Alzheimer’s Disease

Prevalence, Prognosis, and Definition

Alzheimer’s disease is a neurodegenerative disease of the brain typically characterized by a prominent memory impairment and having a specific pathology including senile plaques and neurofibrillary tangles ( ). Over time, Alzheimer’s disease produces neurochemical deficits and prominent brain atrophy. Alzheimer’s disease is by far the most common cause of dementia, either by itself or in combination with other disorders. Although the exact prevalence is difficult to ascertain, it is estimated that approximately 5.8 million Americans are living with Alzheimer’s disease dementia. The overall prevalence of Alzheimer’s disease dementia in the community is estimated at about 10% in population-based studies. Although there are approximately 200,000 Americans under age 65 living with Alzheimer’s, the disease becomes more prevalent with age, with most cases being diagnosed after the age of 65. It is estimated that approximately 3% of people aged 65 to 74 years, 17% of people aged 75 to 84 years, and 32% of people aged 85 years and older have Alzheimer’s disease dementia. Worldwide, it is estimated that 50 million people have dementia, comprising 5% of the world’s population over age 60 ( ). Because the population is aging, the number of individuals with Alzheimer’s disease is rapidly rising ( Figs. 4.1–4.4 ). Approximately two-thirds of patients with Alzheimer’s disease are women, with the overall lifetime risk being 11.6% for men and 21.1% for women. The incidence of Alzheimer’s disease is lower in Asian Americans and higher in American blacks and Hispanics/Latinos compared with non-Hispanic American whites. The average patient with Alzheimer’s disease dementia lives approximately 4 to 8 years from diagnosis until death, with the range being approximately 4 to 12 years. On average, the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) decline approximately 2 or 3 points per year in these patients. Alzheimer’s disease and related dementias are also some of the most expensive health conditions in the USA with a total annual cost for 2019 estimated to be $290 billion for healthcare and long-term care—not including the contribution of unpaid caregivers ( ).

Alzheimer’s Pathology

Brain weight is typically reduced in Alzheimer’s disease by 100 to 200 grams. Examination of the surface of the brain reveals cortical atrophy of the temporal, parietal, and frontal lobes, as well as the hippocampus ( Fig. 4.5 ). The ventricular system becomes enlarged ( Fig. 4.6 ). The occipital lobes, along with primary sensory and motor cortices, are usually preserved. Microscopically, Alzheimer’s pathology consists of two main features, senile plaques and neurofibrillary tangles ( Figs. 4.7 and 4.8 ). Additional microscopic features include selective loss of neurons and synapses, and an increase in the number and activation of astrocytes. Neuropil threads (short, often curly silver-stained fibers) also accumulate in the neocortex. The exact relationship between Aβ, plaques, tangles, cognitive impairment, and disease progression is an active area of research.

Senile plaques contain a specific type of amyloid, often referred to as β-amyloid or as “Aβ.” (Note that the amyloid in Alzheimer’s disease is not related to the amyloid in systemic amyloidoses.) Aβ is a 40- or 42-amino acid peptide that is a fragment of a larger, membrane-spanning glycoprotein known as the amyloid precursor protein or APP. The normal function of Aβ is unclear, although it may be part of the brain’s immune system ( ). Up to 50% of the Aβ found in plaques is Aβ42. Senile plaques are extracellular structures that are composed of Aβ, dystrophic neuritic processes (axons and dendrites), astrocytes and their processes, and microglial cells (see Fig. 4.8 ). When axons and dendrites are disrupted, the communication between neurons becomes impaired. When microglial cells attempt to remove amyloid and remnants of axons and dendrites, an inflammatory reaction can start causing more damage. Under light microscopy senile plaques appear to have a fluffy central core with surrounding thick irregular processes ( Fig. 4.9 ). Various classifications of senile plaques have been proposed, including diffuse and neuritic types. Neuritic plaques are associated with the destruction of axons and dendrites of neurons. Diffuse plaques do not disrupt these neuronal processes, but are thought to be the precursor of neuritic plaques.

Neurofibrillary tangles are intraneuronal cytoplasmic structures that are composed of paired filaments with a regular helical periodicity (see Fig. 4.8 ). Neurofibrillary tangles appear to be composed primarily of a hyperphosphorylated form of the microtubule-associated protein tau. Microtubules are one of the three major constituents of the neuronal cytoskeleton, an infrastructural element of neurons that participate in functions such as axonal transport and maintenance of the structural integrity of the cell. Among other roles, tau and other microtubule-associated proteins stabilize the microtubule assembly (think of tau as the support beams or rivets for this system). Although neurofibrillary tangles begin as intracytoplasmic structures, they may remain behind after the neuron dies, forming “ghost” or “tombstone” tangles in the neuropil. Under the microscope neurofibrillary tangles can look like skeins of yarn (see Fig. 4.9 ).

Neurochemistry

A deficit in acetylcholine is the most consistently found alteration of brain chemistry in Alzheimer’s disease. Early in the disease there is a loss of choline acetyltransferase and reduced high-affinity choline uptake and acetylcholine synthesis ( ). Studies have shown a correlation between the loss of choline acetyltransferase and impairment of cognition ( ). These data have led to the cholinergic hypothesis of Alzheimer’s disease that, in turn, has led to the development of acetylcholinesterase inhibitor therapies to treat this disorder (see Chapter 19 ). Other studies have shown that, in addition to acetylcholine, many other neurotransmitters also become disrupted as the disease progresses, including norepinephrine, serotonin, glutamate, and dopamine ( Fig. 4.10 ).

Diagnostic Criteria

There are several different clinical diagnostic criteria that are used for Alzheimer’s disease. The two most common are from the Diagnostic and Statistical Manual of Mental Disorders (DSM; current edition 5) and the National Institute on Aging–Alzheimer’s Association Criteria ( ) ( Boxes 4.1–4.3 ). Each has provided criteria for Alzheimer’s disease dementia (called major neurocognitive disorder due to Alzheimer’s disease in DSM-5) and mild cognitive impairment due to Alzheimer’s disease (called mild neurocognitive disorder due to Alzheimer’s disease in DSM-5).

For Alzheimer’s disease dementia, common elements of each are:

• the presence of dementia (see Chapter 3 )

• deficits in two or more cognitive areas

• insidious onset and a gradually progressive decline

• no evidence of another etiology that could substantial contribute to the dementia.

For mild cognitive impairment due to Alzheimer’s disease, the common elements of each are:

• the presence of mild cognitive impairment (see Chapter 3 )

• deficits in one or more cognitive areas, including memory (for DSM-5) or typically including memory (for NIA-AA)

• gradual onset and progression

• no evidence of another etiology that could substantially contribute to the mild cognitive impairment.

There is also a more recent National Institute on Aging–Alzheimer’s Association research framework ( ) that offers clarification and simplification of several aspects of the 2011 criteria. First, as described in Chapter 3 , they provide new definitions for cognitively unimpaired, mild cognitive impairment, and dementia due to any cause. Second, they separate Alzheimer’s disease as a pathologic entity from the Alzheimer’s clinical syndrome. Other terms previously used for Alzheimer’s clinical syndrome include “progressive amnestic dysfunction” ( ), “probable Alzheimer’s dementia,” and “dementia of the Alzheimer’s type.” (We prefer the term progressive amnestic dysfunction because it is simple, self-explanatory, and less likely to be confused with the pathologic entity of Alzheimer’s disease.) Third, they provide a new definition of biomarkers to help identify when Alzheimer’s disease pathology is actually present (which requires evidence of both amyloid and phosphorylated tau deposition in the brain), as well as when neurodegeneration is present ( Box 4.4 ). This framework can be used to simplify the cumbersome nomenclature of the 2011 criteria ( ). In this chapter we have provided the 2011 core criteria for probable Alzheimer’s disease dementia (see Box 4.2 ) and mild cognitive impairment due to Alzheimer’s disease (see Box 4.3 ) because of their clinical utility, as well as the 2018 syndromal cognitive stage and biomarker profile table ( Table 4.1 )—rather than the somewhat confusing 2011 definitions of possible Alzheimer’s disease and probable Alzheimer’s disease dementia with increased level of certainty.

Risk Factors, Pathology, and Pathophysiology

Age is the primary risk factor for Alzheimer’s disease. Other risk factors include family history of Alzheimer’s disease, female gender, few years of education, medical factors (including strokes, elevated plasma homocysteine levels, obstructive sleep apnea, and other risk factors for cerebrovascular disease), lifestyle choices, and genetic factors, particularly certain allelic forms of the gene coding for apolipoprotein E (APOE). Head injury may also be a risk factor for Alzheimer’s disease in addition to dementia with Lewy bodies (see Chapter 8 ) and chronic traumatic encephalopathy (CTE) (see Chapter 15 ). Late-onset depression has been associated with increased risk of cognitive decline, although depression may be an early sign of Alzheimer’s disease (see Chapter 17 ). In addition, as many as 90% of individuals with trisomy 21 (Down’s syndrome) who die over the age of 30 show Alzheimer’s disease pathology in their brains, suggesting that it may be found in all older individuals with Down’s syndrome. Several studies have suggested that having high premorbid intelligence (often correlated with many years of education) may be protective, in addition to healthy lifestyle choices such as physical activity, Mediterranean-style diet, and social engagement (see Chapter 22 ). Some possible disease-modulating factors have shown mixed results: some studies show a beneficial effect whereas other studies show either no effect or a detrimental effect. The factors with mixed results include estrogen supplementation, certain nonsteroidal antiinflammatory drugs (NSAIDs), certain statin-based lipid-lowering agents, and smoking. Note that intervention trials with NSAIDs and statins have been negative to date (see Chapter 21 ). One reason that NSAIDs have been suspected as possibly being protective is that inflammation has been postulated as playing an important role in the pathophysiology of Alzheimer’s disease (see Fig. 4.10 ). Lastly, it should also be noted that some of these factors—including but not limited to obesity, diabetes, hypertension, and cardiac disease—may increase the risk of progressive amnestic dysfunction (Alzheimer’s clinical syndrome), but not Alzheimer’s disease pathology ( ). Nonetheless, we certainly want to encourage our patients to reduce their risk of dementia, whether from Alzheimer’s disease or cerebrovascular pathology. As mentioned in Chapter 3 , most clinical dementia results from mixed pathology,

Genetic Predisposition

Specific mutations on chromosomes 21, 14, and 1 have been associated with early-onset familial Alzheimer’s disease. These patients with autosomal-dominant early-onset disease are relatively rare, and are typically easy to diagnose by family history. Patients with early-onset disease present clinically in their 40s and 50s, and usually family members can detect subtle changes years before clinical onset. The genetics of late-onset Alzheimer’s disease has been harder to elucidate. The strongest genetic risk factor for late-onset Alzheimer’s disease is the APOE allele. Relative to having an APOE ε3 allele, patients having an APOE ε4 allele are at increased risk of developing Alzheimer’s disease (see Fig. 4.10 and 4.11 ).

Apolipoprotein E

APOE is a major component of lipoproteins and has many normal functions, including lipid transport. The gene coding for APOE is on chromosome 19. The three common isoforms of APOE are APOE-2, APOE-3, and APOE-4, coded for by alleles ε2, ε3, and ε4, respectively. APOE ε3 is the most common allele in the population, with a frequency of about 78%. Patients with familial and sporadic late-onset Alzheimer’s disease (onset after age 55 years) have an approximately 3-fold increased likelihood of having an APOE ε4 allele. Conversely, the likelihood of having an APOE ε2 allele is lower than expected by allelic frequencies alone. Numerous studies have confirmed these findings, which suggest that APOE ε4 is a risk factor for developing Alzheimer’s disease, whereas APOE ε2 is a protective factor. In addition to conferring increased risk of developing Alzheimer’s disease, having an APOE ε4 allele also lowers the age of onset of the disease compared with those without an ε4 allele who develop it ( ). The majority of studies suggest that the course of Alzheimer’s disease is not affected by the presence of an ε4 allele, although a few studies have disagreed with this finding. Neuropathologically, in patients with Alzheimer’s disease there is more Aβ deposition in the brains of those with an ε4 allele than in those who have only ε3 alleles.

Should APOE genotyping be ordered routinely? Given the wealth of clinical and basic science data on the relationship between APOE and Alzheimer’s disease, the question arises as to whether APOE genotyping should be performed routinely. We would argue that, in general, it is not clinically useful. Although carrying an APOE ε4 allele is a significant risk factor, it is neither necessary nor sufficient to cause Alzheimer’s disease. First, approximately half of patients with Alzheimer’s disease do not carry an APOE ε4 allele. Second, up to one-quarter of patients with non-Alzheimer’s dementias carry an ε4 allele. Third, 10% to 19% of healthy older adults carry one or two ε4 alleles. Fourth, because APOE alleles are present from birth, APOE genotyping cannot be used to distinguish mild Alzheimer’s disease from normal aging. Thus using the APOE ε4 allele as a marker of Alzheimer’s disease would result in huge numbers of both false positives and false negatives. Although it can be helpful in research, we do not recommend APOE genotyping in clinical practice.