatric features, with 41% of patients experiencing mild EOAD manifesting psychiatric symptoms in one study. [8][9][10] Others have found an increased risk for a family history of depression among depressed LOAD patients. [11][12] Additionally, AD patients with a family history of dementia were more likely to have a family history of a psychiatric disorder than AD patients without a family history of dementia.…”