• Articles
  • September 2019
  • 5 minutes

The Changing Face of Alzheimer's Disease: Current Knowledge, Areas of Research Interests, Drug Development

Puzzle pieces and Cognitive decline
In Brief

Alzheimer’s disease (AD) was first described over a century ago, but it may be time to re-evaluate this devastating disease, look at possible etiologies and focus research in different areas. RGA's Dr. Lisa Duckett shares current research into prevention and treatment. 

Amyloid plaques and phosphorylated tau protein tangles do not reveal the entire story for development of Alzheimer’s dementia. Many efforts related to therapeutic and pharmacologic interventions have fallen short. It is time to re-evaluate this devastating disease, look at possible etiologies and focus research in different areas of understanding in this complex disease.

As the world’s population ages and demand for health care resources increase, society will have to accommodate the increasing burden of chronic diseases characteristic of the aging population. Prevention and treatment of AD becomes imperative. Research must look into different avenues of disease development. Currently, the only consistent research finding that is effective in prevention of disease is lifestyle modification: healthy diet, regular exercise, smoking cessation and moderate alcohol intake. Lifestyle modification has influence on the development of disease and may be the best way to avoid it altogether since therapeutic alternatives are not effective.

Current Understanding of Alzheimer’s

Alzheimer’s disease (AD), currently the most common form of dementia in the U.S., is reaching epidemic proportions. Recent data estimates 5.7 million Americans are living with AD, and an additional 11.6 million have mild cognitive impairment.1 The rapidly aging U.S. population means the number of AD cases will most likely triple in the next 30 years.2

Not only is the U.S. impacted by an aging population, worldwide the number of people living with dementia in 2017 was estimated to be close to 50 million. The number of dementia cases globally will nearly double every 20 years, to 75 million in 2030 and to 131.5 million in 2050. China, India, and other developing nations have the fastest-growing elderly populations due to improved health care, which has extended life expectancies.3

Women make up the majority of individuals living with AD, attributable to greater longevity and biological factors.4 Lifetime risk of AD for women at age 65 is 21.1% and for men is 11.6%.1, 5 Survival after diagnosis is influenced by multiple factors, including age at diagnosis, gender, presence of psychotic features, motor system involvement, and medical comorbidities.6 On average, survival after diagnosis ranges from four to eight years if comorbid conditions are present, and best-case scenarios for survival may be up to 15 to 20 years.6, 7

Unfortunately, neither a cause nor a cure for this devastating disease has yet been found. Most recent research efforts have focused on the role of amyloid plaques and neurofibrillary tangles (NFTs). These abnormal proteins are found in the brains of individuals with AD and are composed primarily of phosphorylated tau protein. It has become clear, however, that abnormal proteins by themselves do not explain the disease’s etiology. Further research into the systems that support protein homeostasis in the brain and regulate inflammation and protein removal is underway, and may be what is needed to develop a more complete understanding of the pathology of AD.

Amyloid Plaques and Neurofibrillary Tangles

The characteristics of amyloid and tau proteins in brains of individuals with AD were elucidated in the 1980s. Both proteins are generated in the normal course of brain function, but can become toxic if they aggregate abnormally in the brain.

The amyloid beta (Aß) protein is a peptide formed by neurons in the cortex of the brain – particularly in the hippocampal area, which is where memory function is housed. However, as Aß is released into the brain’s extracellular spaces, it can become distorted, forming chains of Aß oligomers that conglomerate to form insoluble amyloid plaques. These plaques grow in size and interfere with neuronal function by destroying dendritic connections between cells.

Amyloid plaques accumulate in the brain in a predictable manner,8 and their presence can be detected in the brain by testing for it in cerebrospinal fluid (CSF) and by PET (positron emission tomography) scans using radiotracers that bind selectively to Aß protein. PET scans are reliable predictors of brain amyloid plaque burden. These imaging findings, however, are not specific to the brains of individuals with AD. Plaques are also found in brains of individuals with other neurodegenerative disorders, such as Lewy body dementia and cerebral amyloid angiopathy, and in those of cognitively healthy older individuals as well.9

NFTs are composed of hyperphosphorylated tau protein. When normal, this protein is part of the structural support system of neurons that maintain integrity of the neuronal axon. However, when tau protein accumulates, it leads to interruption of normal neuronal function and ultimately to death of neurons. Today, deterioration of cognition is seen as correlating more strongly with tau protein burden and distribution than with that of amyloid plaques.10

Autopsy findings of people with late-onset dementia, particularly the oldest old (now frequently defined as age 90 and older) and even individuals with mild cognitive impairment (MCI), will exhibit multiple pathologies at autopsy, including vascular brain injury, Lewy body dementia, and hippocampal sclerosis.11, 12

AD: A Vascular Disease?

Large epidemiologic studies and an accumulation of scientific data associate vascular risk factors and vascular markers with subsequent development of dementia. The large database of 7,000 subjects of the Rotterdam Study has followed elderly individuals since 1990. This study group was compared to an age-matched control group. A series of reports comparing those who develop dementia and the nondementia group identified an association between the presence of vascular risk factors and the development of

AD in older individuals.13,14 Risk factors confirmed by the Rotterdam Study as well as other independent studies include diabetes mellitus,15 atrial fibrillation,16 smoking,17, 18 and atherosclerosis.19 Each of these risk factors directly influences perfusion to the brain in a negative manner.

Hypertension has been demonstrated in many studies to be a contributing factor to AD. Indeed, long-term follow-up of middle-aged men with hypertension in the Honolulu-Asia Aging Study noted a higher burden of NFTs and brain atrophy post-mortem compared to normotensive individuals with AD.20 Additional studies have substantiated the ill effects of long-term hypertension after following a large group of individuals with stroke history. In the 1990s, the FINMONICA Stroke Register in Finland, for one, began to track trends and determinants of vascular disease among participants. Early studies noted a relationship between middle-aged individuals with hypertension and hyperlipidemia and subsequent development of MCI and AD: the higher the blood pressure and lipid abnormalities, the higher the risk of developing cognitive impairment later in life. When both blood pressure and cholesterol are abnormal, the risk for both MCI and AD increases in a synergistic manner.21

Knowing that vascular risk factors can be modified, a group of researchers recently published their findings on the risk of developing dementia when healthy lifestyle habits are followed in individuals with varying degrees of genetic propensity for dementia. Results of the study demonstrate that unhealthy lifestyles with any degree of genetic predisposition will increase risk for dementia development. Hazard ratios, in this study, increased with dose-dependent exposure to unhealthy life styles combined with high polygenic risk scores. (Unhealthy lifestyles are defined in this study as: smoking, poor diet, no regular exercise, and high alcohol intake.) Controlling risk factors for vascular health is important and consistently demonstrates protective value in preventing dementia.22

AD: An Inflammatory Disease?

Another area of research which has grown in importance is the role of neuroinflammation and its contribution to the development of AD. Post-mortem brain tissue indicates there is a prominent inflammatory response to the deposition of abnormal proteins in the brain. Aß peptides have been shown to be cytotoxic in laboratory analysis, stimulating synaptic loss, mitochondrial dysfunction, and eventually neuronal death.23

Accumulation of cytotoxic misfolded amyloid protein in the brain is an example of a proteopathy, a condition in which the integrity of protein is controlled through phagocytosis and degradation of abnormal proteins in a healthy brain. However, AD creates an unhealthy environment where microglia cells have a central role in clearance of toxic proteins. With aging, disease, or genetic mutations, microglia cells become dysfunctional. Similar to other situations in which inflammation is nonproductive, microglia activity causes harm through propagation of inflammation by antigen-specific and nonspecific mechanisms. One novel therapeutic approach is to control brain inflammation through the inhibition of microglia activity.24

AD: An Infectious Disease?

Many aspects of AD may be similar to known physiological responses to infection. One researcher has even posited a possible AD germ.25 Clues that an infectious etiology could be the root cause for AD include observation that various antibiotics have been reported to have beneficial effects on patients with AD.26

University of California San Francisco (UCSF) scientists have indicated that AD could be the result of tau and amyloid proteins behaving more like prions (i.e., infectious protein particles). Prions are proteins lacking nucleic acids that have the genetic capability to self- propagate. Two examples of cognitive-related prion diseases are Creutzfeldt-Jakob disease and mad cow disease.25 UCSF researchers have developed analytic tools to identify and quantify prion levels. Tau prion levels appear to correlate most closely with disease activity in middle-aged onset AD. The higher the levels, the higher the disease activity and risk for death. In older individuals with AD (late-onset), tau prion levels are much lower, suggesting slower propagation time and a less aggressive form of the disease.27, 28

Another pathogen of interest is the herpes simplex virus (HSV). Researchers have demonstrated that Aß and fibril development pathways mediate antimicrobial activities in the brain. Amyloid oligomers bind the glycoprotein molecules on the surface of herpes virus to engulf the virus and render it inactive. Herpes virus subtypes 6A and 7 have been identified in significant amounts in the brains of individuals with AD. In addition, there is a link between viral activity in the brain and pathologic changes of the brain in those with late-onset AD.29

Therapeutic Developments

Drug development for the treatment of AD has been very slow and disappointing. Initially, acetylcholinesterase inhibitors (AChEls) were approved in 1993 by the U.S. Food and Drug Administration (FDA), based on the understanding that an acetylcholine deficit develops in the brain as a result of neuronal loss. AChEIs are considered symptomatic therapies, as they do not alter the progression of the disease, they do not have neuroprotective qualities,7 and no proven benefit has been demonstrated in MCI.Namenda (memantine), the only FDA-approved AChEI for moderate dementia, has been used successfully in treating behavioral disturbances in the advancing stages of the disease, but it has not been shown to be effective for arresting disease progression.30

Presently, approximately 200 compounds are being researched and developed for AD treatment or prevention. Challenges exist with the research and development of AD-specific pharmacologic agents, particularly since the disease moves very slowly and there is a very long preclinical interval before symptoms develop. Clinical trials need to extend over years and even decades, making trials expensive and lengthy.31

Biomarkers used to identify abnormalities in CSF and brain imaging are being used more frequently to identify patients for drug studies, especially those with preclinical and early symptomatic disease. Going forward, biomarkers will likely become the tool of choice to provide an objective measurement of response to potential therapeutic modalities, which should shorten time for clinical trials.32

Tomorrow’s drug therapies will likely continue to unravel the mystery behind amyloid diseases, targeting abnormal production and aggregation as well as clearance of amyloid protein. Several immunotherapies are under investigation to promote clearance of Aß, including passive immunization with monoclonal antibodies, either directly or through the activity of microglial cells or complement activation.33

Another area of research focus is chaperone molecules. These molecules are proteins that appear to inhibit the propagation of deformed amyloid fibrils and, in turn, reduce the toxicity of the abnormally folded amyloid protein. Harnessing the function of chaperone molecules could have therapeutic potential as a way to reduce the production of amyloid deposits in the brain.34 It is interesting to note that pathologic amyloid fibrils are associated with about 40 different diseases in addition to AD, including type 2 diabetes and mad cow disease.35

Stem cell therapies are in early phases of development as possible viable solutions for replacement of neurons, disease modeling, and drug development. Restoration of lost neurons and ineffective microglial cells via transplant or in situ stem cell self-renewal and differentiation may offer an effective addition to current AD treatments.

Despite the excitement about cell replacement therapy in AD, challenges do remain. Transplantation data suggests that genetic and epigenetic backgrounds of donor cells are extremely important, so donor-to-donor variation of stem cells must be considered in relationship to propensity for disease development. In addition, transplantation of genetic defects that cause biochemical symptoms of AD must be corrected in donor cells before successful transplantation can occur.36, 37

Researchers are investigating the mechanism of clearance of Aß from the brain across the blood-brain barrier (BBB) as another possible target for therapeutic intervention. The primary receptors for passage of Aß across the BBB are lipoprotein receptor-related protein 1 (LRP1) and receptor for advanced glycation end products (RAGE). A soluble form of the LRP1 molecule sequesters the majority of amyloid peptides in the brain and reduces the plasma levels of the protein. However, in AD the function of the LRP1 molecule is disrupted, leading to abnormally high levels of amyloid in the brain. The other transport molecule, RAGE, when bound to the soluble form of Aß, appears to malfunction and facilitates amyloid passage across the BBB from the peripheral circulation into the brain and acts to promote endothelial inflammation and decreased blood flow. Inhibitors that block RAGE and Aß interaction are plausible targets for intervention.38

Insurance Industry Implications

Dementia is an extremely slow-moving disease with a very long preclinical stage – 15 to 25 years, according to some studies. Biochemical changes occur during this period without outward symptoms. Age is the most important risk factor in the development of dementia, and the presence of vascular risk factors such as smoking, diabetes, hypertension, sleep disorders (particularly obstructive sleep apnea), and atherosclerotic disease, both in the brain and in peripheral arteries, all increase the risk for later-life cognitive impairment. In addition, brain trauma, coronary artery bypass surgery, silent stroke seen on brain imaging studies, and medications such as benzodiazepines and anticholinergics (which treat disorders as diverse as asthma, incontinence, and Parkinson’s disease) have been associated with increased dementia risk.39, 40, 41

Applicant mortality assessments should include evaluation of the presence and severity of risk factors for future AD, as well as family history. Older-age questionnaires that focus on subtle changes in cognition or memory function, mental status evaluation, brain imaging, and medical records can all help insurance underwriters develop a history for possible impaired cognition. Work and education history information can also be used to develop baseline cognition function profiles. Independence measured by performance of instrumental activities of daily living, as well as ability to manage finances and use technology such as e-mail, mobile phone, and the internet, should be included in cognitive screenings.

Use of social services may signal a loss of ability to manage instrumental activities of daily living, particularly when the use of in-home social or support services are initiated. However, education, physical activity, and social engagement may offset the negative influence of the aforementioned factors.

Corroboration of the facts by a family member or close friend would be optimal to verify the information acquired through the interview process. Any red flags should warrant additional investigation.


Normal aging manifests as slowed memory and learning acquisition that does not interfere with function in the community. Older-age underwriting will always be challenging due to the heterogeneous nature of the aging process. Biomarkers will continue to evolve and may become more commonly utilized in the diagnostic process, but today, brain imaging and cognitive screening tests are the methods used to diagnose dementia.

AD remains a puzzle that medical science has yet to understand fully. The disease presents many concerns and challenges, particularly since the global population is aging and rates of occurrence for dementia are likely to increase rapidly over the next 30 years. Potential etiologies for the disease are diverse and are the focus of ongoing research. Trials of pharmaceuticals to prevent and treat disease have been unsuccessful to date. Clearly, new avenues for research and development will have to be examined to address this complex disease. 

More Like This...

Related Solutions


  1. Alzheimer’s Association. 2018 Alzheimer’s disease facts and figures. Alzheimer’s Dement 2018. https:// Figures/facts-and-figures.pdf

  2. Petersen RC, Lopez O, Armstrong MJ, et al. Practice guideline update summary: Mild cognitive impairment: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2018 Jan 16; 90(3):126-35. https://www.ncbi.nlm.nih.govpubmed/29282327

  3. Alzheimer’s Disease International. The WORLD Alzheimer Report 2015. research/statistics

  4. Hebert LE, Weuve J, Scherr PA, et al. Alzheimer disease in the United States (2010-2050) estimated using the 2010 census. Neurology 2013 May 7; 80 (19):1778-83.

  5. Chêne G, Beiser A, Au R, et al. Gender and incidence of dementia in the Framingham Heart Study from mid- adult life. Alzheimer’s Dement. 2015 Mar; 11(3): 310-20.

  6. Brodaty H, Seeher K, Gibson L. Dementia time to death: a systematic literature review on survival time and years of life lost in people with dementia. Int Psychogeriatr. 2012 Jul; 24(7): 1034-45. https://www.

  7. Rabinovici G. Article 1: Late-onset Alzheimer Disease. Contiuum (Minneap Minn) 2019 Feb; 25(1): 14-33. Fulltext/2019/02000/Key_Points_for_Issue.21.aspx

  8. Thal DR, Rub U, Orantes M, et al. Phases of A beta- deposition in the human brain and its relevance for the development of AD. Neurology. 2002 Jun 25; 58(12): 1791-800. pubmed/12084879

  9. Ossenkoppele R, Jansen WJ, Rabinovici GD, et al. Prevalence of amyloid PET positivity in dementia syndromes: a meta-analysis. JAMA. 2015 May 19; 313 (19): 1939-49. pubmed/25988463

  10. Nelson PT, Alafuzoff I, Bigio EH, et al. Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol. 2012 May; 71(5): 362-81.

  11. Schneider JA, Arvanitakis Z, Leurgans SE, et al. The neuropathology of probable Alzheimer disease and mild cognitive impairment. Ann Neuro. 2009 Aug; 66(2): 200-8. pubmed/19743450

  12. Kawas CH, Kim RC, Sonnen JA, et al. Multiple pathologies are common and related to dementia in the oldest-old: The 90+ Study. Neurology. 2015 Aug 11; 85(6): 535-42.

  13. Breteler MM. Vascular risk factors for Alzheimer’s disease: an epidemiologic perspective. Neurobiol Aging. 2000 Mar-Apr; 21(2): 153-60. https://www.ncbi.

  14. Breteler MM. Vascular involvement in cognitive decline and dementia: epidemiologic evidence from the Rotterdam Study and the Rotterdam Scan Study. Annals of the New York Academy of Sciences. 2000 Apr; 903: 457-65. pubmed/10818538

  15. Ott A, Stolk RP, Hofman A, et al. Diabetes mellitus and the risk of dementia: the Rotterdam Study. Neurology. 1999; 53: 1907-9. https://www.ncbi.nlm.

  16. Ott A, Breteler MM, deBruyne MC, et al. Atrial fibrillation and dementia in a population-based study: The Rotterdam Study. Stroke. 1997 Feb; 28(2): 316-21.

  17. Ott A, Slooter AJ, Hofman A, et al. Smoking and risk of dementia and Alzheimer’s disease in a population- based cohort study: the Rotterdam Study. Lancet. 1998; 351(9119): 1840-3. https://www.ncbi.nlm.nih. gov/pubmed/9652667

  18. Van Duijn CM, Havekes LM, van Broeckhoven C, et al. Apolipoprotein E genotype and association between smoking and early onset Alzheimer’s disease. BMJ. 1995 Mar 11; 310(6980): 627-31.

  19. Hofman A, Ott A, Breteler MM, et al. Atherosclerosis, apolipoprotein E, and prevalence of dementia and Alzheimer’s disease in the Rotterdam Study. Lancet. 1997 Jan 18: 349(9046): 151-4. https://www.ncbi.nlm.

  20. Petrovitch H, White LR, Izmirillian G, et al. Midlife blood pressure and neuritic plaques, neurofibrillary tangles, and brain weight at death: the HAAS. Honolulu-Asia Aging Study. Neurobiol Aging. 2000 Jan-Feb; 21(1): 57-62. pubmed/10794849

  21. Kivipelto M, Helkala EL, Hanninen T, et al.Midlife vascular risk factors and late-life cognitive impairment: a population-based study. Neurology. 2001 Jun 26; 56(12): 1683-9. https://www.ncbi.nlm.

  22. Lourida I, Hannon E, Littlejohns TJ, et al. Association of Lifestyle and Genetic Risk With Incidence of Dementia. JAMA. 2019 Jul 14; 322(5): 430-7. abstract/2738355

  23. Clayton KA, Van Enoo AA, Ikezu T. Alzheimer’s Disease: The Role of Microglia in Brain Homeostasis and Proteopathy. Front Neurosci. 2017 Dec 12; 11: 680.

  24. Keren-Shaul H, Spinrad A, Weiner A, et al. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell. 2017 Jun 15. 169(7), 1276-90. pubmed/28602351

  25. Norins LC. It’s Time to Find the "Alzheimer’s Germ." 2018 Jan 15. whitepaper/

  26. Loeb MB, Molloy DW, Smieja M, et al. A randomized, controlled trial of doxycycline and rifampin for patients with Alzheimer’s disease. J AM Geriatric Soc. 2004 Mar; 52(3): 381-7. pubmed/14962152

  27. Weller N. Alzheimer’s Disease is a ‘Double-Prion Disorder,’ Study Shows. (Press Release) UCSF. 2019 1 May. alzheimers-disease-double-prion-disorder-study- shows

  28. Aoyagi A, Condello C, Stöhr J, et al. Aß and tau prion- like activities decline with longevity in the Alzheimer’s disease human brain. Science Translational Medicine. 2019 May 1; 11(490). content/11/490/eaat8462

  29. Readhead B, Haure-Mirande JV, Funk CC, et al. Multiscale Analysis of Independent Alzheimer’s Cohorts Finds Disruption of Molecular, Genetic, and Clinical Networks by Human Herpesvirus. Neuron. 2018 Jul 11; 99(1): 64-82. https://www.ncbi.nlm.nih. gov/pubmed/29937276

  30. Gauthier S, Cummings J, Ballard C, et al. Management of behavioral problems in Alzheimer’s disease. IntPsychogeriatric. 2010 May; 22(3): 346-72.

  31. Burke M. Why Alzheimer’s Drugs Keep Failing. Scientific American. 2014 Jul 14. https://www. keep-failing

  32. Thal LJ, Kantarci K, Reiman EM, et al. The Role Of Biomarkers in Clinical Trials for Alzheimer Disease. Alz Dis Assoc Disord. 2006 Jan-Mar; 20(1): 6-15.

  33. Counts SE, Lahiri DK. Overview of Immunotherapy in Alzheimer’s Disease (AD) and Mechanisms of IVIG Neuroprotection in Preclinical Models of AD. Curr Alzheimer Res. 2014; 11(7): 623-5. https://www.ncbi.

  34. Marino Gammazza A, Bavisotto CC, Barone R, et al. Alzheimer’s Disease and Molecular Chaperones: Current Knowledge and the Future of Chaperonotherapy. Curr Pharm Des. 2016: 22(26); 4040-9. pubmed/27189602

  35. Marzban L, Park K, Verchere CB. Islet amyloid polypeptide and type 2 diabetes. Exp Gerontol. 2003 Apr; 38(4): 347-51. pubmed/12670620

  36. Lee JH, Oh IH, Lim HK. Stem Cell Therapy: A Prospective Treatment for Alzheimer’s Disease. Psychiatry Investig. 2016 Nov; 13(6): 583-9. https://

  37. Yagi T, Ito D, Okada Y, et al. Modeling familial Alzheimer’s disease with induced pluripotent stem cells. Hum Mol Genet. 2011 Dec 1; 20(23): 4530-9.

  38. Deane R, Bell RD, Sagare A, et al. Clearance of amyloid-beta peptide across the blood-brain barrier: Implication for therapies in Alzheimer’s disease. CNS Neurol Disord Drug Targets. 2009 Mar; 8(1): 16-30.

  39. Keene CD, Montine TJ, Kuller LH. Epidemiology, pathology, and pathogenesis of Alzheimer disease. UpToDate. 2019 Jul. contents/epidemiology-pathology-and-pathogenesis- of-alzheimer-disease

  40. Newman MF, Kirchner JL, Phillips-Bute B, et al. Longitudinal assessment of neurocognitive function after coronary-artery bypass surgery. N Engl J Med. 2001 Feb 8; 344: 395-402. full/10.1056/NEJM200102083440601

  41. Yao H, Fujishima M. Cerebral blood flow and metabolism in silent brain infarction and related cerebrovascular disorders. Ann Med. 2001 Mar; 33(2): 98-102. pubmed/11327121

Additional Resources

© 2019, Reinsurance Group of America, Incorporated. All rights reserved. No part of this publication may be reproduced in any form without the prior permission of the publisher. For requests to reproduce in part or entirely, please contact: RGA has made all reasonable efforts to ensure that the information provided in this publication is accurate at the time of inclusion and accepts no liability for any inaccuracies or omissions. None of the information or opinions contained in this publication should be construed as constituting medical advice.