We reveal the genetic profiles of people at higher risk of Alzheimer's

The Genetic Neuroepidemiology and Biostatistics team of the Barcelonaβeta Brain Research Center (BBRC), research center of the Pasqual Maragall Foundation, has characterized the genetic predisposition to Alzheimer's and other neurological disorders in cognitively healthy people in the preclinical stages of the disease, that is, when there are still no obvious symptoms but brain and biomarker changes associated with the degenerative process already occur. Although genetics is a direct cause of Alzheimer's in only 1% of cases, characterizing genetic predisposition will open the door to more personalized medical care and prevention, and allow a better selection of participants for specific clinical studies based on their genetic profile. In this sense, Dr. Natàlia Vilor-Tejedor, senior researcher of the study and team leader, emphasizes that "this characterization allows us to obtain a more complete profile of the study participants, and thus facilitate the development of personalized preventive strategies, a better selection of participants for clinical trials and prediction of treatment response".
 

The research, published in the scientific journal Alzheimer's & Dementia: The Journal of the Alzheimer's Association, is based on data from the Alfa cohort, promoted by ”la Caixa” Foundation and made up of more than 2,700 participants without cognitive impairment, and includes also data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). The results of this research, according to Patricia Genius, predoctoral researcher of the team and also author of the study, "will improve the accuracy of the conclusions of epidemiological studies, and open the door to a better knowledge of the biological pathways associated with the neurodegenerative processes".
 

Measures of genetic predisposition beyond the APOE gene

Although genetics is only a direct cause of Alzheimer's in a very low percentage of cases (around 1%), the genetic predisposition to develop the disease can have an impact on processes of cognitive impairment or brain atrophy that could precede the development of symptoms. In addition, people with a high genetic predisposition could be more susceptible to the effect of other risk factors, such as environmental exposures, causing an acceleration of cognitive deterioration or even brain atrophy. The APOE gene is the main genetic risk factor for Alzheimer's, but there are other variables. "Knowing in detail the non-modifiable factors, such as the genetic predisposition to the disease, allows us to identify the people most vulnerable to the risk, and to take action on the modifiable risk factors", highlights Vilor-Tejedor.

In this regard, the team calculated polygenic risk scores (PRS) for Alzheimer's and other neurological disorders, risk factors associated with Alzheimer's disease and aging processes. The PRS are measures that estimate a person's genetic predisposition to develop a disease based on the weighted sum of the effect of the genetic variants associated with this disease in previous studies.

"The results will allow us to decipher how the genetic predisposition to Alzheimer's interacts with other risk factors to influence the development of the disease and the processes prior to the appearance of the symptoms", explains the researcher. "It will also allow a better characterization of the mechanisms that influence these biological processes".

More than 2500 participants of the Alfa cohort

The team analyzed this data in 2,527 participants of the Alfa study, a longitudinal project that follows healthy people between the ages of 45 and 75, mostly descendants of people with Alzheimer's, to study cognitive, biological and neuroimaging changes related to aging and Alzheimer's. The genetic predisposition to Alzheimer's has been characterized among these participants of the BBRC and those of the clinical groups of the ADNI, an international consortium that includes healthy people with mild cognitive decline or Alzheimer's dementia.

The research team found that BBRC participants, especially those with amyloid protein alterations, have a distribution of Alzheimer's genetic predisposition similar to that of clinical groups, further characterizing the Alfa cohort for study the early pathological changes of Alzheimer's. "Alfa is one of the few cohorts in the world with such an extensive characterization," Vilor-Tejedor points out. "We knew it was a cohort enriched in Alzheimer's risk factors, but with this new study we have taken a step further by adding a new dimension of biological variables, which will allow prevention studies to be even more precise", concludes the researcher.

Bibliographic reference:
Vilor-Tejedor, N., Genius, P., Rodríguez-Fernández, B., et al. ‘Genetic characterization of the ALFA study: Uncovering genetic profiles in the Alzheimer's continuum’. Alzheimer’s & Dementia. DOI:  10.1002/alz.13537