Abnormal Proteins in Alzheimer’s Disease

Alzheimer’s disease (AD) is associated with two abnormal proteins that make up the extracellular “senile” plaques and intracellular neural fibrillary tangles (NFT s ) found histopathologically. NFTs are composed of a protein called tau, whereas the plaques are largely made up of abnormally folded amyloid protein, beta-amyloid (also referred to as amyloid-β or Aβ). The abnormal configuration of Aβ causes fragments to autoaggregate, forming pleated sheets and insoluble fibrils.

The amyloid cascade hypothesis proposes that Aβ deposition is the central event that incites the neuroinflammation, NFT formation, vascular damage, and synaptic loss that ultimately lead to neuronal death in AD. This theory is supported by studies showing that the Aβ fibrils are neurotoxic. Additionally, the genetic defects found in familial forms of AD cause an increase in abnormal Aβ by altering amounts of the amyloid precursor protein (APP) or by changing the way APP is cleaved during posttranslational processing. The abnormal Aβ (i.e., Aβ42) fragments have a different configuration that leads to the auto-aggregation and formation of insoluble fibrils and pleated sheets found in Alzheimer’s.

In the search for a cure for AD, attention has focused on the extracellular fibrillar plaques in accordance with the amyloid cascade hypothesis. However, clinical trials with new therapies that correct amyloid buildup have so far failed to correct cognitive decline or alter the course of disease. Several other facts are difficult to explain if the amyloid cascade hypothesis is entirely correct. First, significant Aβ deposition is seen in 15% to 30% of cognitively normal elderly patients. Also, amyloid volume and distribution fail to reflect the stage or severity of symptoms. For example, anteromedial temporal lobe dysfunction develops very early in the course of AD, but plaques are not detected there until later (first occurring in the basal temporal lobe, anterior cingulate, and parietal operculum). Also, Aβ plaque appears decades before the disease is clinically manifest and plateaus many years before the symptoms peak.

Despite the conflicting information as to the importance of amyloid, detecting its presence with PET or measuring changes in CSF amyloid concentration can help with the diagnosis of dementia, particularly in differentiating AD from frontotemporal lobar degeneration (FTLD). Other contributing factors that could play a role in dementia include inflammation from overactive microglial cells, decreased phagocytosis of toxic debris, and toxicity related to the combination of abnormal proteins present. In AD, the relationship between abnormal Aβ and tau proteins is increasingly attracting interest.

The protein tau is normally involved in the regulation of intracellular transport by the cellular microtubules and is encoded for by the MAPT gene located on chromosome 17. NFTs are largely composed of an insoluble, abnormally phosphorylated (hyperphosphorylated) form of the microtubule-associated protein tau (MAPT or tau).

In AD, tau accumulates in a pattern that mirrors the progression of functional changes. Filaments are first found in the anteromesial temporal lobe and hippocampus, then spread to involve the lateral temporal and temporoparietal cortex. The posterior cingulate cortex (PCC) and superior posterior parietal lobe are next involved. Unlike amyloid, the amount of tau present appears to correlate with the severity of disease, and evidence increasingly points to tau as a critical factor in the development of the AD.

Different forms of tau accumulate have been found to be characteristic in several other neurodegenerative disorders. These disorders are cumulatively referred to as “tauopathies” and include the behavioral variant frontotemporal lobar dementia (bvFTLD), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP). In the past, FTLD was referred to as Pick’s disease, but that term is now used to refer to the subset of frontotemporal dementia (FTD) cases where Pick bodies, intracellular inclusions containing tau, are seen in tissue specimens.

Lewy bodies are another type of intracellular inclusion, composed largely of abnormal α-synuclein protein. Lewy bodies were originally described in Parkinson’s disease (PD), but they are also found in dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD). It is likely that DLB and PDD are related on a spectrum of disease. Neuronal involvement in each disease progresses in a predictable pattern marked by the spread of the abnormal protein. For example, Lewy bodies in DLB are found in the brainstem and substantia nigra before moving rostrally to dopaminergic neurons in the striatum. This is followed by the cingulate region, insula, and finally widely through the cortex. Lewy bodies are not specific to diseases of striatal or motor neurons and are found in other conditions, including 50% of patients with AD. In fact, the overlap between AD and DLB is significant in other ways, with patients with DLB frequently showing AD cellular pathology (i.e., amyloid), and the F-18 FDG PET patterns of the two disorders are sometimes difficult to differentiate in clinical cases. Abnormal α – synuclein can be found in forms other than as Lewy bodies. For example, glial intracellular inclusions, primarily in oligodendrocytes, are the hallmark of the atypical parkinsonian syndrome, multisystem atrophy (MSA).

Roughly 50% of FTLD cases are tau negative. The abnormal proteins related to these cases have been characterized recently, with two proteins being involved in almost all cases: TAR-DNA binding protein of 43 kDa (TDP-43) and fused in sarcoma (FUS) protein. These two proteins also often occur in a subset of amyotrophic lateral sclerosis (ALS), and accumulations of FUS are found in some patients with essential tremor. The two proteins can also be seen as secondary proteins in other degenerative diseases when more than one protein is present.

Abnormal protein accumulation characterizes several other diseases. In Huntington’s chorea, an abnormal protein, Huntingtin, is found. Prion disease, such as in Creutzfeldt–Jakob disease, will also result in abnormally folded protein deposition. The dementia of Down’s syndrome (trisomy 21) is associated with AD pathology because of the presence of the amyloid precursor protein gene on chromosome 21. In addition, traumatic brain injury that leads to chronic traumatic encephalopathy (CTE) is strongly associated with NFT deposition. Understanding the different abnormal proteins found in the dementias may help uncover new diagnostic tests and therapies.

AD typically occurs after age 60 to 65 and is characterized primarily by progressive cognitive decline with episodic memory loss, difficulty navigating familiar places, and organizational problems (i.e., amnestic AD). AD is the most common cause of dementia, accounting for 60% to 80% of cases diagnosed in the United States and affecting 10% of the population over 65 years of age and nearly 50% in those over 85 years of age. In those under 65, dementia is rare (comprising roughly 5% of diagnosed cases), but when it occurs, early-onset dementia is most commonly caused by AD. Roughly half the cases are caused by AD, and most of the remainder are a result of FTLD/FTD. Early-onset AD is more frequently associated with familial inherited patterns of disease and demonstrates a more aggressive clinical course than the classic late-onset form.

More than 80% of AD cases are sporadic, but in those cases of inherited forms of disease, three important autosomal-dominant genetic defects have been found ( Table 14.3 ). In nonfamilial and late-onset disease, a strong correlation has been found with abnormalities in the genes for apolipoprotein (ApoE). Specifically, an increased incidence of AD is seen in those who carry the ApoE ε ₄ allele, and the risk increases when more than one copy of the ApoE ε ₄ is present. In both early- and late-onset disease, defects result in the buildup of abnormal forms of Aβ related to these genes. Other factors that have been linked to Alzheimer’s are diabetes mellitus, elevated serum glucose/hyperinsulinemia, hypertension, and head injury.

Occasionally, AD will present clinically in an atypical fashion with symptoms other than memory loss dominating early in the course of disease. These disorders include aphasia in logopenic primary progressive aphasia (verbal variant AD), visual deficits in posterior cortical atrophy (visual variant), corticobasal degeneration (motor variant), and personality or behavioral changes (frontal lobe variant). Although clinical findings and corresponding F-18 FDG PET (or Tc-99m HMPAO/ECD SPECT) imaging findings vary widely in cases of atypical AD, the AD variants demonstrate the same underlying histopathological findings typical of amnestic AD (i.e., increased Aβ and NFT buildup and decreased CSF Aβ or tau).

Different phases of disease are now recognized in AD: preclinical, prodromal mild cognitive impairment, and dementia from Alzheimer’s ( Table 14.4 ). Preclinical amyloid deposition begins years before patients demonstrate symptoms. Such patients may be identified by genetic markers or abnormal imaging or CSF biomarker findings. In the early stages of disease progression, memory and cognitive issues are usually not serious enough to affect daily living activities. These patients are said to have MCI. MCI is present in 15% to 20% of the population over 65 years of age and can be caused by multiple etiologies. Patients may not develop dementia in 35% to 40% of cases. However, patients with MCI are at high risk for the development of AD, with 15% of patients with MCI converting to AD in 2 years and more than a third in 5 years (up to perhaps half of the cases). When MCI is caused by the early stages of AD, F-18 FDG PET (or sometimes SPECT) will often reveal abnormal patterns similar to AD. Additionally, amyloid PET scans will usually be positive in these cases. Thus, these scans can help predict which MCI cases will progress to actual AD. Once neurologic deficits have worsened to a level that affects daily living activities, the clinical diagnosis of dementia is made.

Table 14.4

Stages in Alzheimer’s Dementia Diagnosis

B[AU2]ased on National Institute on Aging Criteria 2011 with subsequent modifications.

			Clinical	Biomarkers
Category	Stage		Cognitive Change	Aβ PET or CSF	Neuronal Injury (Tau, MR, FDG)
Normal	0	AD biomarkers normal	–	–	–
Preclinical AD	1	Amyloidosis	–	+	–
	2	Amyloidosis and neurodegeneration	–	+	+
	3	Plus early cognitive change	+ (subtle—doesn’t meet MCI criteria)	+	+
	SNAP	Neurodegeneration without amyloid	–	–	+
MCI	Symptomatic predementia—daily living activities not affected		+ (mild)	+	+
Alzheimer’s Dementia	Symptomatic dementia	Affects daily living activities	+	+	+

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