Alzheimer Disease

Lawrence S. Honig

Scott A. Small

Richard Mayeux

INTRODUCTION

The most common dementia is Alzheimer disease. The disease was first named by Emil Kraepelin in 1910, after Alois Alzheimer, who in 1906 had described the clinical features and pathologic manifestations of dementia in a 51-year-old woman. For some decades, Alzheimer disease was considered a presenile form of dementia, affecting individuals with symptoms beginning before age 65 years. But the mid-20th century brought the understanding that the same clinical, pathologic, ultrastructural, and biochemical features of presenile Alzheimer disease are shared by those with the more common “senile” (older than age 65 years) dementia. The disease is commonly sporadic, although susceptibility relates to a variety of genetic risk factors. Uncommonly, the disease has an autosomal dominant inheritance pattern, particularly in younger persons. In a look back to the past, an analysis of the DNA of Alois Alzheimer’s first described case, nearly 100 years after her evaluation, revealed that her condition resulted from a mutation (F176L) in exon 6 of one of these autosomal dominant genes, presenilin 1.

EPIDEMIOLOGY

Alzheimer disease is a chronic disease of aging, and both the incidence and prevalence of disease increase with age. Prevalence estimates reveal that fewer than 1% of persons younger than age 65 years are clinically affected, but about 5% are affected at age 65 to 75 years, about 20% at age 75 to 85 years, and likely over 50% at age 85 years and older. The increasing prevalence with age is because the age-specific incidence, or the number of new cases arising over a specific period of time, rises steeply from less than 1% per year before age 65 years to about 6% per year for individuals aged 85 years and older. The average duration of symptoms from first noticeable symptoms until death is typically from 10 to 20 or more years.

It is presumed that both environmental and genetic factors are involved in the risk of the disease. But extensive investigations, as to environmental risk factors other than age, have not resulted in clear risk factors for Alzheimer disease itself. Late-life depression is associated with Alzheimer disease, although the direction of causality is unclear—it is likely that depressive symptoms are often early manifestations of this dementing disorder. Traumatic head injury has been associated with increased risk of dementia, but it is not clear that trauma is a risk for Alzheimer disease itself versus other dementias. Likewise, diabetes and cardiovascular and cerebrovascular disorders have been associated with increased risk of dementia, but these may be due to additive ischemic injury to the brain, rather than a true increase in Alzheimer disease. Studies of identical twins show that they are not necessarily concordantly affected, so almost certainly there are some factors other than classic genetic ones. However, the main risk factors for development of Alzheimer disease, each small in and of itself, appear to be the members of a growing long list of genetic variations (Table 50.1).

GENETIC BASIS OF ALZHEIMER DISEASE

Most Alzheimer disease is “sporadic” rather than a mendelian dominant or recessive condition. However, a small proportion of the total number of persons with Alzheimer disease (<0.5%) have disease that is transmitted as an autosomal dominant identified monogenic familial disorder, commonly, but not always, with onset before age 65 years. Mutations in three genes, the amyloid precursor protein (APP) gene on chromosome 21, the presenilin 1 (PSEN1) gene on chromosome 14, and the presenilin 2 (PSEN2) gene on chromosome 1, result in such autosomal dominant forms of the disease beginning as early as the third decade of life, with essentially complete penetrance (see Table 50.1). In addition, trisomy 21, or Down syndrome, results in near certainty of Alzheimer disease pathology by age 50 years and in symptoms of the disease in those who survive long enough. Finally, there is a mutation in APP (the “Icelandic” allele, A673T) which is highly correlated with protection from Alzheimer disease. There are at least 204 described different pathogenic mutations in PSEN1, and it is the most common form of familial early-onset Alzheimer disease. Mutations in these three genes account for as many as half of the familial forms of early-onset Alzheimer disease and may be considered deterministic because of nearly complete correspondence between the genotype and phenotype. Mutations in these three genes seem to lead to increased production of amyloid-β (Aβ) or specifically the Aβ42 peptide.

There is a higher risk of Alzheimer disease in first-degree relatives of persons with Alzheimer disease. Siblings of patients have about twice the expected lifetime risk of developing the disease. Monozygotic twins have significantly higher concordance of Alzheimer disease than do dizygotic twins. Some of the genetic risk relates to the ε4 polymorphism of the APOE gene on chromosome 19, which shows a strong association with onset of Alzheimer disease in the age range of 60 to 80 years. The ε4 polymorphism of APOE is a normally occurring variant of the gene present in about one-third of the unaffected American population but present in about two-thirds of those with late-onset Alzheimer disease. APOE has been called a susceptibility gene because possession of the ε4 allele, a polymorphism, does not always lead to Alzheimer disease. One APOE-ε4 allele is associated with about a 2- to 3-fold increased risk, whereas having two copies is associated with a 5- to 10-fold increased risk. The population attributable risk associated with APOE-ε4 is approximately 20%, making it one of the most important risk factors for the disease.

A large number of gene variants have now been identified, that each conveys a smaller risk of Alzheimer disease than that of APOE-ε4 (see Table 50.1). About 20 such genes are currently identified including some involved in lipid biology, intracellular processing, or endosomal pathways (e.g., SORL1) and others involved in inflammation or the immune response, cell migration, cytoskeleton, axonal transport, and microglial cell function. Other genes will likely be identified adding to the already complex genetic architecture of this disease.

TABLE 50.1 Chromosomal Loci and Genes Related to Alzheimer Disease

Chromosome Locus	Gene/Candidate	Genetic Inheritance	Possible Mechanism
14q24.13	PSEN1	Autosomal dominant	Increased generation of Aβ42
1q31.42	PSEN2	Autosomal dominant	Increased generation of Aβ42
21q21.3	APP	Autosomal dominant	Increased Aβ42 or Aβ42 aggregation
21q21.3	APP(A673T)	Protective factor	Decreased generation of Aβ42
19q13.2	APOE	Risk factor	Decreased clearance of Aβ42
11q23.3	SORL1	Risk factor	Lipid/protein endocytosis/trafficking
2q14.3	BIN1	Risk factor	Lipid/protein endocytosis/trafficking
6p12.3	CD2AP	Risk factor	Lipid/protein endocytosis/trafficking
11q14.2	PICALM	Risk factor	Lipid/protein endocytosis/trafficking
19p13.3	ABCA7	Risk factor	Lipid/protein endocytosis/trafficking
8p21.1	CLU	Risk factor	Lipid/protein endocytosis/chaperone
1q32.2	CR1	Risk factor	Cell adhesion to particles/complexes
19q13.3	CD33	Risk factor	Cell adhesion/immune response
18q12.1	DSG2	Risk factor	Cell adhesion
14q22.1	FERMT2	Risk factor	Cell adhesion/cytoskeletal function
20q13.31	CASS4	Risk factor	Cell adhesion/cytoskeletal function
7p14.1	NME8	Risk factor	Cytoskeletal function
6p21.3	HLA-DRB5/1	Risk factor	Immune response/trafficking
5q14.3	MEF2C	Risk factor	Immune response/synaptic function
2q37.1	INPP5D	Risk factor	Immune response/signaling
11q12.1	MS4A6A	Risk factor	Signal transduction
7q34	EPHA1	Risk factor	Receptor tyrosine kinase/signaling
8p21.2	PTK2B	Risk factor	Receptor tyrosine kinase/signaling
14q32.12	SLC24A4–RIN3	Risk factor	Cation exchange transporter
7q22.1	ZCWPW1	Risk factor	Regulation gene expression
11p11.2	CELF1	Risk factor	Regulation gene expression (splicing)
6p21.1	TREM2(R47H)	Risk factor	Immune response/Aβ42 clearance
6p21.1	TREML2(S144G)	Protective factor	Immune response/Aβ42 clearance
List of genetic markers related to risk of Alzheimer disease. PSEN1, PSEN2, and APP are genes for which mutations can lead to autosomal dominant inherited Alzheimer disease, although a particular mutation in APP can also be protective against Alzheimer disease. APOE, SORL1, and the other genes listed all have been shown to have allelic variation that affects risk of Alzheimer disease.

PATHOBIOLOGY

Alzheimer disease pathology is marked by two specific neuropathologic features (Table 50.2; Fig. 50.1): extracellular amyloid plaques molecularly consisting in large part of a fibrillar aggregation of the 40 and 42 amino acid peptides A β40 and A β42 and intracellular neurofibrillary tangles, which consist of paired helical filamentous polymers of hyperphosphorylated tau protein. Although these specific features permit pathologic diagnosis of Alzheimer disease, it is likely that the symptoms of the disease relate primarily to extensive synaptic losses and later to frank neuronal losses. Much of the earliest brunt of this injury is borne by the entorhinal region of the medial temporal lobe.

The senile neuritic plaques are spherical microscopic lesions with a core of extracellular A β infiltrated and surrounded by abnormal nerve fibers (neurites). The A β40 and A β42 peptides are derived from the APP, a transmembrane protein present in most tissues. A region of the APP resides within an intramembranous domain of intracellular organelles in neurons, and several proteolytic enzyme activities, known as secretases, are responsible for cleavage of the protein. When cleaved by α-secretase, a soluble peptide derivative of amyloid is formed. However, when the APP is cleaved by β-secretase, and subsequently by γ-secretase, the peptides Aβ40 and Aβ42 are generated. These Aβ peptide monomers aggregate, forming oligomers, and ultimately large polymers, a process that can be demonstrated in vitro and presumably results in the amyloid plaques observed histologically. It is thus not surprising that the three autosomal dominant genes for Alzheimer disease are the APP gene itself and the PSEN1 and PSEN2 genes, which contribute to γ-secretase activity. Although there is little doubt as to a pathologic role of APP products, it is not clear which products might be most responsible for presumed neurotoxicity and synaptic losses: monomers, oligomers, polymers, or even other more soluble fragments. In addition to the parenchymal deposition of amyloid in
Alzheimer disease, there is in nearly all cases amyloid angiopathy, which is amyloid deposition around meningeal and cerebral vessels. This condition is of varying severity and import in different patients but is accompanied by a propensity for hemorrhages, which may be microscopic, although visible on T2*-weighted gradient echo magnetic resonance imaging (MRI), or macroscopic, with medium or large lobar hemorrhages. In a small proportion of patients, acute localized or diffuse brain edema may occur, now known as amyloid-related imaging abnormality edema or ARIA-E, either spontaneously or after delivery of investigational antiamyloid therapies.

TABLE 50.2 Pathologic Hallmarks of Alzheimer Disease

Macroscopic/Regional	Clinical Implications
Hippocampal atrophy	Memory impairment
Parietotemporal atrophy	Dysnomia/visuospatial impairment
Nucleus basalis cell loss	Attentional impairment
Microscopic	Molecular Concomitant
Neuritic plaques	Aβ42 and Aβ40 fibrillar aggregates with associated neuritic changes
Diffuse plaques	Aβ42 and Aβ40 fibrillar aggregates
Neurofibrillary tangles	Paired helical filamentous aggregates of phosphorylated tau protein
Synaptic loss	Not known—but accompanied by decreases in various neurotransmitters
Neuronal loss	Not known
Granulovacuolar degeneration	Intraneuronal vesicular changes
List of pathologic hallmarks of Alzheimer disease, including macroscopic/regional changes and microscopic changes and their clinical and molecular correlates.