 Bridging the Entrepreneurship Gender Gap: The Power of Networks

Choose your location to get a site experience tailored for you.

Remember my region and language settings

Bridging the Entrepreneurship Gender Gap: The Power of Networks

October 21, 2014 By Maria Blomqvist , Emma Chastain , Brenda Thickett , Shalini Unnikrishnan , and Wendy Woods

The reality, however, is that far more men than women start, sustain, and grow their own businesses. The underlying reasons for this imbalance are complex and varied, but they include differences in access to human, financial, and social capital. Unless these differences are addressed, the gender gap will likely remain wide, and global economic development and growth will not reach their full potential.

The specific focus of this report is on the importance of social capital for the success of female entrepreneurs. Both men and women need social capital—the access to networks that can support, connect, and mentor entrepreneurs—to successfully establish and run a business. But social capital’s particular importance for women—and how they can systematically develop it—isn’t well understood. The framework in this report provides a starting point for designing effective professional networks. Corporations, governments, and nongovernmental organizations (NGOs) should consider the principles we offer to ensure that conditions for success are built into programs that support female entrepreneurs and economic progress.

The Entrepreneurial Gender Gap

We define an entrepreneurial venture as an owner-managed business of any size. It could be a necessity-based venture, such as a woman selling goods in a market stall as the best available option to support her family, or an opportunity-based venture designed to capitalize on a market need or trend. Entrepreneurial ventures have three primary stages: start-up, sustainability, and growth. In examining social capital, we focus on the first two phases and define success as sustaining a business for three and a half years or longer.

Globally, women own 40 percent fewer businesses than men. The reason for this gender gap is twofold. First, women start fewer businesses than do men. According to the Global Entrepreneurship Monitor (GEM) project, only 11 percent of women around the world start new businesses—30 percent less than men. Second, women have a lower success rate than men when it comes to sustaining a business. There is an additional 10 percent entrepreneurship gender gap in the rates at which women and men sustain their businesses, as measured by the proportion of sustained businesses versus new businesses. While the gender gap in the start-up rate has decreased over the past few years, a similar decrease has not been seen in the success rate. Not addressing the success rate of female-owned businesses cuts in half the potential global GDP increase of $1.5 trillion, as more mature businesses are more likely to grow and hire additional people.

Three types of capital—human, financial, and social—are crucial for starting and sustaining an entrepreneurial venture. Human capital refers to the skills, business knowledge, and experience an entrepreneur needs to draw on. Financial capital refers to the necessary monetary resources. And social capital, as mentioned earlier, refers to access to networks that provide information and resources, as well as access to formal and informal mentor relationships.

These three types of capital are interlinked—and women tend to be less likely than men to have access to them all. As a result, women are less able to fully take advantage of the opportunities that are available to them. Many valuable initiatives are under way to provide female entrepreneurs with greater access to human and financial capital. Although gender gaps still remain, much of the progress that has been made to date is due to these efforts. Social capital is equally important, but it is less well understood.

The Power of Social Capital

Although less research has been done on social capital than on other forms of capital, the data suggests that social capital has a significant impact on the success of female entrepreneurs. Higher rates of entrepreneurial affiliation—defined as knowing another entrepreneur and a proxy for social capital—are linked to smaller gender gaps in business sustainability in developing countries. For example, data from Latin America and the Caribbean shows that a 10 percent increase in women’s entrepreneurial affiliation appears to reduce the sustainability gap between genders by as much as 25 percent. (See Exhibit 1.)

To better understand the impact of having social capital, we interviewed decision makers at 13 organizations around the world whose mission is to support female entrepreneurship. These interviews with experts in the field reinforced that social capital supports female entrepreneurs in many ways, ultimately helping them to run and grow their businesses better. The benefits of social capital include higher aspirations and better long-term planning, which result in growth; new or improved business skills and better business ideas; collaboration and credibility; greater access to funding; and emotional support. Let’s look at these benefits more closely.

Aspirations, Long-Term Planning, and Growth. According to the experts we spoke with, social capital enables female entrepreneurs to increase their aspirations, envision long-term plans, and set more ambitious growth targets for their businesses. According to GEM, the growth aspirations of female entrepreneurs typically lag behind those of their male peers. The percentage of male entrepreneurs projecting growth over a five-year period and the hiring of six or more employees is 7 to 9 percentage points higher than the percentage of female business owners making the same prediction. Role models and mentors encourage, inspire, and build confidence in female entrepreneurs, helping them envision long-term success, develop skills for growing their businesses, and cultivate professional networks.

The Asia Foundation, an international development organization, found that women in Malaysia, the Philippines, and Thailand who use established networks and associations are 24 percent more likely to plan for growth than women who don’t use such resources. In addition, the businesses of women using networks and associations are, on average, 38 percent larger than those of women who don’t access such resources. The need to acknowledge the benefits of social capital is highlighted by the Asia Foundation’s research, which found that a higher percentage of female business owners than male business owners in these countries never interact with business associations.

Going for Growth, an organization for female entrepreneurs in Ireland, offers peer-based programs that include regular roundtables led by successful women who explore growth-related topics. In a recent program, three-quarters of the participants reported that their sales had risen by an average of 15 percent, more than half of the women said that they had hired additional employees, and the number of businesses exporting goods had increased. A Going for Growth pilot was recently set up in Finland, adding an international dimension to the organization to further support its aim of connecting a diverse group of female entrepreneurs, helping them grow, learn, network, and do business together.

New or Improved Business Skills and Better Business Ideas. Through mentor relationships and by sharing the experiences of other entrepreneurs, female business owners learn new business skills, gain valuable insights, and receive feedback on business innovation, processes, and ideas. The Cherie Blair Foundation for Women has a program that pairs female entrepreneurs with knowledgeable mentors, and it reports that 96 percent of its entrepreneurs increase their innovation skills. (See “Social Capital in Action.”)

The Cherie Blair Foundation for Women’s mission is to build the confidence and capabilities of female entrepreneurs and to improve their access to financial capital. The foundation’s global Internet-based program matches women with mentors, who help the entrepreneurs set personal business goals, develop business plans, and tackle difficult problems. The mentorship pairing is complemented by an online community that allows program participants and alumni to collaborate, share ideas, and learn from each other. The women who participate see real business results. Ninety-six percent report a greater ability to innovate, 94 percent say that they’ve improved their business skills, and 93 percent have achieved a business goal through the program.

A successful participant in the foundation’s mentorship program is Zeti, whose story demonstrates the importance of social capital. Zeti started making cakes and cookies from her home in Malaysia to sell during religious holidays. When this mother of six joined the Cherie Blair Foundation for Women’s program, she was pregnant and, like many other entrepreneurs, felt isolated working alone on her small enterprise. Zeti was connected with a strategy and management consultant from the UK. By working with a mentor, she developed a business strategy, financial plan, and ways to promote her products. Her mentor helped her think of ways to expand and pushed her to enter new markets. Zeti learned how to use the Internet to find new products and connect with new customers.

Using her new skills, Zeti expanded her baking business and increased revenues thirteenfold. Busy and turning away orders, Zeti has hired an employee to help her. Zeti hopes to open a cake shop in Kuala Lumpur and eventually sell her delicacies around the world.

Perhaps even more informative are the stories of female entrepreneurs themselves. California-based Sue was at a turning point and decided that she was ready to launch her own bakery. She found the turmoil of navigating the necessary steps to run her business daunting at times and lonely. It was through a network of female entrepreneurs, supported by an organization called Smarty, that she was able to participate in “brain circles” and other programs and learn from experienced leaders and other entrepreneurs. The feedback, advice, and emotional support from women in the network facing similar challenges ultimately helped her launch a new website and make her bakery successful.

Collaboration and Credibility. A network can lead to valuable connections and confer credibility on a new venture, ultimately providing opportunities for improved operations and increased business scale. For instance, The BOMA Project, which helps Kenyan women in extreme poverty start their own businesses, has created an informal network of BOMA alumni who band together to buy supplies more cheaply from wholesalers in remote villages, achieving cost savings that would be unavailable to them individually. Similarly, WEConnect International provides legitimacy and game-changing growth opportunities by connecting female-owned businesses with global corporate-purchasing organizations that individual entrepreneurs wouldn’t otherwise have access to.

Greater Access to Funding. The connections and credibility that networks deliver can improve access to financing. According to BCG data on Africa, female entrepreneurs with more social capital also have greater access to more varied sources of credit, such as microfinancing and loans from cooperatives. Opportunity International provides loans, savings programs, insurance, and other financial services, as well as business training to entrepreneurs in 22 developing countries. Ninety-one percent of those loans are to women. New applicants must be approved by their local loan group, so women who have built social capital and thereby have greater credibility within their communities are more likely to be approved.

Endeavor Global is an organization that accelerates the growth of high-impact ventures by providing entrepreneurs with social capital, including a network of investors. The organization made about 2,700 introductions in 2012 and 2013, connecting entrepreneurs and investors. The connections bring tangible benefits. For instance, Endeavor entrepreneurs raised $332 million in debt and equity in 2012 alone. Given that a lack of financial capital poses a significant constraint across all phases of entrepreneurship, improving access to funding is a vital enabler of success.

Emotional Support. Starting a business can be difficult, isolating, and stressful—especially for women who are balancing their ventures with family obligations, at times in impoverished conditions. Networks provide valuable support that helps start and sustain a business. For these reasons, Village Enterprise and BOMA make sure that a group of three women run a single business: no one has to balance family and business demands alone. (See “Lifting Women Out of Poverty.”)

Village Enterprise and The BOMA Project help women and their families escape extreme poverty. Village Enterprise equips women with the resources they need to create sustainable businesses in sub-Saharan Africa. BOMA helps women generate a sustainable income in the arid lands of northern Kenya.

The programs take a similar approach—and the role of social capital is critical. Both organizations make sure that groups of three female entrepreneurs run a single business. This way, no one has to balance family and business demands alone, and having partners shields each woman from family requests for  earnings and loans. This structure by itself also assures built-in social capital.

The programs also provide female entrepreneurs with cash grants, extensive training in business skills and financial literacy, and mentorship. The three-woman units join larger business-savings groups, which provide access to capital for business expansion and emergencies as well as greater purchasing power. The larger networks also provide essential moral support, new-business information and opportunities, and expanded financial services.

The programs provide substantial, sustainable benefits to impoverished families. At Village Enterprise, 75 percent of the businesses are still operating after four years. After only one year, savings groups (made up of ten businesses) have typically saved more than $850—six times the seed capital of only one business in Uganda. According to program alumni and managers, the overwhelming success factor is the synergy among a group’s members and their support of each other. BOMA reports similar levels of success. All but 1 percent of BOMA businesses are still operating after one year, and 93 percent are still running after three years. The businesses are also profitable. On average, the value of these businesses doubles in one year and more than triples after three years.

Given the benefits of social capital, we believe that solutions aimed at supporting female entrepreneurs should seek to incorporate it in a systematic, structured way.

The “Three I” Framework of Social Capital

The programs we examined use social capital to achieve tangible results for female entrepreneurs, allowing them to reach their targets and empowering them in a sustainable way. It’s important to note, however, that the mere existence of networks does not convey benefits or ensure results. Networks must be designed, managed, and sustained according to proven principles. Through interviews with experts and program managers, we found that effective networks consider three interrelated dimensions: intent, inclusion, and interaction. (See Exhibit 2.)

Intent: What is the purpose of the network? Effective networks must have a purpose that is clearly defined and goes beyond simply creating new contacts for its members. Networks must add enough value that membership and participation become priorities and relationships develop. Therefore, the purpose of successful networks often includes increasing access to human or financial capital or helping members develop tangible business goals. Endeavor’s mission, for example, is to be a catalyst for long-term economic growth by selecting and mentoring high-impact entrepreneurs from around the world and accelerating the growth of their ventures. Endeavor achieves its purpose by providing business advice and better access to financial capital through its mentor and investor network. As the Endeavor example points out, a network’s target audience must be clearly defined, and the network itself must be explicitly designed to achieve its stated purpose.

Inclusion: Who should participate in the network? Since the power of a network stems from its participants, three factors are critical for success: the right founder, committed members with time to invest, and member diversity. Formal networks and mentorship programs require major investments of time and effort to maintain and, as a result, often struggle to become long-term, self-sustaining entities. Therefore, passion and energy are integral to their success. That’s why the most effective networks have founders with a long-term interest in developing and running the program or with the ability to empower members to take ownership of the network and sustain it. A founder can be an individual, an NGO, a corporation, or another organization with a long-term interest and presence in the community, such as a bank or hospital, but the founder should have the interest to sustain the network through the start-up phase and beyond.

Just as important, the members themselves must find the resources and develop the strategies to sustain a network—and commit to its purpose. We have observed that networks use a number of approaches to increase member commitment:

  • Charging membership fees
  • Interviewing applicants or asking alumni for recommendations to ensure the right member qualities and mindset
  • Establishing attendance policies that commit members to be present at a minimum number of meetings per year

Finally, diversity can add significant value. Networks should aim to attract members from diverse backgrounds to increase the richness of ideas and experiences. Prospective members might include a mix of new entrepreneurs and more established business owners, successful role models, and subject matter experts—ideally from a variety of cultures. This diversity will likely enhance the meeting discussions and increase the variety and depth of available business skills and feedback that members receive. Our interviews suggest that when networks are too narrow in their membership, their utility for members decreases over time.

Interaction: How will members communicate? Networks must decide how interactions will be managed and how members will request assistance, exchange ideas, and support each other.

The structure of networks should allow for both formal and informal interactions. Formal interactions build a self-sustaining network, but members must also be able to use the network informally as needed. For instance, the Cherie Blair Foundation for Women has formal mentor programs, but it also encourages informal relationships, idea exchanges, and collaboration through its online forum for members and alumni. Participants appreciate the flexibility of the more informal online option, but they regard both parts of the program as critical for success—each enhancing the impact of the other.

Easy and efficient interaction is a prerequisite for member participation and commitment. Successful programs do their best to adapt to member needs in terms of the exchange platforms used and the cadence of meetings. For instance, the Cherie Blair Foundation for Women’s online forum allows members to access advice on demand, whenever they have an Internet connection, making participation easy.

Finally, defining potential layers and subcommunities, their structure, and how they should connect and interact can also be a source of value. Networks aiming for impact on a larger scale may need to link members to resources at the local and regional levels and beyond—especially to create and capitalize on growth opportunities. For instance, female entrepreneurs who win larger supply contracts through WEConnect’s global sourcing program can subcontract parts of their contracts to other female entrepreneurs in the network, thus growing their businesses by fulfilling larger contracts that they could not take on individually. Networks that operate in this fashion have the potential to significantly increase the size and scope of their impact.

Across all of these dimensions, it is vital for the design of a network to account for and adapt to the local culture, norms, needs, and infrastructure of a given environment. A female entrepreneur in Africa may need access to a savings account, whereas one in the U.S. may need training in how to evaluate a potential investment. There is no easy, one-size-fits-all solution for all circumstances.

Looking Forward

Despite the progress to date, continued efforts must be made to empower female entrepreneurs and close the gender gap in economic opportunity. Although women today have greater access to human and financial capital, the gender gap in starting and sustaining a business remains wide.

BCG’s analysis of existing support programs reveals the importance of social capital and the significant benefits that networks and mentors deliver. The challenge is how to create networks with true, sustainable impact. The framework we’ve outlined is a starting point for designing successful networks. The framework provides a platform for the continued sharing of best practices and is an important call to action for stakeholders around the world. We urge organizations to consider the importance of female entrepreneurs and the role social capital plays in their success. Governments and NGOs should capitalize on the power of social capital when funding and developing support programs, with a particular focus on female entrepreneurs whose businesses hold the potential to grow and create jobs. Corporations should seek opportunities to expand their partnerships with networks of female entrepreneurs to enable mutually beneficial growth.

By recognizing the importance of social capital for women and by helping them develop it systematically, we can continue to close the gender gap in global entrepreneurship. By working together, we can help women around the world achieve their economic potential, which in turn could lift the global economy.

Bridging the Entrepreneurship Gender Gap: The Power of Networks


Bake - Clean Eating Magazine

Bruchetta Chicken recipe

Bruschetta Chicken

Try Jesse Lane Lee's famous Bruschetta Chicken recipe — it contains all the same enticing flavors as regular bruschetta, but she’s swapped out the refined white bread for protein-rich chicken to help keep blood sugar stable for sustained energy.

Skinny Spanakopita recipe

Skinny Spanakopita

This savory Greek-style pastry is a great way to incorporate more spinach in your diet. We use a whole-grain phyllo dough brushed with olive oil and feta cheese to add a creamy, salty kick. If you’re sensitive to gluten, see the tip at the bottom of the recipe to easily adapt it. For a prettier presentation, we simply take the phyllo and crumble it over the top of the pie before baking it.

Crispy Apple Chips

Crispy Apple Chips

These sweet, delicate munchies with satisfy your midday urge for a crunch. If you prefer chewy chips, though, remove them from the oven after 90 minutes.

Miso Chicken recipe

Miso Chicken recipe

As a fermented food, miso provides the gut with beneficial bacteria that help us to stay healthy, vibrant and happy. These miso chicken tenders are so savory and delicious, this dish will end up in your regular rotation.


Showing posts from October, 2016

Essay on 'A visit to a Theater ' For Class 5

Theatre is a place not only for watching movies but also to spend time with your loved ones because in this technological world we find no time to spend with our families. The theatre is a dark room indeed but it fills our mind with a brightness which is filled with joy. The characters in the movie make us laugh till our stomach hurt, we don't realise that in that moment we are not only living in the present but we are making memories which will intensify us into a human who has lived his life to the fullest. The most important thing other than the movie in the theatre which everyone loves is delicious, lip smacking popcorn. I visited the theatre for the first time when I was in my 5th grade, I was really excited to see the dark big room which had the biggest screen ever. The movie which I watched was "The Lion King" which was a Hollywood animated movie. I really had fun watching that movie and it was the best time of my childhood. During my teenage, I visited the thea…

Essay on How to deal with Boredom

It was said that "Time is like a sword. If you did not cut it, it will cut you." This saying was kept all by heart and told in most of our meetings and our events, but we often forget when we feel bored. Many of us miss the practical meaning of this parable and we get ourselves into a whole lot of trouble, boredom, frustration and discontent. We feel that there is no meaning to the life and adopt some wrong behaviors. That's because we do not know what to do and how to get out of the cycle of boredom. All religions have urged the need to exploit the time and spend what is useful. So Eliminating feeling bored task due. It is not a difficult or impossible, but easy to implement if anyone decides to fight the boredom, Here I sum up the most important steps to get rid of the boredom that have proved successful: 1. You must ask yourself why do I feel bored? If the cause is a routine you have to break it either by adding some new things or to do your work differently, …

Essay on Fashion Design

Fashion design is the art of the application designs and aesthetics, which are designed on the different tools and components such as clothing and accessories. It is influenced by different cultures that vary according to time and place.  Stylists are keen at the designs that take into account what the signs that point to these designs are. Fashion design is a craft,  an art, and  a skill; these elements must come together with each other to be an attractive design. It is taught in some specialized institutes  for these purposes and there are some centres held various courses for the beginners and advanced under the supervision of designers. They are currently held concerts under the supervision of a commercial reputation of international companies to provide fashion at parties In the presence of media in order to promote the work of these designs. There are many fashion designers who are working as part of a team to get out the best designs, the team contributes to the inspiratio…

Essay on 'You had a Wonderful Dream That Came True After Six Months'

Dreams we say are the infinite foam of imagination, it is that wonderful place where each and everything can happen, it is that place where we want to escape in, it is a story which is unsaid to anyone but ourselves. It is said that dreams come true when it is dreamt at dawn but is it true? only time will tell us. At first, I always dreamt in an unclear manner but as I dreamt on and on, I started getting engulfed in it. In my dreams, I always found myself atop of everything, be it a tree where I would climb on the top branch, be it a building where I would find myself on the top floor or be it a ferric wheel where the wheel would always stop on the top where I could gaze at the clouds. It felt very strange at first and I couldn't decipher the code behind it but when the dream kept presenting itself with various scenarios but with the same motive, I had to understand what was going on, it made me curious, it made me irresistible and I was famished for the very knowledge which was…


Mecocci, Paolacci, and Boccardi: Biomarkers of dementia: from bench to clinical side

Biomarkers of dementia: from bench to clinical side

To date Alzheimer’s dementia (AD) is defined biologically, by neuropathologic change, and clinically treating cognitive impairment as a symptom of the disease rather than the definition of the disease. This approach underlines the complexity of such a disease and should enhance efforts to identify a sensitive but easy to get biomarker that will play a key role when innovative and efficacious treatment for AD will be found because, then it will be possible to treat this disease before the onset of clinical symptoms. Several biomarkers have been studied in cerebrospinal fluid: amyloid beta 1-42 (Aβ1-42), total tau (t-tau), phospho-tau (ptau), Aβ1-42/t- tau ratio and Aβ1-42/p-tau ratio are currently revealed in clinical practice. In the next future, it would be useful to dose biomarkers in less invasive samples (such as blood or urine) as like as to use OMICs technologies, including proteomics and metabolomics, to find more predictive and diagnostic biomarkers for AD.

Diagnosis of dementia should be set as soon as possible to allow the most appropriate treatment and the use of sensitive biomarkers - defined as indicators of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention that is objectively measured - to support the diagnosis. The ideal biomarker should be: i) sensitive and specific of almost 80%; ii) have a positive predictive value (PPV or the probability that subjects with positive screening test truly have disease-) of almost 90%; iii) reliable, reproducible and repeatable; iv) strictly related to the pathophysiological process; v) able to set an early and differential diagnosis; vi) cheap and slightly invasive. The last published Alzheimer’s dementia (AD) criteria included cerebrospinal fluid (CSF) and neuroimaging markers to improve the diagnostic accuracy, early and differential diagnosis between several dementia types and to predict the conversion from the prodromal stage to full-blown dementia. CSF biomarkers are represented by amyloid beta 1-42 (Aβ1-42), total tau (t-tau), phospho-tau (ptau), Aβ1-42/t- tau ratio and Aβ1-42/p-tau ratio. Their diagnostic accuracy is shown in Table 1. To date, the use of biomarkers is based more on practical considerations that reflect resources and experience, rather than on clinical and evidence-based considerations. European guidelines state that they are rated as class II and class III of evidence - i.e., slightly supportive - respectively for positive and differential diagnosis of ADwith some difficulties related to a different reimbursement through different countries.

Biomarkers in clinical practice from healthy subjects through mild cognitive impairment

To detect cognitive impairment in prodromal or early stages, the use of biomarkers as a screening tool for apparently healthy individuals is still under debate. Firstly because it is not feasible to accurately identify all individuals with prodromal dementia with the sole recruitment of general practice physicians, as demonstrated in the UK, where such an attempt was phased out in two years.1 Secondly, because the clinical course of dementia is not yet amenable to intervention since currently there is no curative drug for such a disease. Therefore, the use of diagnostic biomarkers in the absence of efficacious treatments able to cure or to delay disease progression, do not make available a population screening.

Another problematic issue is the usefulness of CSF biomarkers in mild cognitive impairment (MCI), a condition of cognitive decline without interference with activities of daily life, with a wide range of prevalence (5-37%), due to changes in criteria and differences in populations studied and methodology.2 Published studies show accuracy for Aβ1-42, t-tau, and p-tau in detecting prodromal AD subjects up to 90% (93.5%) of sensibility and 80% (82.7%) of specificity, but data are widely variable.3 To have an appropriate evaluation it might be essential to know the predictive value (PV) that depends also from prevalence of disease: if the prevalence is low in general population, predictive value will be lower than specificity and sensibility values, hence if prevalence is 5% PV will be lower than in case of 37% of prevalence of disease. However, the CSF mentioned above biomarkers is likely to predict the clinical progression of AD. Sierra-Rio and coll.4 found that MCI and subjective cognitive decline (SCD) individuals with abnormal Aβ42/ phosphorylated tau ratio had a higher proportion of conversion to dementia during 5-year follow-up, supporting the utility of AD CSF biomarkers to predict a clinical decline in subjects with SCD or MCI in the medium term. On the other hand, the normality of AD CSF biomarkers could exclude progression to AD dementia. Although we do not have therapeutic tools for the disease, this prognostic information might have clinical relevance in subjects seeking answers when attending a specialist setting.4

Interlaboratory and interlaboratory variability in dosing CSF biomarkers represent a critical problematic issue to define their accuracy. Therefore different efforts on biomarkers harmonization studies have been made with the introduction of novel assays to provide a minimal lot-to-lot variation and thus leading to a higher agreement between different centers and measurements.

Finally, another limitation is represented by CSF biomarkers usefulness in the oldest olds, the part of population aged 85 years or more, who has been growing very fast in last decades reaching more than 1% of the Italian population. They are an extremely heterogeneous group, also according to the clinical and neuropathological presentation of dementia. In fact, oldest olds can be classified as: i) escapers (who reach 100 years and more without diseases); ii) delayers (who start to be affected by chronic diseases after 85 years old); iii) and survivors (who survive together with their chronic diseases after 85 years old).5 Despite the presence of classical neuropathological hallmarks, oldest old subjects often preserve their cognitive performances. It is unclear if they had better tolerate the adverse effects of neuropathological alterations or if they do not live long enough to express their clinically visible effects. Mattson and coll.6 showed that the diagnostic accuracy of CSF biomarkers for AD decreases with age; nevertheless the negative (NPV) predictive values remains persistently high also in oldest old, allowing to rule out AD even in this class of age.

However, biomarkers have beneficial and potential use in the oldest old population, mainly with the evaluation of the progression from MCI to dementia. Adding CSF biomarkers to the usual care diagnostic workup can improve the ability to differentiate between subjects with or without progression to dementia,7 especially for escapers, who might also benefit of their strong negative predictive value. In fact, the exclusion of AD pathology in a well-fit subject older than 85 years means that he could spend the rest of life without the fear of dementia, improving quality of life. Conversely, fit oldest old subjects with the mild cognitive decline with positive biomarkers could be included in clinical trials that currently exclude the oldest olds. In survivors and delayers, the medical practice should be performed according to ethical principles of beneficence, autonomy, justice, integrity, dignity, and vulnerability, so that it is often dispensable to make an accurate diagnosis or to predict MCI conversion in these classes.

Pathogenesis of dementia: toward new markers

CSF biomarkers limitations are probably due to an erroneous rationale behind dementia pathogenesis: amyloid and tau hypothesis have been widely studied in recent years, but according to several studies, they should represent a final stage of neuronal damage rather than the primary and only cause of neurodegeneration. Furthermore, Giuffrida and coll.8 even showed that Aβ1-42 monomers have a broad neuroprotective activity related to insulin/IGF-1 signaling. Many other hypotheses have been proposed, and they could contribute all together to dementia pathogenesis (Table 2). Indeed, lumbar puncture is a safe procedure but it is quite invasive and expensive, so it would be more comfortable and cheaper to obtain diagnostic biomarkers from blood taking advantage of new methodologies such as proteomic, lipidomic, and genomic profiling.

New potential cerebrospinal fluid biomarkers

Cerebrospinal fluid visinin-like-protein-1

Visinin-like-protein-1 (VILIP-1) belongs to the family of visinin-like proteins, which are neuronal calcium sensor proteins, and it is implicated in both neuroprotective and neurotoxic functions. In particular, VILIP-1 is released into the CSF from injured neurons and in neurodegenerative diseases. Tarawneh and coll.9 showed a role of this protein as a diagnostic and prognostic marker of AD in subject aged 38-93 years old.

Neurogranin and YKL-40

Neurogranin is a marker of synaptic dysfunction that may be an early pathologic process in age-related neurodegeneration, and a sensitive marker of age-related cognitive abilities, potentially preceding or even acting independently from AD pathogenesis. YKL-40 (chitinase-3 like-1) is a marker of neuroinflammation, and it is up-regulated in various inflammatory conditions and expressed by neutrophils, macrophages, chondrocytes, and vascular smooth muscle cells and astrocytes. Their CSF levels are increased in AD, and decreased in Parkinson dementia or dementia with Lewy Body; moreover, the first one seems to be reduced in vascular dementia and Frontotemporal dementia, and the latter appears to be increased in CSF of people with frontotemporal dementia.10,11 Neurogranin detection along with the β-site amyloid precursor protein cleaving enzyme 1 (BACE1) (i.e., the enzyme that catalyzes the first step in the formation of an amyloid beta peptide from amyloid precursor protein in AD brain) improves diagnostic performance rather than neurogranin alone. De Vos and coll.11 showed that NGRN/BACE1 ratio was well related with the yearly decline in mini-mental state examination (MMSE) scores in patients with MCI and AD.

NTP (neuronal thread proteins) are a family of proteins expressed in brain and some neuroectodermal tumor cell lines; ADassociated NTP (AD7c-NTP) seems to be elevated in brain tissue, cerebrospinal fluid, and even in urine of patients with Alzheimer’s disease reflecting the severity and progression of dementia as demonstrated in several recent studies.2,12 The high accuracy of urine measurement (sensibility of 89% and specificity of 85%) makes of AD7c-NTP a promising biomarker of dementia.

Microbiota biomarkers

Gut microbes can produce secretory products as amyloids, lipopolysaccharides, virulence factors rhamnolipids (RLs), toxins, and other neuroactive compounds; in particular elevated RLs, levels have been found in cerebrospinal fluid of both AD and MCI patients compared to healthy. Moreover, they seem to be related to the AD stages clinical severity.13

Blood biomarkers

Aβ1-42/Aβ1-40 ratio

Findings on the relationship between AD pathogenesis and plasmatic Aβ levels are contradictory, but new elaborate techniques revealed a correlation between an increase in the plasma Aβ42/Aβ40 ratio and risk of developing AD.14 Fei and coll.15 also found a link between this ratio and the risk of progression from MCI to AD with a specificity of 70% and sensibility of 85%.

Biomarkers of neocortical amyloid burden (NAB): the fibrinogen gamma chain

It represents the gamma component of fibrinogen, produced by FGG, a human gene found on chromosome 4. It can predict high NAB when combined with age, yielding a sensitivity of 59% and specificity of 78%16 that increase respectively to 71% and 84% if combined with a 4-plex metabolic panel (phosphatidylcholine, PE 39:7, anandamide, and anandamide isotope).17

Clusterin is a protein overexpressed in the brain of AD patients associated with the clearance of cellular debris and apoptosis. It has been demonstrated that MCI patients have higher plasmatic clusterin levels compared to healthy controls; moreover higher clusterin levels were associated with significantly lower MMSE scores at baseline and with the longitudinally structural atrophy for patients with MCI.18

It is a protein of neuronal cytoskeleton where it provides mechanical strength and regulates axonal diameter; its levels are higher in AD, FTD and Parkinsonism compared to healthy control, also in oldest olds, and it is related to brain atrophy.19

Metabolic biomarkers

Lipidomics research involves the identification and quantification of cellular lipid molecular species and their interactions with other lipids, proteins, and different metabolites. Extensively studied lipidomic biomarkers of AD include abnormal glycerophospholipids (due to an abnormality in the integrity of cell membranes). Notably, Mapston and coll.20 reported a set of 10 phospholipids from peripheral blood that predicted phenoconversion to either aMCI or AD within 2-3 years, with over 90% accuracy.

mi-RNA is endogenous ~23-nucleotide non-coding RNA molecules highly conserved in eukaryotes that regulate gene expression through post-transcriptional repression. Deregulation in their expression modulate some AD-related genes (such as Aβ, BACE1, tau, α and γ secretase genes) and promotes disease progression affecting levels of Aβ, p-tau and synaptic damage. Recently Reddy and coll.21 reviewed the role as potential biomarkers of miRNAs in blood and CSF from patients with AD showing neuroprotective forms (e.g., miRNAs 101, 124, 219, 16) and neurodegenerative forms (e.g., RNAs-26b, 206, 125, 33) in the brain and hippocampus.22-24

So far it is corroborated the measurement of CSF classical biomarkers (CSF Aβ42, t-tau, and p-tau) in clinical practice, but they are not entirely suitable for AD diagnosis showing several limitations, such as variability inter and intra-laboratory, lack of universal cut-off, partial usefulness in MCI and oldest olds, absence of indication in healthy subjects screening. Hence, efforts are needed to find novel candidates in CSF, or in more suitable and easy to get samples including blood or urine. In the next future, it is hopeful that research will find easily measurable biomarkers that can predict cognitive decline in subjects who have a preclinical, prodromal, or clinical AD.

LW Chambers, S Sivananthan, C. Brayne Is dementia screening of apparently healthy individuals justified? Adv Prev Med 2017;2017:9708413.

PS Sachdev, DM Lipnicki, NA Kochan. The prevalence of mild cognitive impairment in diverse geographical and ethnocultural regions: The COSMIC Collaboration. PLoS ONE 2015;10: e0142388.

C Sheng, Y Huang, Y. Han Dissection of prodromal Alzheimer’s disease. Front Biosci (Landmark Ed) 2018;23:1272-91.

A Sierra-Rio, M Balasa, J Olives. Cerebrospinal fluid biomarkers predict clinical evolution in patients with subjective cognitive decline and mild cognitive impairment. Neurodegener Dis 2016;16:69-76.

J Evert, E Lawler, H Bogan, T. Perls Morbidity profiles in centenarians: survivors, delayers, and escapers. J Gerontol A Med Sci 2003;58:232-7.

N Mattsson, E Rosen, O Hansson. Age and diagnostic performance of Alzheimer disease CSF. Neurology 2012;78:468-76.

RLH Handels, SJB Vos, MG Kramberger. Predicting progression to dementia in persons with mild cognitive impairment using cerebrospinal fluid markers. Alzheimers Dement 2017;13: 903-12.

ML Giuffrida, MF Tomasello, G Pandini. Monomeric s-amyloid interacts with type-1 insulin-like growth factor receptors to provide energy supply to neurons. Front Cell Neurosci 2015;9: 297.

R Tarawneh, G D’Angelo, E Macy. Visinin-like protein-1: diagnostic and prognostic biomarker in Alzheimer disease. Ann Neurol 2011;70:274-85.

S Janelidze, J Hertze, H Zetterberg. Cerebrospinal fluid neurogranin and YKL-40 as biomarkers of Alzheimer’s disease. Ann Clin Transl Neurol 2015;3:12-20.

A De Vos, H Struyfs, D Jacobs. The cerebrospinal fluid neurogranin/BACE1 ratio is a potential correlate of cognitive decline in Alzheimer’s disease. J Alzheimers Dis 2016;53:1523-38.

L Ma, J Chen, R Wang. The level of Alzheimer-associated neuronal thread protein in urine may be an important biomarker of mild cognitive impairment. J Clin Neurosci 2015;22:649-52.

E Andreadou, AA Pantazaki, M Daniilidou, M. Tsolaki Rhamnolipids, microbial virulence factors, in Alzheimer’s disease. J Alzheimers Dis 2017;59:209-22.

A Nakamura, N Kaneko, VL Villemagne. High-performance plasma amyloid-β biomarkers for Alzheimer’s disease. Nature 2018;55:249-54.

M Fei, W Jianghua, M Rujuan. The relationship of plasma Aβ levels to dementia in aging individuals with mild cognitive impairment. J Neurol Sci 2011;305:92-6.

NJ Ashton, SJ Kiddle, J Graf. Blood protein predictors of brain amyloid for enrichment in clinical trials? Alzheimer’s Dement 2015;1:48-60.

N Voyle, M Kim, P Proitsi. Blood metabolite markers of neocortical amyloid- β burden: discovery and enrichment using candidate proteins. Transl Psychiatry 2016;6:e719.

JL Hsu, WJ Lee, YC Liao. The clinical significance of plasma clusterin and Aβ in the longitudinal follow-up of patients with Alzheimer’s disease. Alzheimers Res Ther 2017;9:91.

JB Pereira, E Westman, O. Hansson Association between cerebrospinal fluid and plasma neurodegeneration biomarkers with brain atrophy in Alzheimer’s disease. Neurobiol Aging 2017;58:14-29.

M Mapstone, AK Cheema, MS Fiandaca. Plasma phospholipids identify antecedent memory impairment in older adults. Nat Med 2014;20:415-8.

PH Reddy, S Tonk, S Kumar. A critical evaluation of neuroprotective and neurodegenerative MicroRNAs in Alzheimer's disease. Biochem Biophys Res Commun 2017;483:1156-65.

RA Huynh, C. Mohan Alzheimer’s Disease: biomarkers in the genome, blood, and cerebrospinal fluid. Front Neurol 2017;8:102.

S Lehmann, A Gabelle, C. Paquet Can we rely only on ratios of cerebrospinal fluid biomarkers for AD biological diagnosis? Alzheimers Dement 2015;11: 1125-26.

X Du, X Wang, M. Geng Alzheimer’s disease hypothesis and related therapies. Transl Neurodegener 2018; 7:2.

Table 1.

The accuracy of available cerebrospinal fluid biomarkers.22,23

Biomarker Specificity (95% CI) Sensitivity (95% CI) PPV
Aβ1-42 0.58-0.80 0.55-0.82 0.48-0.92
t-tau 0.61-0.96 0.60-0.98 0.57-0.98
p-tau 0.76-0.86 0.82-0.92 0.86-0.94
A 1-42/t- tau ratio 0.38-0.86 0.71-0.98 0.57-1.00
A 1-42/p-tau ratio 0.89-0.96 0.74-0.86 0.83-0.91

[i] CI, confidence interval; PPV, positive predictive value.

Table 2.

The pathogenic hypothesis of Alzheimer’s dementia.24

Hypothesis Mechanism
Inflammatory hypothesis Microglial activation, pro-inflammatory cytokines release, insulin/IGF-1 resistance
Oxidative hypothesis Radical oxidative species exposure, cellular oxidative stress, protein oxidation, protein nitration, glycoxidation and lipid peroxidation.
Cholinergic hypothesis Degeneration of cholinergic neurons, reduction of cholinergic tone in the cortex and hippocampus, cognitive dysfunction
Insulin resistance Impairments of insulin/IGF-1 signaling and glucose metabolism, impaired synaptic plasticity, synaptic degeneration, cell death
Gut microbiota activity Interactions with the central nervous system through direct and indirect pathways involving vagal nerve activation, cytokine production, and release of neuropeptide/neurotransmitters and short-chain fatty acids
Abstract views:

Article Metrics

Metrics Loading ...

Metrics powered by PLOS ALM

Copyright (c) 2018 Patrizia Mecocci, Lucia Paolacci, Virginia Boccardi

Creative Commons License


It seems to have become a common dogma in many countries that whaling is evil, even when it is for food, and that any people who hunt whales are benighted almost beyond redemption. However, there is another side of the story.

The International Whaling Commission's Scientific Committee in 1981 has made several estimates of the population of Northwest Pacific sperm whales, with the lowest or minimum figure by British scientists indicating the presence of 210,000 mature sperm whales in the area. The present Japanese catch is 890 whales, or 0.4 percent of the total mature whales. Catches at this level do not endanger the survival of the sperm whales and provide a large margin for replenishment of the stock. Japanese whalers carefully follow the scientific recommendations to make sure that the various species are in no danger of becoming extinct or seriously reduced. There is no scientific basis in the The Post's editorial assertion ("Save the Whales," Nov. 28) that the sperm whale stock is endangered.

The IWC did not decide to ban sperm whaling totally, as has been reported. It left the catch quota in the Northwest Pacific in abeyance, due to the rather wide gaps in the population estimates. Japan, in filing objections to the delay in determining a quota, and to the new IWC requirement for using explosive harpoons on small minke whales, did not do so in defiance of the IWC. It did so only as a precautionary measure to provide for the contingency that the new, explosive harpoons may not be ready for use before the next whaling season, and for the possibility that the IWC may fail to agree on any catch limits before the whaling season opens next fall.

As regards the ethics of whaling, it is easy for Americans, with their vast expanse of land and their great surpluses of meat and grains, to regard whale meat and whaling with distaste. When Americans did hunt whales, it was only for their oil, not for food. But in Japan, which has very little arable space, the sea has always been the main source of protein, and whales have provided valuable meat for Japanese for many centuries.

This does not mean that Japanese are any less sensitive than Americans to animal life, but they do draw the line at regarding whales as near-human. Whales probably enjoy more protection from man than any other form of wildlife, and commercial whalers pose no threat to the continued existence of any of the world's whale species. While Japan probably could survive without whale meat, it nonetheless does have a strong interest in retaining some supply as a source of protein in a country that depends on imported food for 50 percent of its diet, and whaling is an irreplaceable means of livelihood for some communities.

It does not seem entirely appropriate for non-whaling countries to tell people who have long caught whales for food that they must no longer do so because this offends their ethics. If the whales were truly in danger, it would be different, but the IWC has indicated they are not. We believe that Japanese attitudes toward whales as a food source deserve to be respected as much as some environmentalists' pronouncements that whales should not be hunted at all.