Clinical Manifestations.

Area of Science:

• Neuroscience
• Genetics
• Pathology

Background:

• Autosomal dominant Alzheimer's disease (ADAD) is a rare form of Alzheimer's disease (AD) caused by fully penetrant mutations in PSEN1, APP, or PSEN2 genes.
• PSEN1 mutations are the most common cause of ADAD, with founder effects observed in specific populations, enabling detailed genetic and phenotypic studies.
• Studying founder populations enhances the identification of genetic/non-genetic factors influencing AD phenotype and intervention effects.

Purpose of the Study:

• To review the literature on the A431E PSEN1 mutation, a specific cause of autosomal dominant Alzheimer's disease.
• To analyze the phenotype, pathology, and potential therapeutic targets associated with the A431E PSEN1 mutation.

Main Methods:

• Literature review focused on the A431E mutation in the PSEN1 gene.
• Analysis of clinical data from over 100 families with the A431E PSEN1 mutation in the US and Mexico.
• Review of preliminary pathological and neuroimaging (Flortaucipir PET, diffusion MRI) data.

Main Results:

• The A431E PSEN1 mutation, identified in over 100 families in Mexico (Jalisco State) due to a founder effect, leads to a mean age of onset of 41 years.
• Clinical presentation includes spastic paraparesis (40% of cases) and cognitive deficits (episodic memory, language, or executive dysfunction).
• Pathology reveals severe cerebral amyloid angiopathy (CAA) and atypical amyloid plaques; neuroimaging shows characteristic brain region involvement and white matter abnormalities.

Conclusions:

• The A431E PSEN1 mutation, affecting an estimated 1,260 at-risk individuals, represents a significant target for AD intervention strategies.
• This mutation is a prime candidate for developing mutation-specific genetic therapies and general anti-AD treatments.
• Further research and therapeutic development are warranted for this specific ADAD genetic cause.