β-Amyloid is a short fragment of the APP, typically 40–42 amino acids in length, which accumulates outside the cell during APP processing (Figs. 18-3 and 18-4). The tertiary structure of the 42–amino acid fragment is a β-pleated sheet that renders it insoluble. Consequently, it accumulates slowly, over many years, in the extracellular space and within synapses. In vitro studies confirm that β-amyloid is toxic to surrounding synapses and neurons, causing synaptic membrane destruction and eventual cell death. Transgenic mouse models show a clear association between accumulation of β-amyloid fragments, formation of amyloid plaques, and development of cognitive impairment.

Figure 18-3 Amyloidogenesis in Alzheimer Disease.

Figure 18-4 Amyloid Cascade Hypothesis in Alzheimer Disease.

In vivo, β-amyloid fragments coalesce to form “diffuse” or immature plaques, best seen with silver-staining techniques. Diffuse plaques, however, are not sufficient to produce dementia; many nondemented elderly patients have substantial depositions of diffuse plaques throughout the cortex, a condition termed pathologic aging. It is when these plaques mature into “senile” or neuritic plaques that dementia becomes more likely (Fig. 18-5, top). Senile plaques consist of other substances in addition to β-amyloid, including synaptic proteins, inflammatory proteins, neuritic threads, activated glial cells, and other components. Unlike diffuse plaques, senile plaques are composed of a central core of β-amyloid surrounded by a myriad of proteins and cellular debris. Senile plaques are distributed diffusely in the cortex, typically starting in the hippocampus and the basal forebrain. Senile plaque formation correlates with increasing loss of synapses, which correlates with the earliest clinical sign, namely, short-term memory loss. The anatomic pattern of progression gradually spreads to neocortical and subcortical gray matter of the temporal, parietal, frontal, and, eventually, occipital cortex. Subcortical nuclei become involved relatively late in the process.

Figure 18-5 Microscopic Pathology in Alzheimer Disease.

Neurofibrillary Tangles

The second pathologic hallmark of AD is the neurofibrillary tangle (Fig. 18-5, bottom). These lesions develop and conform to an anatomic pattern that correlates with the clinical syndrome; the number and distribution of tangles are directly related to the severity and clinical features of the dementia. Neurofibrillary tangles form intracellularly, consisting of a microtubule-associated protein, tau, which has a vital role in the maintenance of neuronal cytoskeleton structure and function. Tau is hyperphosphorylated in AD, causing it to dissociate from the cytoskeleton and accumulate, forming a paired helical filament protein structure. The cytoskeleton is compromised structurally and functionally, disrupting normal cell function. The most commonly used pathologic criteria for definitive AD diagnosis at autopsy require the presence of senile plaques and neurofibrillary tangles. Other lesions, such as Hirano bodies, are also seen in AD but have little diagnostic specificity.

Neurotransmitters

In addition to neuronal and synaptic loss, there is a gradual loss of various neurotransmitters. Acetylcholine synthesis is the earliest and most prominently affected. Most acetylcholinergic neurons arise within the nucleus basalis of Meynert in the basal forebrain (see Fig. 18-2). This nucleus is affected relatively early in the process; acetylcholine levels within the brain and spinal fluid of patients with AD quickly decline with disease progression. This observation supported the cholinergic hypothesis—that acetylcholine depletion results in the cognitive decline observed in patients with AD—eventually leading to the first symptomatic treatment of AD.

Risk Factors

Epidemiologic studies identify several potential risk factors for AD. The most consistent risk factors include advanced age, family history (especially in first-degree relatives), and ApoE genotype. Other risk factors include hypertension, stroke, and fasting homocysteine levels (Fig. 18-6). Because vascular risk factors are modifiable, they may affect risk reduction and treatment for patients with AD and those at risk for development of AD.

1. Advanced age is the single consistently identified risk factor for AD across numerous all-international studies. AD incidence and prevalence increase with advancing age, leading to the hypothesis that AD would develop in all individuals if they lived long enough. The true incidence in persons older than age 85 years is difficult to ascertain because of sharp decline in life expectancy. However, there are many instances of nondemented elders where no pathologic evidence of AD is found at autopsy, including in centenarians. Therefore, dementia is not considered a “normal” part of aging.

2. Family history of dementia is another consistent risk factor in many studies; however, the most common form of AD occurs sporadically. Establishing accurate family history of dementia is difficult because many of these patients’ relatives may not have survived into older ages where dementia risk is greatest. Rare, early-onset, presenile (before age 65 years) forms of AD occur with an autosomal-dominant pattern of inheritance. The genetic basis for many hereditary AD forms is identified. Most mutations affect the genes that encode APP and the presenilins. Each mutation leads to increased deposition of amyloid in affected individuals, predisposing to earlier onset. Individuals with trisomy 21 (Down syndrome) also have a high deposition of β-amyloid. AD develops in all patients with Down syndrome by age 35 years.

3. ApoE genotype is another genetic risk factor (Fig. 18-7). The three common allelic forms of this gene, epsilon 2 through 4, are encoded on chromosome 19. The presence of an e4 allele is associated with increased risk of AD and younger age at onset. This risk is greatly increased in e4 homozygotes. Conversely, the e2 allele appears to impart a protective, risk-lowering effect, as replicated in numerous international, population-based studies. The association between the ApoE e4 allele and AD seems to be disease specific. There is no clear association between e4 and other neurodegenerative or amyloid-based diseases.

The mechanism underlying this increased risk associated with the Apo e4 allele is not well understood but may relate to the role of ApoE in cell membrane repair. Phenotypically, the e4 cases have greater amyloid deposition than do the non-e4 cases. Although ApoE genotyping is available, it is not a diagnostic test for AD, nor is it recommended for routine testing. Most patients with AD are non-e4 carriers. ApoE genotyping is largely used in research, primarily as a biological marker to differentiate cases. Some studies suggest differential response to medications in cases stratified by ApoE genotypes.

4. In recent years, cerebrovascular disease and vascular disease risk factors have emerged as significant risk factors for AD. The presence of stroke increases the likelihood of dementia in old age. Diabetes, hypertension, and hyperlipidemia consistently elevate relative risk of dementia across international epidemiologic surveys of AD and dementia. Moreover, multiple observational studies show reduced risk among individuals receiving treatment for these conditions. This connection between AD and cerebrovascular disease may provide an important focus for premorbid dementia prevention. It is unknown whether secondary stroke prevention reduces the likelihood of dementia or its rate of progression. Nevertheless, assessment of stroke risk factors may become increasingly important for the management of dementia patients.

Figure 18-6 Risk Factors for Alzheimer Disease.

Figure 18-7 Possible Factors in Development and Progression of Alzheimer Disease.

Clinical Presentation

The early signs of AD may be subtle (Fig. 18-8). In the initial stages of AD, memory losses can be clinically distinguished from normal aging, although formal memory testing is often required to confirm suspicion of early dementia. The early signs of Alzheimer begin insidiously, progress slowly, and are often covered up by patients. Detection may be challenging even for close family members. The physician may observe changes in patient’s pattern of behavior, such as missing appointments or poor compliance with medications. It is important to discuss such issues openly with family members given the patient often cannot recall examples of memory problems. Indeed, it is common for patients to have limited insight into their deficit, and for family members to initiate an evaluation for memory loss. In these early stages, patients maintain their social graces. It is not uncommon during mental status testing to discover the significant cognitive problems concealed by a patient’s friendly and sociable affect. “Very pleasant” patients sometimes fool even seasoned geriatricians. The Alzheimer’s Association lists 10 key warning signs of AD.