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January 19, 2023
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Alzheimer's disease – is there hope?
Alzheimer's disease (AD) is a debilitating neurodegenerative condition causing cognitive and psychiatric problems. Diagnosis is complicated, and no disease-modifying therapy is available at the moment
Highlights:
- Alzheimer's disease (AD) is a debilitating neurodegenerative condition causing cognitive and psychiatric problems, along with eventual loss of autonomy
- Though detailed etiology is still unknown, AD is proven to be connected to the formation of protein aggregates in the brain
- Age is one of the main risk factors for AD
- Diagnosis is complicated, and no disease-modifying therapy is available at the moment. All existing AD drugs are for symptomatic treatment
- New drug search is mainly focused on clearing amyloid and tau aggregates
- The range of lifestyle interventions was connected with alleviating the risks of developing AD, including diet and exercise
Introduction
Affecting 25 million people worldwide, Alzheimer's disease (AD) is one of the most feared neurological disorders. Characterized by rapidly deteriorating memory and psychiatric problems, AD presents the most common cause of dementia. In the US, AD prevalence was estimated to be 5 million in 2007, and by 2060, this number is predicted to increase to more than 13 million. Dealing with AD is additionally complicated by the lack of knowledge about precise etiology. Due to this, AD remains the largest unmet medical need in neurology despite being an enormous economic and personal burden. Existing therapies are primarily targeted at alleviating the symptoms, with no successful disease-modifying therapies existing up to this moment.
Image 1
AD pathogenesis
For the first time, clinical and neuropathological characteristics of AD (1) were described in 1906 by Alois Alzheimer (after whom the condition was subsequently named). A 51-year-old woman suffered from progressive memory loss, focal symptoms (nerve or brain function impairments affecting a specific body area, such as limb weakness or loss of vision), and hallucinations. After the patient's death, her brain was autopsied, and, for the first time, the specific AD signs – neuritic plaques and neurofibrillary tangles – were observed.
After this observation, it took 20 years before the major components were identified. Nowadays, it is known that the neuritic plaques majorly consist of amyloid-β, while the major tangle component is tau protein. Amyloid-β is a peptide of 40-42 amino acids in length generated from larger amyloid precursor protein (APP). APP's function is not yet fully understood, but multiple pieces of evidence point toward its role in neuronal survival. APP mutations can lead to the emergence of misfolded amyloid peptides. And amyloid-β, when misfolded, can form aggregates toxic to neural cells (2). The most neurotoxic amyloid aggregates are able to block glutamate receptors, disrupting neuronal communication, and Ca2+ channels, influencing cardiovascular system and muscle strength.
Tau protein maintains the shape and assembly of microtubules (cellular structures that provide cells their shape and integrity) and exists in six isoforms (highly similar proteins originating from a single gene). Like amyloid-β, tau proteins are usually highly soluble. However, in the case of AD development, tau proteins become hyperphosphorylated (phosphoryl groups get attached to all possible protein sites), thus forming tangles and leading to neurotoxicity (3).
Amyloid aggregates induce apoptosis of neural cells, initiate a local inflammatory response, and increase reactive oxygen species production (4). Tau aggregates block communication between neurons, ultimately causing neuronal death (5).
Infographic 1
Onset, risk, and consequences
Late-onset AD occurs more commonly, usually in people over 65. Much rarer early-onset AD can occur in individuals between 30 to 65 years. Early-onset AD is mainly associated (6) with the mutations in APP and presenilin-2 (a protein involved in APP production), while multiple factors govern the development of late-onset AD. Among identified risk factors are age, female gender, low educational level, and occupational fulfillment, previous head injuries, sleep disorders, and hypertension (7). The presence of E4 variant of apolipoprotein is linked with a significantly increased risk of developing late-onset AD, and the risk significantly increases if a person carries several copies of the gene (8). Other factors that possibly play a role in AD development are cardiovascular disease, diabetes, obesity, elevated cholesterol, smoking, and high alcohol intake (9).
The most significant risk factor for AD is, nevertheless, age. The incidence of AD steadily increases with age and doubles every five to ten years. Prevalence increases exponentially from 3% amongst 65-74 years old to around 50% amongst people older than 85 (10). The gradual loss of personal autonomy accompanied by problems in language, memory, and cognitive skills is a mark of AD. Due to its debilitating effects, AD carries not only a human impact but also an enormous financial cost. In 2005, more than $90 billion were spent by Medicare on persons with AD, of which more than $20 billion went to long-term care services. The knowledge of age-connected risks combined with the growth of the aging population requires a series of measures for early diagnostics, treatment, and prevention.
AD diagnostics and treatment
Both diagnostics and treatment of AD remain highly problematic. In AD, neurodegeneration is estimated to start 20-30 years before the onset of symptoms, thus, there is a pressing need for diagnostic tools. As of the moment, there are no reliable peripheral blood markers allowing early diagnostics of AD, though some promising results have been obtained as to using plasma amyloid levels (11). Conflicting reports (12) address the usage of PET (positron emission tomography) scanning with thioflavin T derivative, which selectively binds to amyloid-β. While PET allows for improving clinical accuracy, more longitudinal studies are needed to establish its robustness. Some attempts are being made to introduce the amnestic mild cognitive impairment as a marker of an early clinical phase of the disease. Unfortunately, a definitive diagnosis can be made only post-factum by histological examination of the brain at autopsy.
As of currently approved therapies (13), they are mostly symptom-alleviating and can be divided into three main groups:
- Cholinesterase inhibitors,
- NMDA (N-methyl D-aspartate) antagonists,
- Combination therapy.
In AD, acetylcholine (a neurotransmitter able to speed up or slow down nerve signals) gets depleted, hence cholinesterase inhibitors limit its reduction in the brain. NMDA-receptor in healthy individuals regulates the transport of calcium ions. In AD, the receptors become over-activated, causing an abundance of Ca2+ leading to neurotoxicity. NMDA-antagonists help to regulate the Ca2+ levels, thus alleviating the symptoms. Combination therapy unites both approaches with better outcomes in severe cases but limited success in mild and moderate AD. Unfortunately, all of these agents offer only temporary relief.
The emerging therapies are focused on amyloids, tau proteins, mitochondrial dysfunction, and neuroinflammation. As of 2021, more than 140 drug candidates have been registered for various phases of clinical trials. Some of them, such as J-147 – an orally available curcumin derivative, have already shown promising results (14). But it remains to be seen how many of these drug candidates would be able to progress to clinical practice. At the moment of writing, the only FDA-approved disease-modifying drug for AD remains aducanumab – a compound able to remove amyloid-β plaques from the brain (15). Still, its use remains problematic due to the connected brain abnormality risks, inconsistent results in improving function, and extremely high price.
Image 2
Prevention strategies
A range of modifiable factors has been associated with AD prevention, including psychosocial and lifestyle ones. General strategies applicable to brain health seem to work as a protective factor in AD.
Studies demonstrated a causal association between long-term adult education and reduced AD risk and delayed onset (16). A 44-year longitudinal study of women (17) demonstrated that cognitive activity in midlife is linked with a 46% reduction in AD risk. Bilingualism, which is connected to enhanced neuroplasticity, is also beneficial. In a study of lifelong Cantonese/Mandarin bilinguals (18), the first AD symptoms were marked significantly later than in monolinguals. Higher educational attainment, in general, is thought to be beneficial against AD due to building cognitive reserve and increasing brain volume.
Social engagement proves to be a vital protective buffer against dementia risks. Frequent social contacts help to create additional cognitive reserves. A 28-years follow-up study demonstrated that establishing social connections in midlife is associated with lower risks of developing dementia, including AD (19). Surprisingly, this finding held only for friendship but not relationship contacts. Partner relationships seem to be of great importance, as was shown in the study on marital status and cognitive abilities later in life (20).
Regulating stress and maintaining self-regulation is also recommended as higher risks of AD incidence were found among those with stress-related disorders (21). Chronic work-related stress is also an emerging risk factor for AD.
Pre-existing diseases, such as diabetes and cardiovascular disease, bring a higher risk of being affected by AD. So, careful management of these diseases is required. Research shows that pharmaceutical interventions such as regular intake of antidiabetic (22) and antihypertensive (23) drugs are linked to delayed progression and lowered AD risk. Due to the association between cognitive decline and insulin resitance, many researchers even regard AD as type 3 diabetes. However, more studies are required to analyze the efficacy of particular medications as a preventative treatment.
Non-linear dependency was noticed between body mass index (BMI) and AD. Consistent evidence demonstrates a higher AD risk among middle-aged patients with heightened BMI and elderly patients with lowered BMI (24). Proper diet and exercise can help maintain BMI in a healthy range. Three dietary patterns, including the Mediterranean diet, the DASH (Dietary Approaches to Stop Hypertension) diet, and the MIND (Mediterranean-DASH Intervention for Neurodegenerative Delay) diet, were linked to the decreased risk of AD (25). Among other preventative measures are maintaining good sleep quality, avoiding smoking and excessive alcohol consumption.
Conclusions
Much remains to be done in the field of AD prevention and treatment. Multiple etiology details still remain unknown, including the link between amyloid and tau proteins and mechanisms behind neuronal vulnerability. Meanwhile, the essential thing that can be done for people at risk is educating them on putative prevention measures and promoting brain health.
References
1. Goedert M, Spillantini MG. A Century of Alzheimer’s Disease. Science. 2006 Nov 3;314(5800):777–81.
2. Haass C, Selkoe DJ. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid β-peptide. Nat Rev Mol Cell Biol. 2007 Feb;8(2):101–12.
3. Wegmann S, Biernat J, Mandelkow E. A current view on Tau protein phosphorylation in Alzheimer’s disease. Curr Opin Neurobiol. 2021 Aug;69:131–8.
4. Mattson MP. Pathways towards and away from Alzheimer’s disease. Nature. 2004 Aug 5;430(7000):631–9.
5. Wang JZ, Xia YY, Grundke-Iqbal I, Iqbal K. Abnormal Hyperphosphorylation of Tau: Sites, Regulation, and Molecular Mechanism of Neurofibrillary Degeneration. Perry G, Zhu X, Smith MA, Sorensen A, Avila J, editors. J Alzheimers Dis. 2012 Dec 27;33(s1):S123–39.
6. DeFina PA, Moser RS, Glenn M, Lichtenstein JD, Fellus J. Alzheimer’s Disease Clinical and Research Update for Health Care Practitioners. J Aging Res. 2013;2013:1–9.
7. Hersi M, Irvine B, Gupta P, Gomes J, Birkett N, Krewski D. Risk factors associated with the onset and progression of Alzheimer’s disease: A systematic review of the evidence. NeuroToxicology. 2017 Jul;61:143–87.
8. Safieh M, Korczyn AD, Michaelson DM. ApoE4: an emerging therapeutic target for Alzheimer’s disease. BMC Med. 2019 Dec;17(1):64.
9. Solomon A, Mangialasche F, Richard E, Andrieu S, Bennett DA, Breteler M, et al. Advances in the prevention of Alzheimer’s disease and dementia. J Intern Med. 2014 Mar;275(3):229–50.
10. Zhu CW, Sano M. Economic considerations in the management of Alzheimer’s disease. Clin Interv Aging. 2006;1(2):143–54.
11. Li Y, Schindler SE, Bollinger JG, Ovod V, Mawuenyega KG, Weiner MW, et al. Validation of Plasma Amyloid-β 42/40 for Detecting Alzheimer Disease Amyloid Plaques. Neurology. 2022 Feb 15;98(7):e688–99.
12. Klunk WE. Biopsy Support for the Validity of Pittsburgh Compound B Positron Emission Tomography With a Twist. Arch Neurol [Internet]. 2008 Oct 1 [cited 2022 Apr 27];65(10). Available from: http://archneur.jamanetwork.com/article.aspx?doi=10.1001/archneur.65.10.1281
13. Athar T, Al Balushi K, Khan SA. Recent advances on drug development and emerging therapeutic agents for Alzheimer’s disease. Mol Biol Rep. 2021 Jul;48(7):5629–45.
14. Prior M, Dargusch R, Ehren JL, Chiruta C, Schubert D. The neurotrophic compound J147 reverses cognitive impairment in aged Alzheimer’s disease mice. Alzheimers Res Ther. 2013;5(3):25.
15. Lalli G, Schott JM, Hardy J, De Strooper B. Aducanumab: a new phase in therapeutic development for Alzheimer’s disease? EMBO Mol Med [Internet]. 2021 Aug 9 [cited 2022 Apr 27];13(8). Available from: https://onlinelibrary.wiley.com/doi/10.15252/emmm.202114781
16. Scheltens P, Blennow K, Breteler MMB, de Strooper B, Frisoni GB, Salloway S, et al. Alzheimer’s disease. The Lancet. 2016 Jul;388(10043):505–17.
17. Najar J, Östling S, Gudmundsson P, Sundh V, Johansson L, Kern S, et al. Cognitive and physical activity and dementia: A 44-year longitudinal population study of women. Neurology. 2019 Mar 19;92(12):e1322–30.
18. Zheng Y, Wu Q, Su F, Fang Y, Zeng J, Pei Z. The Protective Effect of Cantonese/Mandarin Bilingualism on the Onset of Alzheimer Disease. Dement Geriatr Cogn Disord. 2018;45(3–4):210–9.
19. Sommerlad A, Sabia S, Singh-Manoux A, Lewis G, Livingston G. Association of social contact with dementia and cognition: 28-year follow-up of the Whitehall II cohort study. PLoS Med. 2019 Aug;16(8):e1002862.
20. Hakansson K, Rovio S, Helkala EL, Vilska AR, Winblad B, Soininen H, et al. Association between mid-life marital status and cognitive function in later life: population based cohort study. BMJ. 2009 Jul 2;339(jul02 2):b2462–b2462.
21. Song H, Sieurin J, Wirdefeldt K, Pedersen NL, Almqvist C, Larsson H, et al. Association of Stress-Related Disorders With Subsequent Neurodegenerative Diseases. JAMA Neurol. 2020 Jun 1;77(6):700.
22. McIntosh EC, Nation DA, for the Alzheimer’s Disease Neuroimaging Initiative. Importance of Treatment Status in Links Between Type 2 Diabetes and Alzheimer’s Disease. Diabetes Care. 2019 May 1;42(5):972–9.
23. Larsson SC, Markus HS. Does Treating Vascular Risk Factors Prevent Dementia and Alzheimer’s Disease? A Systematic Review and Meta-Analysis. J Alzheimers Dis JAD. 2018;64(2):657–68.
24. Tolppanen AM, Ngandu T, Kåreholt I, Laatikainen T, Rusanen M, Soininen H, et al. Midlife and late-life body mass index and late-life dementia: results from a prospective population-based cohort. J Alzheimers Dis JAD. 2014;38(1):201–9.
25. Morris MC, Tangney CC, Wang Y, Sacks FM, Bennett DA, Aggarwal NT. MIND diet associated with reduced incidence of Alzheimer’s disease. Alzheimers Dement J Alzheimers Assoc. 2015 Sep;11(9):1007–14.
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Highlights:
- Alzheimer's disease (AD) is a debilitating neurodegenerative condition causing cognitive and psychiatric problems, along with eventual loss of autonomy
- Though detailed etiology is still unknown, AD is proven to be connected to the formation of protein aggregates in the brain
- Age is one of the main risk factors for AD
- Diagnosis is complicated, and no disease-modifying therapy is available at the moment. All existing AD drugs are for symptomatic treatment
- New drug search is mainly focused on clearing amyloid and tau aggregates
- The range of lifestyle interventions was connected with alleviating the risks of developing AD, including diet and exercise
Introduction
Affecting 25 million people worldwide, Alzheimer's disease (AD) is one of the most feared neurological disorders. Characterized by rapidly deteriorating memory and psychiatric problems, AD presents the most common cause of dementia. In the US, AD prevalence was estimated to be 5 million in 2007, and by 2060, this number is predicted to increase to more than 13 million. Dealing with AD is additionally complicated by the lack of knowledge about precise etiology. Due to this, AD remains the largest unmet medical need in neurology despite being an enormous economic and personal burden. Existing therapies are primarily targeted at alleviating the symptoms, with no successful disease-modifying therapies existing up to this moment.
Image 1
AD pathogenesis
For the first time, clinical and neuropathological characteristics of AD (1) were described in 1906 by Alois Alzheimer (after whom the condition was subsequently named). A 51-year-old woman suffered from progressive memory loss, focal symptoms (nerve or brain function impairments affecting a specific body area, such as limb weakness or loss of vision), and hallucinations. After the patient's death, her brain was autopsied, and, for the first time, the specific AD signs – neuritic plaques and neurofibrillary tangles – were observed.
After this observation, it took 20 years before the major components were identified. Nowadays, it is known that the neuritic plaques majorly consist of amyloid-β, while the major tangle component is tau protein. Amyloid-β is a peptide of 40-42 amino acids in length generated from larger amyloid precursor protein (APP). APP's function is not yet fully understood, but multiple pieces of evidence point toward its role in neuronal survival. APP mutations can lead to the emergence of misfolded amyloid peptides. And amyloid-β, when misfolded, can form aggregates toxic to neural cells (2). The most neurotoxic amyloid aggregates are able to block glutamate receptors, disrupting neuronal communication, and Ca2+ channels, influencing cardiovascular system and muscle strength.
Tau protein maintains the shape and assembly of microtubules (cellular structures that provide cells their shape and integrity) and exists in six isoforms (highly similar proteins originating from a single gene). Like amyloid-β, tau proteins are usually highly soluble. However, in the case of AD development, tau proteins become hyperphosphorylated (phosphoryl groups get attached to all possible protein sites), thus forming tangles and leading to neurotoxicity (3).
Amyloid aggregates induce apoptosis of neural cells, initiate a local inflammatory response, and increase reactive oxygen species production (4). Tau aggregates block communication between neurons, ultimately causing neuronal death (5).
Infographic 1
Onset, risk, and consequences
Late-onset AD occurs more commonly, usually in people over 65. Much rarer early-onset AD can occur in individuals between 30 to 65 years. Early-onset AD is mainly associated (6) with the mutations in APP and presenilin-2 (a protein involved in APP production), while multiple factors govern the development of late-onset AD. Among identified risk factors are age, female gender, low educational level, and occupational fulfillment, previous head injuries, sleep disorders, and hypertension (7). The presence of E4 variant of apolipoprotein is linked with a significantly increased risk of developing late-onset AD, and the risk significantly increases if a person carries several copies of the gene (8). Other factors that possibly play a role in AD development are cardiovascular disease, diabetes, obesity, elevated cholesterol, smoking, and high alcohol intake (9).
The most significant risk factor for AD is, nevertheless, age. The incidence of AD steadily increases with age and doubles every five to ten years. Prevalence increases exponentially from 3% amongst 65-74 years old to around 50% amongst people older than 85 (10). The gradual loss of personal autonomy accompanied by problems in language, memory, and cognitive skills is a mark of AD. Due to its debilitating effects, AD carries not only a human impact but also an enormous financial cost. In 2005, more than $90 billion were spent by Medicare on persons with AD, of which more than $20 billion went to long-term care services. The knowledge of age-connected risks combined with the growth of the aging population requires a series of measures for early diagnostics, treatment, and prevention.
AD diagnostics and treatment
Both diagnostics and treatment of AD remain highly problematic. In AD, neurodegeneration is estimated to start 20-30 years before the onset of symptoms, thus, there is a pressing need for diagnostic tools. As of the moment, there are no reliable peripheral blood markers allowing early diagnostics of AD, though some promising results have been obtained as to using plasma amyloid levels (11). Conflicting reports (12) address the usage of PET (positron emission tomography) scanning with thioflavin T derivative, which selectively binds to amyloid-β. While PET allows for improving clinical accuracy, more longitudinal studies are needed to establish its robustness. Some attempts are being made to introduce the amnestic mild cognitive impairment as a marker of an early clinical phase of the disease. Unfortunately, a definitive diagnosis can be made only post-factum by histological examination of the brain at autopsy.
As of currently approved therapies (13), they are mostly symptom-alleviating and can be divided into three main groups:
- Cholinesterase inhibitors,
- NMDA (N-methyl D-aspartate) antagonists,
- Combination therapy.
In AD, acetylcholine (a neurotransmitter able to speed up or slow down nerve signals) gets depleted, hence cholinesterase inhibitors limit its reduction in the brain. NMDA-receptor in healthy individuals regulates the transport of calcium ions. In AD, the receptors become over-activated, causing an abundance of Ca2+ leading to neurotoxicity. NMDA-antagonists help to regulate the Ca2+ levels, thus alleviating the symptoms. Combination therapy unites both approaches with better outcomes in severe cases but limited success in mild and moderate AD. Unfortunately, all of these agents offer only temporary relief.
The emerging therapies are focused on amyloids, tau proteins, mitochondrial dysfunction, and neuroinflammation. As of 2021, more than 140 drug candidates have been registered for various phases of clinical trials. Some of them, such as J-147 – an orally available curcumin derivative, have already shown promising results (14). But it remains to be seen how many of these drug candidates would be able to progress to clinical practice. At the moment of writing, the only FDA-approved disease-modifying drug for AD remains aducanumab – a compound able to remove amyloid-β plaques from the brain (15). Still, its use remains problematic due to the connected brain abnormality risks, inconsistent results in improving function, and extremely high price.
Image 2
Prevention strategies
A range of modifiable factors has been associated with AD prevention, including psychosocial and lifestyle ones. General strategies applicable to brain health seem to work as a protective factor in AD.
Studies demonstrated a causal association between long-term adult education and reduced AD risk and delayed onset (16). A 44-year longitudinal study of women (17) demonstrated that cognitive activity in midlife is linked with a 46% reduction in AD risk. Bilingualism, which is connected to enhanced neuroplasticity, is also beneficial. In a study of lifelong Cantonese/Mandarin bilinguals (18), the first AD symptoms were marked significantly later than in monolinguals. Higher educational attainment, in general, is thought to be beneficial against AD due to building cognitive reserve and increasing brain volume.
Social engagement proves to be a vital protective buffer against dementia risks. Frequent social contacts help to create additional cognitive reserves. A 28-years follow-up study demonstrated that establishing social connections in midlife is associated with lower risks of developing dementia, including AD (19). Surprisingly, this finding held only for friendship but not relationship contacts. Partner relationships seem to be of great importance, as was shown in the study on marital status and cognitive abilities later in life (20).
Regulating stress and maintaining self-regulation is also recommended as higher risks of AD incidence were found among those with stress-related disorders (21). Chronic work-related stress is also an emerging risk factor for AD.
Pre-existing diseases, such as diabetes and cardiovascular disease, bring a higher risk of being affected by AD. So, careful management of these diseases is required. Research shows that pharmaceutical interventions such as regular intake of antidiabetic (22) and antihypertensive (23) drugs are linked to delayed progression and lowered AD risk. Due to the association between cognitive decline and insulin resitance, many researchers even regard AD as type 3 diabetes. However, more studies are required to analyze the efficacy of particular medications as a preventative treatment.
Non-linear dependency was noticed between body mass index (BMI) and AD. Consistent evidence demonstrates a higher AD risk among middle-aged patients with heightened BMI and elderly patients with lowered BMI (24). Proper diet and exercise can help maintain BMI in a healthy range. Three dietary patterns, including the Mediterranean diet, the DASH (Dietary Approaches to Stop Hypertension) diet, and the MIND (Mediterranean-DASH Intervention for Neurodegenerative Delay) diet, were linked to the decreased risk of AD (25). Among other preventative measures are maintaining good sleep quality, avoiding smoking and excessive alcohol consumption.
Conclusions
Much remains to be done in the field of AD prevention and treatment. Multiple etiology details still remain unknown, including the link between amyloid and tau proteins and mechanisms behind neuronal vulnerability. Meanwhile, the essential thing that can be done for people at risk is educating them on putative prevention measures and promoting brain health.
References
1. Goedert M, Spillantini MG. A Century of Alzheimer’s Disease. Science. 2006 Nov 3;314(5800):777–81.
2. Haass C, Selkoe DJ. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid β-peptide. Nat Rev Mol Cell Biol. 2007 Feb;8(2):101–12.
3. Wegmann S, Biernat J, Mandelkow E. A current view on Tau protein phosphorylation in Alzheimer’s disease. Curr Opin Neurobiol. 2021 Aug;69:131–8.
4. Mattson MP. Pathways towards and away from Alzheimer’s disease. Nature. 2004 Aug 5;430(7000):631–9.
5. Wang JZ, Xia YY, Grundke-Iqbal I, Iqbal K. Abnormal Hyperphosphorylation of Tau: Sites, Regulation, and Molecular Mechanism of Neurofibrillary Degeneration. Perry G, Zhu X, Smith MA, Sorensen A, Avila J, editors. J Alzheimers Dis. 2012 Dec 27;33(s1):S123–39.
6. DeFina PA, Moser RS, Glenn M, Lichtenstein JD, Fellus J. Alzheimer’s Disease Clinical and Research Update for Health Care Practitioners. J Aging Res. 2013;2013:1–9.
7. Hersi M, Irvine B, Gupta P, Gomes J, Birkett N, Krewski D. Risk factors associated with the onset and progression of Alzheimer’s disease: A systematic review of the evidence. NeuroToxicology. 2017 Jul;61:143–87.
8. Safieh M, Korczyn AD, Michaelson DM. ApoE4: an emerging therapeutic target for Alzheimer’s disease. BMC Med. 2019 Dec;17(1):64.
9. Solomon A, Mangialasche F, Richard E, Andrieu S, Bennett DA, Breteler M, et al. Advances in the prevention of Alzheimer’s disease and dementia. J Intern Med. 2014 Mar;275(3):229–50.
10. Zhu CW, Sano M. Economic considerations in the management of Alzheimer’s disease. Clin Interv Aging. 2006;1(2):143–54.
11. Li Y, Schindler SE, Bollinger JG, Ovod V, Mawuenyega KG, Weiner MW, et al. Validation of Plasma Amyloid-β 42/40 for Detecting Alzheimer Disease Amyloid Plaques. Neurology. 2022 Feb 15;98(7):e688–99.
12. Klunk WE. Biopsy Support for the Validity of Pittsburgh Compound B Positron Emission Tomography With a Twist. Arch Neurol [Internet]. 2008 Oct 1 [cited 2022 Apr 27];65(10). Available from: http://archneur.jamanetwork.com/article.aspx?doi=10.1001/archneur.65.10.1281
13. Athar T, Al Balushi K, Khan SA. Recent advances on drug development and emerging therapeutic agents for Alzheimer’s disease. Mol Biol Rep. 2021 Jul;48(7):5629–45.
14. Prior M, Dargusch R, Ehren JL, Chiruta C, Schubert D. The neurotrophic compound J147 reverses cognitive impairment in aged Alzheimer’s disease mice. Alzheimers Res Ther. 2013;5(3):25.
15. Lalli G, Schott JM, Hardy J, De Strooper B. Aducanumab: a new phase in therapeutic development for Alzheimer’s disease? EMBO Mol Med [Internet]. 2021 Aug 9 [cited 2022 Apr 27];13(8). Available from: https://onlinelibrary.wiley.com/doi/10.15252/emmm.202114781
16. Scheltens P, Blennow K, Breteler MMB, de Strooper B, Frisoni GB, Salloway S, et al. Alzheimer’s disease. The Lancet. 2016 Jul;388(10043):505–17.
17. Najar J, Östling S, Gudmundsson P, Sundh V, Johansson L, Kern S, et al. Cognitive and physical activity and dementia: A 44-year longitudinal population study of women. Neurology. 2019 Mar 19;92(12):e1322–30.
18. Zheng Y, Wu Q, Su F, Fang Y, Zeng J, Pei Z. The Protective Effect of Cantonese/Mandarin Bilingualism on the Onset of Alzheimer Disease. Dement Geriatr Cogn Disord. 2018;45(3–4):210–9.
19. Sommerlad A, Sabia S, Singh-Manoux A, Lewis G, Livingston G. Association of social contact with dementia and cognition: 28-year follow-up of the Whitehall II cohort study. PLoS Med. 2019 Aug;16(8):e1002862.
20. Hakansson K, Rovio S, Helkala EL, Vilska AR, Winblad B, Soininen H, et al. Association between mid-life marital status and cognitive function in later life: population based cohort study. BMJ. 2009 Jul 2;339(jul02 2):b2462–b2462.
21. Song H, Sieurin J, Wirdefeldt K, Pedersen NL, Almqvist C, Larsson H, et al. Association of Stress-Related Disorders With Subsequent Neurodegenerative Diseases. JAMA Neurol. 2020 Jun 1;77(6):700.
22. McIntosh EC, Nation DA, for the Alzheimer’s Disease Neuroimaging Initiative. Importance of Treatment Status in Links Between Type 2 Diabetes and Alzheimer’s Disease. Diabetes Care. 2019 May 1;42(5):972–9.
23. Larsson SC, Markus HS. Does Treating Vascular Risk Factors Prevent Dementia and Alzheimer’s Disease? A Systematic Review and Meta-Analysis. J Alzheimers Dis JAD. 2018;64(2):657–68.
24. Tolppanen AM, Ngandu T, Kåreholt I, Laatikainen T, Rusanen M, Soininen H, et al. Midlife and late-life body mass index and late-life dementia: results from a prospective population-based cohort. J Alzheimers Dis JAD. 2014;38(1):201–9.
25. Morris MC, Tangney CC, Wang Y, Sacks FM, Bennett DA, Aggarwal NT. MIND diet associated with reduced incidence of Alzheimer’s disease. Alzheimers Dement J Alzheimers Assoc. 2015 Sep;11(9):1007–14.
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Dr. Ana Baroni MD. Ph.D.
Scientific & Medical Advisor
Quality Garant
Ana has over 20 years of consultancy experience in longevity, regenerative and precision medicine. She has a multifaceted understanding of genomics, molecular biology, clinical biochemistry, nutrition, aging markers, hormones and physical training. This background allows her to bridge the gap between longevity basic sciences and evidence-based real interventions, putting them into the clinic, to enhance the healthy aging of people. She is co-founder of Origen.life, and Longevityzone. Board member at Breath of Health, BioOx and American Board of Clinical Nutrition. She is Director of International Medical Education of the American College of Integrative Medicine, Professor in IL3 Master of Longevity at Barcelona University and Professor of Nutrigenomics in Nutrition Grade in UNIR University.
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