Epidemiology of Alzheimer’s Disease Suggested readings: 2000 Progress Report on Alzheimer’s Disease: Taking the next steps. National Institute on Aging, at www.alzheimers.org/ Carla Falkenstein, MS

Course Content Description of the disease process. Possible etiology based on population studies. Global prevalence.

What is Alzheimer’s Disease? Neurodegenerative disease. Most common form of dementia. Causes impaired cognitive functioning. No known cure. Dementia is a medical condition that interferes with brain function. There are many different types of dementia and many different causes. Alzheimer’s Disease (AD) is the most common form of dementia.

Diagnosis of AD Because it is a progressive disease with one of the earliest symptoms being memory loss, diagnosis is difficult. At the earliest stages, age-related memory loss and mild cognitive impairment look very similar to dementia. Some studies suggest that mild cognitive impairment may actually be early-stage AD. People with AD have difficulty recalling information after a short period of delay. New information may be learned, but won’t be remembered after a period of even a few hours. The current reliance of diagnosis on methods that test memory and mental capacity have epidemiologic implications. Different rates of diagnosis may be found depending on literacy and education levels. Cross-cultural diagnostic accuracy is also a concern.

Common Symptoms Forgetting names and objects. Not recognizing family & friends. Forgetting one’s own phone number or address. Difficulty finding a familiar place. Noticeable language & intellectual decline.

Common Symptoms (cont’d) Forgetting to eat or maintain one’s hygiene. Poor judgment, inability to follow simple instructions. Progressive sense of distrust. Unusual agitation and irritability.

Age is a Primary Risk Factor Who gets AD? Advancing age is the most significant risk factor. Three percent of the US population aged 65 to 74 years old suffers from AD. Nearly 20% of those aged 75 to 84 have AD. And that number approaches 50% among the population aged 85 and older. Ages Prevalence 65-74 = 3% 75-84 = 18.7% 85+ = 47%

Stages of AD SEVERE 1-3 Years MODERATE 2-10 Years MILD 2-4 Years These are general patterns that may not apply to everyone. Stages may vary in length, and symptoms may overlap between stages. Patients can suffer for up to 20 years from first symptoms until death. MILD 2-4 Years

Disease Process AD is a neurodegenerative disease. Neurons progressively degenerate, lose function and die. A brain ravaged by Alzheimer’s Disease shrinks in size and weight as the disease destroys neural tissue. The tightly packed ruts and grooves on the surface of a healthy cerebral cortex become vacuous with gaps and crevices. The cause of nerve cell death is currently undergoing intense investigation.

Disease Process (cont’d) 1st destroys neurons in parts of the brain that control memory. Later attacks cerebral cortex - areas responsible for language and reasoning. Eventually nearly the entire brain is atrophied. The hippocampus is a structure deep in the brain that helps encode short-term memories. AD damages nerve cells in the hippocampus and the pathways that link the hippocampus to the rest of the brain. This damage leads to short-term memory failure. When the cerebral cortex is attacked, language skills and ability to make judgments are impaired. Personality changes occur, including emotional outbursts and disturbing behaviors such as wandering and agitation. Once the entire brain is involved, the patient may be bedridden, incontinent, helpless and unresponsive.

Cause of Nerve Cell Death Amyloid Plaques? Neurofibrillary Tangles? Amyloid plaques and neurofibrillary tangles were first associated with AD when Dr. Alois Alzheimer autopsied a brain of a woman with severe dementia in 1908. Today they remain the hallmarks of AD.

Amyloid Plaques Insoluble deposits of beta-amyloid Plaques found in the spaces between the brain’s nerve cells Plaques may be a cause or a by-product of AD Amyloid plaques are insoluble deposits of beta-amyloid - a protein fragment snipped from a larger protein (amyloid precursor protein = APP). Although researchers aren’t sure whether these plaques are a by-product of AD or a cause of AD, it is known that changes in the structure of the APP can cause AD. Scientific research is now focusing on preventing the development of beta-amyloid or inhibiting its deposition into insoluble plaques. Two other protein molecules, presenilin 1 and presenilin 2, may be associated with the actual clipping of APP into beta-amyloid, stress-related cell death, and the ability of neurotransmitters to travel across synapses - the tiny gaps between neurons. Mutations in these three genes located on 3 different chromosomes account for almost all cases of Familial AD.

Neurofibrillary Tangles Twisted threads of a protein called tau. Tau is a protein found inside nerve cells. In AD, Tau changes so that it becomes 2 threads wound around each other.

Other Genetic Factors APOE є4 allele of the APOE gene is a major risk factor for late-onset AD. However, much work is being done to sort out all the potential genetic factors involved in AD. The formation of amyloid plaques may rely on the APOE є4 gene. Therefore, drugs that affect the levels of ApoE protein in the brain may prevent the formation of fibrils, inhibit deposits or promote the removal of amyloid. This process may result in slowing or delaying the development of AD symptoms. Researchers at the University of Washington at Seattle showed that having the APOE є4 allele impacted age at on-set of the disease by as much as 17 years (Warwick Daw et al. 2000).

AD and Other Disorders AD has similarities with other neurodegenerative diseases: Prion, Parkinson’s and Huntington’s diseases all cause dementia. All involve deposits of abnormal proteins in the brain. More and more research is pointing out the similarities between AD and other neurodegenerative diseases. For instance, many patients with Parkinson’s Disease develop dementia and have neurofibrillary tangles and amyloid plaques. Because the number of patients that show signs of both AD and Parkinson’s is so high, some researchers have suggested that they are the same disease occurring over a broad spectrum.

Early Diagnosis The earlier a correct diagnosis can be made, the greater the gain in managing symptoms through pharmaceuticals. MRI PET SPECT Trained clinicians with proper imaging techniques can diagnose AD correctly nearly 90% of the time. Magnetic Resonance Imaging can measure the size of various structures in the brain. Atrophy of the Hippocampus or other regions may be an early sign of AD. Positron Emission Tomogrophy, and Single Photonemission Computed Tomography are able to visualize the activity in particular brain regions while they are being used during cognitive operations (e.g. memorizing, recalling, speaking, reading, etc.) Reduced activity may be indicative of brain atrophy or nerve cell damage associated with AD.

Causal vs. Associative Agents Advanced age Female gender Head Injury Cerebrovascular disease Low education levels Rural Residence Blood cholesterol Low blood levels of folic acid Inflammation Many associations have been made between AD and various factors. However, population studies have not been able to differentiate those agents that may be causative from those that are merely associative. Estrogen use has been associated with improved cognitive function. It has antioxidant and anti-inflammatory effects and enhances growth in neurons important for memory function (Maki et al 2001). Estrogen speeds up the flow of APP throughout the body, preventing it from being snipped into amyloid plaques. That’s why it may be preventive for AD but doesn’t improve outcomes for those who already have plaques deposited and symptoms of AD (Greengard et al. 2002). Patients using cholesterol-lowering statin drugs are 79% less likely to have AD than those who did not (Green et al. 2002). Possible mechanisms: Decreased cholesterol may decrease risk of AD. Statins may prevent mini-strokes. Statins may affect the formation of plaques.

A Chain of Events Leads to Disability and Death GENES LIFESTYLE & ENVIRONMENT BRAIN DEVELOPMENT & RESERVE ALZHEIMER’S SEVERITY IN BRAIN NEURO- DEGENERATION One of the most compelling on-going population-based research projects is Dr. David Snowdon’s “Nun Study.” The Nun Study is a longitudinal study of aging and Alzheimer's disease funded by the National Institute on Aging. Study subjects are 678 American members of the School Sisters of Notre Dame religious congregation who are 75 to 106 years of age. Nearly all of these nuns have agreed to donate their brains to the research project. Numerous studies based on this population have been published. For information go to www.mc.uky.edu/nunnet/ Based on this research, Snowdon theorizes, and many other researchers agree, that AD develops as the result of a complex cascade of events that take place over many years. If you can intervene and weaken or break any of these links in the chain, the disease may be prevented or its severity diminished. OTHER DISEASES AGE AT ONSET OF SYMPTOMS SEVERITY OF SYMPTOMS

Global Prevalence of AD United States Most common cause of AD Current cases: ~4 million Prevalence doubles every 5 years beyond age 65 Nearly 50% of those aged 85+ have AD AD affects more than 4 million Americans. One in 10 people over the age of 65 are affected. Nearly 50% of all people age 85 and older may have symptoms of AD If nothing changes, AD is likely to affect up to 14 million Americans by 2050. An intervention that could delay the onset of AD by 5 years would reduce the number of persons with AD by 50% by the year 2050 (Brookmeyer et al. 1998). The % of non-Caucasians in the US population is growing rapidly. By 2050 the % of Americans >65 year old will have increased from its current 16% to 34%. African Americans and Hispanic Americans may have higher overall risk of AD than do Caucasians (Tang et al. 1998). Therefore forecasts for AD in the US may be underestimated.

Global Prevalence of AD African Americans in Indianapolis are twice as likely as Africans in Ibadan, Nigeria to develop dementia & AD. Higher rates of AD in Japanese men who emigrated to US compared with those who remained in Japan. Epidemiologic data suggests that certain communities in Africa and Asia may have a lower risk for AD when compared to western countries. Nearly 25% of community-dwelling African-Americans aged 65 or older in Indianapolis had measurable cognitive problems. Fewer than half that many, when controlled for age, presented symptoms in Ibadan, Nigeria (Unverzagt et al 2001). Rates increase among Japanese populations who have emigrated to the US. All of these suggest that lifestyle factors greatly impact the risk of developing AD.

Global Prevalence of AD Europe There are currently an estimated 5.5 million people with dementia in Europe. EURODEM - the European Community Concerted Action on the Epidemiology and Prevention of Dementia Group - calculated these prevalence rates based solely on diagnosed cases of AD (Hofman et al 1991). This makes an accurate estimate of the number of people with dementia difficult because: Many people with dementia never receive an AD diagnosis. Estimate excludes those in the early stages of dementia who have yet to be diagnosed. Prevalence rates increase from ~2% in the 65 - 69 year old population to ~22% of those aged 85-89.

Global Prevalence of AD Developing Countries Currently, ~18 million people in the world have dementia. 66% of people with dementia live in developing countries. Tests of mental function typically rely on language and the written word. Therefore, it is difficult to assess mental function across populations with low formal education levels and cultural and language barriers. The 10/66 Dementia Research Group has developed a diagnostic panel that is effective across education levels and across cultures. The panel includes: The Geriatric Mental State - a clinical interview covering symptoms. The Community Screening Instrument for Dementia (CSI-D) - a test of memory, concentration, language and orientation; and a caregiver interview. CERAD 10 Word List - verbal 10 word recall test. Pilot studies have been completed worldwide, successfully identifying 94% of dementia cases correctly. It worked equally well in Indian, Chinese and Latin American countries, demonstrating effectiveness with language and cultural diversity. Additional information on the 10/55 Dementia Research Group is at www.alz.co.uk.

Current Research Continued search for causative agents and etiology. Disease prevalence worldwide with close attention to cultural variations. Animal and population studies that confirm causation and lead to preventive or curative measures. Breakthroughs continue to be made in the study of Alzheimer’s Disease. This research will eventually lead to a set of preventive or curative measures that may prevent the suffering that currently afflicts so many elderly patients and their families.