Asymptomatic subjects at high genetic risk of developing Alzheimer's disease: An OCT study

Abstract

AbstractOne of the major genetic risk factors for developing Alzheimer's disease (AD) is having a first‐degree family history of the disease. Approximately 40% of affected individuals have a family history of AD, and epidemiological studies indicate that the risk of AD in an individual with an affected first‐degree relative is four to ten times higher in cognitively healthy subjects. In addition, epidemiological studies have shown that transmission of the sporadic form of AD is both maternal and paternal, being the risk higher when it is the mother the affected patient, as it was associated with worse cognitive performance and a more predictable age of onset of the pathology. Among the possible explanatory genetic mechanisms, evidence of an inherited predisposition to cerebral metabolic reductions and atrophy in subjects with maternal family history suggests alterations in mitochondrial DNA (mtDNA), which is fully maternally inherited in humans.ApoE mediates another important genetic risk factor and this gene has been implicated in the modulation of Aβ metabolism and aggregation. The allele of APOE, ɛ4, increases the risk of AD threefold for each ɛ4 allele, and the risk is higher among people of European ancestry. Furthermore, ApoE ɛ4 has been reported to affect magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) and cognitive biomarkers, and may have intrinsic effects on brain function. Likewise, ApoE ɛ4 + elevated levels of amyloid beta (Aβ) proteins are associated with episodic memory impairment and high risk for clinical AD, and ApoE ɛ4 carriers are also more vulnerable to environmental factors.There is a clear relationship between retinal and brain changes in AD. In preclinical stages, retinal changes have been reported on optical coherence tomography (OCT), as well as the existence of associations between quadrant‐specific retinal nerve fibre layer thickness and brain regions analysed by 3 T MRI. In addition, both family history of the disease (FH+) and ApoE ɛ4 genotype (ApoE ɛ4+) potentiate each other, contributing to the thinning of the cortex in the hippocampal region. Likewiss, a direct correlation has been observed between the volumes of brain areas measured by magnetic resonance imaging (MRI) and the thickness of specific retina regions using OCT in nondemented older adults.All of these observations support the value of the retina as a biomarker of AD. It is known that signs of dementia can appear decades before clinically detectable symptoms. For all these reasons, interest in finding new biomarkers of the disease has focused on the earliest stages of AD, seeking less invasive and less expensive diagnostic methods for early diagnosis of the disease. OCT, unlike other methods such as AB determination in CSF or PET, is a reliable and inexpensive non‐invasive diagnostic method that allows us to detect retinal changes in individuals at high risk for AD in preclinical stages of the disease, contributing to both early diagnosis and follow‐up of these individuals.