Periodic Reporting for period 1 - BioALFA (The effect of pro-aging and pro-youthful blood factors in normal ageing and Alzheimer’s disease: a multimodal approach)
Periodo di rendicontazione: 2018-01-01 al 2019-12-31
One of the most significant recent findings has been the discovery that some blood factors promote the ageing of the brain (the so-called pro-ageing blood factors) while others help to rejuvenate the brain (the so-called pro-youthful blood factors); these blood factors have been described in animal models but they have not been comprehensively studied in humans and particularly in Alzheimer’s disease (AD). Since one of the main risk factors for AD is aging, in the BioALFA project we measured these blood factors in a large group of volunteers, including healthy individuals and asymptomatic stages of AD. We studied whether the levels of the pro-ageing and pro-youthful blood factors are association with markers pf neurodegeneration. Our aim is to answer the question whether the pro-ageing and pro-youthful blood factors have an impact on human brain and hence be a therapeutic target in AD.
AD is a public health problem at the global level due to the increase in life expectancy. It is estimated that around 45 million persons currently suffer from Alzheimer's disease (AD). To this figure, one must add the impact this disease has on the caregivers of patients, generally close relatives who take care of the patient with the consequent physical, emotional and economic burden. In countries around us, the associated cost per patient is estimated to be >30,000euro/year, which multiplied by the high prevalence of the disease represents 1.24% of the gross domestic product. Projections estimate that by 2050 the number of patients will be >130 million (ADI. World Alzheimer Report, 2015), which would represent an unbearable cost to our society.
Therefore, it is extremely important to find new therapeutic targets for AD.
AD is a public health problem at the global level due to the increase in life expectancy. It is estimated that around 45 million persons currently suffer from Alzheimer's disease (AD). To this figure, one must add the impact this disease has on the caregivers of patients, generally close relatives who take care of the patient with the consequent physical, emotional and economic burden. In countries around us, the associated cost per patient is estimated to be >30,000euro/year, which multiplied by the high prevalence of the disease represents 1.24% of the gross domestic product. Projections estimate that by 2050 the number of patients will be >130 million (ADI. World Alzheimer Report, 2015), which would represent an unbearable cost to our society.
Therefore, it is extremely important to find new therapeutic targets for AD.
In the BioALFA study, we first validated assays to ensure that we were properly measuring the pro-ageing and pro-youthful blood factors. We first tested them in a group of participants of extreme ages, including teenagers (12-16yo), young adults (18-25yo) and old adults (>70yo) and we observed that most of them changed with ageing. Moreover, we observed that higher levels of the pro-ageing blood factors beta2-microglobulin (B2M) and CCL2 were associated with higher levels of Neurofilament in blood, a marker of neuronal injury. In contrast, higher levels of Oxytocin, a pro-youthful blood levels, are associated with lower levels of Neurofilament. In other words, B2-M and CCL2 are associated with more neuronal injury while Oxytocin is associated with less neuronal injury.
Next, we measured the following blood factors in the ALFA+ cohort, which is a very well-characterised cohort of cognitively unimpaired individuals that includes individuals that are in the preclinical stage (asymptomatic) of AD. We measured the following blood factors: CCL2, CCL11, CCL19, VCAM1, B2M and Haptoglobin (pro-ageing) and TIMP2 and GM-CSF (pro-youthful). Our main results were:
1. Plasma GM-CSF is increased in preclinical AD and is higher in females compared to males.
2. In cognitively unimpaired individuals with no evidence of A pathology (A-), increasing age is significantly associated with higher levels of the pro-ageing blood factors CCL11 and B2M and, at a trend level, with lower levels of the pro-youthful blood factor GM-CSF.
3. Higher levels of the pro-youthful blood factor GM-CSF was significantly associated with a higher glucose metabolism (as measured by FDG-PET scans) while higher levels of the pro-ageing blood factor Haptoglobin was associated with lower levels of glucose metabolism.
Although this is an observational study and no causal associations can be drawn, the results of the BioALFA study support the idea that some of the age-related blood factors described in mice may also have an effect on the human brain. The BioALFA study has open a new line of research in our center, which will include a longitudinal study.
Next, we measured the following blood factors in the ALFA+ cohort, which is a very well-characterised cohort of cognitively unimpaired individuals that includes individuals that are in the preclinical stage (asymptomatic) of AD. We measured the following blood factors: CCL2, CCL11, CCL19, VCAM1, B2M and Haptoglobin (pro-ageing) and TIMP2 and GM-CSF (pro-youthful). Our main results were:
1. Plasma GM-CSF is increased in preclinical AD and is higher in females compared to males.
2. In cognitively unimpaired individuals with no evidence of A pathology (A-), increasing age is significantly associated with higher levels of the pro-ageing blood factors CCL11 and B2M and, at a trend level, with lower levels of the pro-youthful blood factor GM-CSF.
3. Higher levels of the pro-youthful blood factor GM-CSF was significantly associated with a higher glucose metabolism (as measured by FDG-PET scans) while higher levels of the pro-ageing blood factor Haptoglobin was associated with lower levels of glucose metabolism.
Although this is an observational study and no causal associations can be drawn, the results of the BioALFA study support the idea that some of the age-related blood factors described in mice may also have an effect on the human brain. The BioALFA study has open a new line of research in our center, which will include a longitudinal study.
The originality of this project resides in the novelty of its rationale. It has been assumed in the AD field that neurodegeneration is a process that basically occurs in the central nervous system and evolves independently of any systemic phenomenon. The rationale of this project relies on the idea that peripheral circulation may have an effect on brain structure of function. To our knowledge, this is the first project that comprehensively studies in a large and well-characterize cohort of participants all the pro-ageing and pro-youthful blood factors that have been described in parabiosis experiments. Our preliminary results indicate that some pro-ageing blood factors may have a deleterious effect on the brain, while some pro-youthful blood factors may have a beneficial effect. These results need to be confirmed in larger and longitudinal cohorts.