Although Alzheimer’s disease (AD) was first described more than a century ago, its complexity and heterogeneity have made early diagnosis and treatment elusive, and its pathogenesis remains uncertain. Research-based understanding of the disease, specifically the interplay between beta-amyloid, phosphorylated tau, and small vessel disease of the brain, biomarkers and imaging techniques that aid in diagnosis of dementia, and MCI definition and risk factors for disease will all be discussed. In addition, potential areas for disease modification through medications will be covered.
AD is the most common form of dementia, and epidemiologists predict it will be “the” epidemic of the 21st century. For asymptomatic individuals, the lifetime risk of developing AD at age 65 is 10.5%
. The world’s population is expanding in such a way that the highest risk cohort for developing the disease is also going to be the fastest-growing segment of the world's population over the next 30 years. By 2050, the U.S. Census Bureau is predicting there will be 88 million Americans over age 65. The world’s over-65 population is projected to swell to 1.6 billion by then, as well. Additionally, Asian and South American countries will all experience a quadrupling of individuals over 80 years of age
Alois Alzheimer, M.D., described the clinical symptoms and histologic changes in the brain of a woman with presenile dementia in 1906. The histologic features Dr. Alzheimer identified in the autopsy – amyloid plaques and neurofibrillary tangles – remain the defining features of the disease and the focus of AD research
The specific protein responsible for the formation of amyloid plaques was identified 30 years ago
and is the product of the cleavage of the amyloid precursor protein (APP), which is tethered to the cell membrane for reasons still not clear. Once APP is cleaved into discrete fragments by secretases, the beta amyloid protein is cut at both ends of the molecule and is released to the space outside the neuron. It then begins to aggregate with other beta-amyloid fragments, forming oligomers, which are believed to be the core components of the amyloid plaques. Over time, other proteins are added to the misfolded oligomers and conglomerate to form insoluble plaques
. Accumulation of amyloid plaques may precede clinical symptoms by 20 years
The second histologic feature, the neurofibrillary tangle, is composed of tau protein and is a component of the microtubular system in neurons. The function of tau protein is to provide structural stability for axons and transport nutrients and neurotransmitter-containing vesicles, from the neuronal cell body to the axon
. The disruption of this microtubular system begins a destructive process that is characterized by accumulation of hyper-phosphorylated tau and the aggregation of tau fibrils, which eventually forms tangles within the cell that lead to synaptic dysfunction. Synaptic dysfunction and loss are the findings most closely associated with cognitive decline in brains of those with dementia
. This stage of the disease is characterized by progressive cognitive decline that correlates with a clinical diagnosis of MCI transitioning to dementia
Diagnosis of MCI
In 2011, the National Institute on Aging and the Alzheimer’s Association convened a working group to revise diagnostic criteria for MCI due to AD. The working group examined clinical, cognitive, and functional criteria to improve the accuracy of the diagnosis and project the risk of future AD. Using MCI clinical criteria along with cognitive screening tools, biomarkers, and imaging studies made it easier to identify the points of transition from AD’s asymptomatic to symptomatic phase.
Early recognition of the pre-dementia state is relevant for therapeutic intervention and to benchmark disease progression8
. MCI is characterized by a change in cognition noted by the patient or other reliable source and is diagnosed by a measureable decline from prior function in one or more cognitive domains. The most important of these is memory loss, as loss of episodic memory correlates with risk for progression to AD8
Cognitive assessment is vital to the diagnosis of MCI. Tests that detect deficits in the ability to acquire new information as well as retention are able to detect decrement in episodic memory include: word list learning test, Logical Memory I and II, the Wechsler Memory Scale, and the Visual Reproduction subsets of the Wechsler Memory Scale I and II. Additional assessment of all cognitive domains is important, since not all MCI patients have decrements in episodic memory8
. MCI patients will typically score 1 to 1.5 standard deviations below their age- and education-matched peers8. To fulfill the diagnosis of MCI, other causes for the cognitive impairment must also be sought, which can include vascular, traumatic, and toxic causes. These causes must be evaluated with the goal of determining the likelihood of neurodegenerative disease with characteristics consistent with AD.
Assessing the Risk for Progression of MCI Via Biomarkers
Dementia may have a very long prodromal stage with normal cognition. Researchers hypothesize that amyloid is deposited in the brain during AD’s asymptomatic period5
. Detecting this process early in the prodromal period may be an opportunity for future therapeutic intervention as well as differentiating risks for insurance products.
As MCI develops, pathologic changes in the brain are characterized by the deposits of tau protein, concomitant loss of synaptic function, and degenerating neurons with abundant NFTs5
. Over time, the loss of neuronal integrity leads to progressive cognitive decline.
Key findings indicating AD’s progression include: predominance of amnestic or episodic memory impairment on cognitive screening tests paired with lower overall memory scores, abnormal imaging studies, positive biomarkers, and testing positive for the gene variant ApoE4
. Some or all of these variables could form the basis for a risk scoring system predicting low to high likelihood that MCI might progress to AD.
Fluid biomarkers in current use include cerebrospinal fluid beta-amyloid 42 (CSF42
), which reflects the deposition of amyloid in the brain, and CSF tau/ phosphorylated tau, which reflects neuronal injury following amyloid deposition. Positive results on tests for both biomarkers confers the greatest likelihood that MCI changes are due to AD. One but not both markers positive confers an intermediate likelihood, and low likelihood of progression to AD would encompass discrepant and/or ambiguous results. Negative biomarker results have a negative predictive value, which may be useful as well8
Imaging studies may substantiate the risk further if they are concordant with the fluid biomarker results. Imaging studies assess amyloid deposition in the brain and quantify the extent of atrophy present in the brain. PET scans that use one of the recently approved amyloid binding agents – florbetapir F-18 (AMYViD), flutemetamol F-18 (Vizamyl), or florbetaben F-18 (Neuraceq) – detect brain amyloid deposition. A volumetric MRI can quantify volume declines in the hippocampus and related regions, making this test a good marker for AD13
. The results of MCI brains studied demonstrate substantial volume loss in the hippocampal region: approximately 50% reduction in volume compared to control subjects without known MCI13
The detection of decreased glucose uptake during FDGPET scanning is another method for detecting the presence of significant neuronal loss. The characteristic areas of the brain that are the most affected are the temporal and parietal lobes. A March 2016 article reported a sensitivity of 94% and a specificity of 73%. This test can also correctly predict a progressive course of dementia with 91% sensitivity and a non progressive course with 75% specificity14, 15
. Combining biomarker results with imaging scans, cognitive testing, and clinical course of symptoms may very accurately predict the possible development of AD8
Many studies have used biomarkers to predict progression of MCI to AD. However, due to the newness of the technology, there are limitations to the use of biomarkers. It is important to note that there is a lack of standardization between labs and thresholds for significance. Controversy exists on how to use the biomarkers and who to evaluate with them. The tests are expensive and may be inconsistent or misleading. Comparisons for accuracy have not been evaluated in multivariate studies. Limited studies have looked at combinations of biomarkers and interpretation of results for multiple biomarkers – particularly if there are discrepant findings. Furthermore, the biomarkers are not necessarily specific for AD and can be present in other neurodegenerative diseases8
Small Vessel Disease Substrate for Neuronal Degeneration and Cognitive Impairment
Inadequate clearance of amyloid plaques from the brain might be one of the reasons beta-amyloid is found in abundance in neurodegenerative diseases. Researchers are studying the association between vascular pathology and the development of cognitive decline. Atherosclerosis and amyloid angiopathy are the leading causes of small vessel disease in the brain9
. Lacunae and white matter lesions are ischemic events that are commonly visualized on neuroimaging; however, less commonly seen are hemorrhagic lesions of blood vessels manifested by cranial microbleeds. Such microbleeds may explain why cardiac risk factors as well as amyloid deposition are important in the development of chronic degenerative brain diseases9
. The atherosclerotic changes that occur in blood vessels with ischemic events are associated with cardiac risk factors: hypertension, smoking, and diabetes. The pathogenesis of hemorrhagic events that occurs in small vessel is related to beta amyloid accumulation in the vessel wall, vascular dysfunction, with resultant inflammation and vessel wall weakness to produce hemorrhages9. Both vascular changes, ischemic and hemorrhagic, appear to be related to decreased clearance of toxic amyloid protein, local ischemia, and ultimately cognitive decline.
To test the hypothesis that there may be a relationship between the number of microbleeds and cognitive dysfunction, the Rotterdam study, a longitudinal prospective population-based study, evaluated individuals for both parenchymal and cognitive changes over time. The study concluded that a high microbleed count of >4 is associated with cognitive decline on serial testing and increases the risk of dementia. The authors of the study remarked that the mechanisms by which microbleeds can influence cognitive function remain speculative; however, it appears that microbleeds may be a biomarker for advanced vascular and neurodegenerative damage that then leads to progressive cognitive decline. Whether this is related to vascular disease that causes local ischemic damage to brain tissue or hypertensive disease that causes decreased clearance of amyloid is uncertain9
Genetics of AD
Presence of genetic mutations in both the amyloid precursor protein (APP) and the presenilin 1 and 2 mutations may develop early-onset disease at 65 years of age or younger with a variable time course from MCI to dementia. ApoE4 allele homozygotes also are at risk for development of late-onset dementia and the genetic phenotype has been used to stratify risk for the development of AD when MCI is present10
Therapeutic Interventions for Disease Modification
Drug development to modify the course of AD has been slow. The last FDA-approved drug for moderate to severe AD, memantine, was released in 200311
. At present, there are no drugs approved for treatment of MCI, and none of the approved medications for AD offers any clear mortality benefit.
Researchers are developing medications aimed at modifying steps in amyloid processing to eliminate the production and deposition of amyloid. Phase 3 trials are in progress to test the efficacy of inhibition of beta secretase (BACE), which cleaves amyloid into the smaller molecules with potential to become oligomers of amyloid. Another medication currently in clinical trials that is designed to reduce amyloid production is solanezumab, a monoclonal antibody. This medication binds amyloid protein to reduce the formation of plaques and assists with clearance of amyloid protein. Some encouraging results in mild AD have prompted further studies12
Reducing tau production is another potential method for disease modification. The AADvac1 vaccine, also currently in clinical trials, targets the abnormal tau protein that destabilizes microtubules. Another anti-tau medication in clinical trials, Epothilone D, is designed to stabilize the microtubules in the neurons to decrease the propensity for the formation of neurofibrillary tangles in animal models.
A novel anti-inflammatory drug, CSP-1103, acts to reduce inflammation in the brain associated with the deposition of amyloid protein. The anti-inflammatory activity of this drug, currently in clinical trials as well, is directed against the microglial cells in the brain.
Additional trials are under way to determine the effect of neuroprotective agents such as insulin. Insulin activity is reduced in the brains of individuals with AD, and restoration of normal insulin levels seems to stabilize and improve cognition in those with amnestic mild cognitive impairment (aMCI) and those with mild to moderate AD. Nasally-administered insulin is used here because it is quickly absorbed into the central nervous system and may not affect serum glucose or insulin levels13
. Results of the trials are encouraging; however, they are in the very early stage of research12
Dementia is likely to increase tremendously worldwide over the next 30 years due to the globe’s rapidly aging population. Understanding of the disease is growing, and it is apparent it has a long preclinical stage before cognitive decline actually occurs.
Abnormal accumulations of amyloid and tau proteins interact to cause AD. Research has advanced the diagnostic accuracy of MCI and identified risk factors for disease progression.
Vascular pathology is also important in neurocognitive disease development and substantiates the importance of vascular health in disease prevention. Vascular risk factor modification, particularly treatment of hypertension and smoking cessation, appears to play an important role for initiation of neurodegenerative processes that occur in blood vessels to include ischemic and hemorrhagic changes.
Medications have been slow to develop and few are in trials to determine efficacy. Some have shown progress, but the last time the FDA approved a drug for AD was in 2003 and no drugs are currently available for MCI. Multiple areas of intervention are plausible for reduction of amyloid and tau proteins in the brain and are being studied, but few medications in the more immediate production pipeline are promising.
Insurers will need to remain vigilant and informed with regard to the epidemiology, pathophysiology, and impact of potential treatment trends for neurocognitive risks. Hopefully, with improved predictive and diagnostic testing, risk stratification and claims experience can be refined over time.
- Criteria for preclinical Alzheimer’s disease – June 2, 2010 / Preclinical Alzheimer’s Disease Workgroup. [cited 2016 Sept 22] http://www.alz.org/research/ diagnostic_criteria/preclinical_recommendations.pdf
- United States Census Bureau. An Aging World: 2015, Census Bureau Reports March 2016. Report number CB16-54. http://www.census.gov/newsroom/pressreleases/2016/cb16-54.html
- Major Milestones in Alzheimer’s and Brain Research. Alzheimer’s Organization. Available from http://www.alz.org/research/science/major_milestones_in_alzheimers.asp
- The Hallmarks of AD. National Institute of Aging. [cited 2016 Sept 17]. Available from http://www.nia.nih.gov/alzheimers/publication/part-2-what-happens-brain-ad/
- Jack CR Jr, Knopman DS, Jagust WJ et al. Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol. 2010 Jan; 9(1):119-28. https://www.ncbi.nlm.nih.gov/pubmed/20083042
- Bennett DA, Schneider JA, Wilson RS et al. Neurofibrillary tangles mediate the association of amyloid load with clinical Alzheimer disease and level of cognitive function. Arch Neurol. 2004; 61: 378-384. https://www.ncbi.nlm.nih.gov/pubmed/15023815
- Gomez-Isla T, Hollister R, West H, et al. Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer’s disease. Ann Neurol. 1997 Jan; 41(1):17-24. https://www.ncbi.nlm.nih.gov/pubmed/9005861
- Albert MS, DeKosky ST, Dickson D et al. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: Recommendations from the National Institute on Aging and Alzheimer’s Association workgroup. Alzheimer’s & Dementia 7 (2011) 270-9. http://www.alz.orgdocuments_custom/diagnositic_recommendations_mci_due_to_alz_proof.pdf
- Akoudad S, Wolters FJ, Viswanathan A et al. Association of Cerebral Microbleeds With Cognitive Decline and Dementia. JAMA Neurol.[Internet] 2016 Aug 1:73(8): 934-43. https://www.ncbi.nlm.nih.gov/pubmed/27271785
- Bertram L, Lill CM, Tanzi RE. The Genetics of Alzheimer Disease: Back to the Future. Neuron 2010 Oct 21;68(2):270–81. https://www.ncbi.nlm.nih.gov/pubmed/20955934
- Memantine: Drug information. MedlinePlus. https://medlineplus.gov/druginfo/meds/a604006.html
- Treatment Horizon. Alz.org Research Center. http://www.alz.org/research/science/alzheimers_treatment_horizon.asp
- Therapeutics – Nasal Insulin. Alzforum. http://www.alzforum.org/therapeutics/nasal-insulin
- Salmon E, Gregoire MC, Delfiore G, et al. Combined study of cerebral glucose metabolism and [11C] methionine accumulation in probable Alzheimer's disease using positron emission tomography. J Cereb Blood Flow Metab. 1996 May, 16(3):399-408. https://www.ncbi.nlm.nih.gov/pubmed/8621744
- Ramachandran TS. Alzheimer Disease Imaging. Medscape. Updated March 15, 2016.[cited 2016 Oct 12]. http://emedicine.medscape.com/article/336281-overview
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