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Nervous system

Alzheimer’s disease (AD)

Neurodegenerative disease with insidious onset and progressive impairment of behavioral and cognitive functions including memory, comprehension, language, attention, reasoning, and judgment.

Alzheimer’s disease (AD) is a neurodegenerative disorder and the most common cause of dementia. Neurons communicate via chemical messages passed between two cells across a small gap called a synapse. In AD, abnormal cellular structures lead to a loss of synapses and neurons, which results in atrophy of the brain. The pathogenesis is largely unknown, but there are several characteristic abnormalities found in the brain tissue of patients with AD. These features include excessive granulovacuoles, amyloid plaques, and neurofibrillary tangles. | Jorge Muniz/Medcomic

Neurodegenerative disease with insidious onset and progressive impairment of behavioral and cognitive functions including memory, comprehension, language, attention, reasoning, and judgment.

  • M/C type of dementia (⅔ cases of dementia in ≥ 65 years)
    • Early onset AD (onset < 65 years) (< 10% cases)
  • #6 leading cause of death in the United States.

History:

In 1907, Aloysius “Alöis” Alzheimer carefully described the symptoms of a 51-year-old woman, Auguste Deter, who was under his care at the state asylum in Frankfurt Germany. Alzheimer’s description of her symptoms is almost certainly the first neuropsychological characterization of the disease.

Aloysius “Alöis” Alzheimer (left) carefully described the symptoms of a 51-year-old woman, Auguste Deter (right), who was under his care at the state asylum in Frankfurt Germany
Aloysius “Alöis” Alzheimer (left) carefully described the symptoms of a 51-year-old woman, Auguste Deter (right), who was under his care at the state asylum in Frankfurt Germany. Alzheimer’s description of her symptoms is almost certainly the first neuropsychological characterization of the disease: “Her memory is seriously impaired. If objects are shown to her, she names them correctly, but almost immediately afterwards she has forgotten everything. When reading a test, she skips from line to line or reads by spelling the words individually, or by making them meaningless through her pronunciation. In writing, she repeats separate syllables many times, omits others and quickly breaks down completely. In speaking, she uses gap-fills and a few paraphrased expressions (“milk-pourer” instead of cup); sometimes it is obvious she cannot go on. Plainly, she does not understand certain questions. She does not remember the use of some objects.” | Translated from German

When Auguste Deter died, Alzheimer used the then-new silver staining histological technique to examine her brain microscopically. When he did so, he observed the neuritic plaques, neurofibrillary tangles, and amyloid angiopathy that were to become the hallmarks of the disease that now bears his name. Alzheimer himself did not claim to have discovered “Alzheimer’s disease,” although his mentor Emil Kraepelin at the Munich Medical School rightly credited him with doing so by coining the term in his own Handbook of Psychiatry (Kraepelin, 1910). By 1911, the medical community was using Alzheimer’s depictions of the disease to diagnose patients both in Europe and the United States (Mauer & Mauer, 2003).

Sketches of Auguste Deter’s histopathologic preparations of early and late stage neurofibrillary tangle pathology as drawn by Alzheimer from his 1911 paper entitled “Über eigenartige Krankheitsfälle des späteren Alters.”
Sketches of Auguste Deter’s histopathologic preparations of early and late stage neurofibrillary tangle pathology as drawn by Alzheimer from his 1911 paper entitled “Über eigenartige Krankheitsfälle des späteren Alters.” | Bondi, M. W., Edmonds, E. C., & Salmon, D. P. (2017). Alzheimer’s Disease: Past, Present, and Future. Journal of the International Neuropsychological Society : JINS, 23(9-10), 818–831. https://doi.org/10.1017/S135561771700100X

Etiology

Age

Age-specific incidence of Alzheimer's disease
Age-specific incidence of Alzheimer’s disease (per 1000 person-years) across continents and countries. *, incidence of all types of dementia | Qiu, C., Kivipelto, M., & von Strauss, E. (2009). Epidemiology of Alzheimer’s disease: occurrence, determinants, and strategies toward intervention. Dialogues in clinical neuroscience, 11(2), 111–128.

Cognitive reserve:

Those with higher education levels, a cognitive reserve surrogate, are said to have reduced AD risk. It is heuristically reasoned high cognitive reserve individuals begin their decades-long cognitive decline further from the dementia finish line than low cognitive reserve individuals. Given equal pre-MCI cognitive decline trajectories, low cognitive reserve individuals will cross dementia thresholds before high cognitive reserve individuals.
Alzheimer’s disease dementia develops over decades
Alzheimer’s disease dementia develops over decades: Those with more cognitive reserve and slower decline trajectories dement at the oldest ages. Those with less cognitive reserve and more rapid decline trajectories dement at younger ages. | Swerdlow R. H. (2007). Pathogenesis of Alzheimer’s disease. Clinical interventions in aging, 2(3), 347–359.

APOE-4 gene:

Disproportionately represented among patients with both late-onset and early-onset AD and that the APOE-4 allele shows a dose-dependent relationship with increasing risk for AD and decreasing age at onset.

Early-onset AD:

Identified in patients with familial early-onset autosomal dominant AD, but these mutations are extremely rare, accounting < 1% of cases. All these genes appear to increase the cellular production of Aβ42 by selectively increasing the cleavage of APP by β- or γ-secretase.
  • Amyloid precursor protein (APP) (chromosome 21)
  • Presenilin-1 [PS 1] (chromosome 14) (M/C, 40-70% early-onset AD cases)
  • Prescnilin-2 [PS 2] (chromosome 1)
The amyloid cascade hypothesis
The amyloid cascade hypothesis: A black box is shown in the middle of the figure, since mechanisms through which Aβ42 drives downstream pathology are not well defined. | Swerdlow R. H. (2007). Pathogenesis of Alzheimer’s disease. Clinical interventions in aging, 2(3), 347–359.

Pathophysiology

Neuritic plaques and neurofibrillary tangles represent the pathological hallmarks of AD, and are respectively related to the accumulation of the amyloid-beta peptide (Aβ) in brain tissues, and to cytoskeletal changes that arise from the hyperphosphorylation of microtubule-associated Tau protein in neurons.

Mechanism of neuronal damage and Alzheimer's disease (AD) progression
Mechanism of neuronal damage and Alzheimer’s disease (AD) progression: Extracellular and intracellular amyloid β and tangles cause extreme toxicity, resulting in synaptic damage and increased reactive oxidative stress that then leads to microglial infiltration around the plaque areas. | Tiwari, S., Atluri, V., Kaushik, A., Yndart, A., & Nair, M. (2019). Alzheimer’s disease: pathogenesis, diagnostics, and therapeutics. International journal of nanomedicine, 14, 5541–5554. https://doi.org/10.2147/IJN.S200490

Senile neuritic plaques

Develop first in brain areas associated with cognition, and spread to other cortical areas as the disease progresses.
  • Amyloid p-peptide (Aβ): Overproduction of Aβ is a consequence of the disruption of homeostatic processes that regulate the proteolytic cleavage of the amyloid precursor protein (APP). Aβ seems toxic to the neuron either directly, or indirectly by causing inflammation or increasing the production of free radicals.
  • Subtypes:
    • Aβ42 (longer species): Deposited initially and initiate amyloid deposition
    • Aβ40 (shorter species)

Neurofibrillary tangles in neurons:

Accumulation in neurons, neurofibrillary tangles are formed by chemically altered (abnormally folded and phosphorylaled) tau protein (protein involved in microtubule formation).

Tangle formation is related to the severity of disease; the more advanced the stage of disease, the more tau tangles in the brain.

Hyperphosphorylationof τ
Hyperphosphorylationof τ: Mechanism by which τ hyperphosphorylation leads to instability of the microtubule and finally microtubule subunits fall apart leading to formation of insoluble and big neurofibrillary tangles. | Abbreviation: Aβ, amyloid β. | Tiwari, S., Atluri, V., Kaushik, A., Yndart, A., & Nair, M. (2019). Alzheimer’s disease: pathogenesis, diagnostics, and therapeutics. International journal of nanomedicine, 14, 5541–5554. https://doi.org/10.2147/IJN.S200490

Brain tissue degeneration:

  • Nucleus basalis of Meynert (nbM): Basal forebrain structure housing brain’s largest collection of cholinergic neurons. In AD the nbM suffers severe neuron loss and decreased production of acetylcholine, a neurotransmitter with an important role in learning and memory.
  • Granulovacuolar degeneration: Found within cytoplasm of neurons of the hippocampus. An abnormally high number of fluid-filled spaces, called vacuoles, enlarge the cell’s body causing neuronal dysfunction or cell death.
The pathological evolution of Alzheimer's disease
The pathological evolution of Alzheimer’s disease. | Masters, C., Bateman, R., Blennow, K. et al. Alzheimer’s disease. Nat Rev Dis Primers 1, 15056 (2015). https://doi.org/10.1038/nrdp.2015.56
Healthy Brain compared to a brain suffering from Alzheimer's Disease
Healthy Brain compared to a brain suffering from Alzheimer’s Disease. | Image: National Institutes of Health (NIH)

Presentation

Clinical manifestations of AD include disturbances in the areas of memory and language, visuospatial orientation, and higher executive function. Noncognitive changes include personality changes, decreased judgment ability, wandering, psychosis, mood disturbance, agitation, and sleep abnormalities.

Pre-symptomatic (or pre-clinical) AD:

May last for several years or decades until the overproduction and accumulation of Aβ in the brain reaches a critical level that triggers the amyloid cascade
The risk of clinical AD: Hypothetical model
The risk of clinical AD: Hypothetical model | Abbreviation: AD, Alzheimer’s disease; BM, pathophysiological biomarkers. | Dubois, B., Hampel, H., Feldman, H. H., Scheltens, P., Aisen, P., Andrieu, S., Bakardjian, H., Benali, H., Bertram, L., Blennow, K., Broich, K., Cavedo, E., Crutch, S., Dartigues, J. F., Duyckaerts, C., Epelbaum, S., Frisoni, G. B., Gauthier, S., Genthon, R., Gouw, A. A., … Proceedings of the Meeting of the International Working Group (IWG) and the American Alzheimer’s Association on “The Preclinical State of AD”; July 23, 2015; Washington DC, USA (2016). Preclinical Alzheimer’s disease: Definition, natural history, and diagnostic criteria. Alzheimer’s & dementia : the journal of the Alzheimer’s Association, 12(3), 292–323. https://doi.org/10.1016/j.jalz.2016.02.002

Pre-dementia phase of AD: Progressive, amnestic mild cognitive impairment

Early-stage pathology is present, ranging from mild neuronal dystrophy to early-stage Braak pathology, and may last for several years according to individual resilience and brain reserve

Clinically defined dementia phase of AD:

Cognitive and functional impairment is severe enough to surmount the dementia threshold; at this stage there is significant accumulation of neuritic plaques and neurofibrillary tangles in affected brain areas, bearing relationship with the magnitude of global impairment.
  • Dementia: Clinical syndrome characterized by progressive decline in two or more cognitive domains, including memory, language, executive and visuospatial function, personality, and behavior, which causes loss of abilities to perform instrumental and/or basic activities of daily living.

Case studies:

Diagnosis

The diagnosis of AD is made by clinical history, documentation of functional decline, and ruling out other potential etiologies of cognitive decline.

Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5):

  • Major neurocognitive impairment: Objective cognitive decline that is severe enough to interfere with activities of daily living and is not caused by delirium or another neurologic, medical, or psychiatric disorder.
  • Mild neurocognitive impairment: Milder cognitive decline that does not yet deprive them of the ability to lead an independent lifestyle and perform complex daily activities such as managing finances or driving a car.
Summary of Diagnostic Criteria for Mild and Major Neurocognitive Disorder
Summary of Diagnostic Criteria for Mild and Major Neurocognitive Disorder | American Psychiatric Association. Diagnostic and statistical manual of mental disorders, fifth edition Washington, DC: American Psychiatric Publishing, 2013.

NIA-AA criteria for dementia:

Developed by the National Institute on Aging (NIA) and the Alzheimer’s Association (AA) spanning all three major stages of AD (ie, the preclinical, the prodromal, and the overt dementia stages)
Summary of Diagnostic Criteria for Dementia Syndrome and Probable Alzheimer Disease from the National Institute on Aging and the Alzheimer’s Association
Summary of Diagnostic Criteria for Dementia Syndrome and Probable Alzheimer Disease from the National Institute on Aging and the Alzheimer’s Association | McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 2011; 7(3): 263– 269. doi:10.1016/j.jalz.2011.03.005.

Functional neuroimaging:

  • Single Photon Emission Computed Tomography (SPECT): 99mTc hexamethyl-propylene-aminoxime (HMPAO) SPECT
    • Decreased blood flow in parietal, emporal and posterior cingulate cortex
  • Positron Emission Tomography (PET): 18-fluorodeoxyglucose (18FDG) PET 
Tc-99m HMPAO SPECT in the evaluation of Alzheimer’s disease
(I) Group mean Tc-99m HMPAO SPECT images of Alzheimer’s patients and normal subjects. The mean global value is 100 counts/pixel. Transverse slices are with reference to the Telairach grid and parallel to intercommissural line. The anterior represents the top of the image and the subject’s right is on the left. Top row shows mean images of group A patients with severe dementia, middle row shows mean images of group B patients with early and mild dementia, and the bottom row shows mean images of normal controls. (II) z map (mean image of normal subjects−mean image of patients with Alzheimer’s disease) displayed on a glass brain. Significant differences in frontal, parietal, and temporal regions are shown. That for periventricular regions is due to the effect of global normalisation. (III) z Map (mean image of Alzheimer’s disease group B−mean image of Alzheimer’s disease group A) displayed on a glass brain. A significant difference in the left parietal region is shown. | Imran MB, Kawashima R, Awata S, et alTc-99m HMPAO SPECT in the evaluation of Alzheimer’s disease: correlation between neuropsychiatric evaluation and CBF imagesJournal of Neurology, Neurosurgery & Psychiatry 1999;66:228-232.

Differential diagnosis:

Other types of dementia (mixed, vascular dementia, Lewy body dementia, frontotemporal dementia, normal pressure hydrocephalus, HIV, and other rare forms of dementia), delirium, and, less frequently, seizure disorders.
  • Frontotemporal dementia (FTD): Early marked behavioral disinhibition or apathy; early perseverative or compulsive behavior; hyperorality and dietary changes; executive function deficits but sparing of memory and visuospatial functions; prominent early aphasia (particularly loss of word and object knowledge, motor speech, and grammatical deficits).
  • Dementia with Lewy bodies (DLB): Fluctuating cognition; recurrent visual hallucinations, typically well-formed and detailed; spontaneous features of parkinsonism; REM sleep behavior disorder; severe neuroleptic sensitivity; deficits on tests of attention, executive function, visuospatial ability.
  • Vascular dementia (VD): Onset of dementia within 3 months of recognized stroke; abrupt deterioration in cognitive function; fluctuating, stepwise progression of cognitive deficits; early presence of gait disturbance; early urinary symptoms not due to urologic disease; pseudobulbar palsy (dysphagia, dysarthria, emotional lability, inappropriate laughter or crying); depression, emotional incontinence, psychomotor retardation and abnormal executive function. (Note: Sudden onset of aphasia suggests a vascular etiology.)
  • Idiopathic normal pressure hydrocephalus (NPH): Urinary incontinence not due to urologic conditions (e.g., prostatism or chronic UTI); “glue-footed,” “magnetic” gait.

Management

There is no cure for Alzheimer’s disease. Only symptomatic treatment is available.

Psychosocial treatment:

These measures can improve functioning of AD patients. In attempting to maintain patients with AD in their homes for as long as possible, some adjustment of a patient’s environment is important.
  • Environmental manipulation
  • Family support
  • Prevention of other medical comorbidities

Cholinesterase inhibitors: Treatment of choice for cognitive disturbance

Use is based on the cholinergic deficiency observed in the disease. There is an increase in the acetylcholine concentration available for synaptic transmission by inhibiting enzymes responsible for its hydrolysis (ie, acetylcholinesterase).
  • Donepezil, tacrine, galantamine, rivastigmine
Complementary mechanisms of action for ChEI, memantine, and MCTs in the treatment of AD
Complementary mechanisms of action for ChEI, memantine, and MCTs in the treatment of AD: AChE inhibitors are believed to correct the cholinergic deficit seen in AD in which there is a loss of ACh producing neurons in the brain. These agents increase ACh concentrations by blocking the action of AChE which catalyzes the hydrolysis of acetylcholine into choline and acetic acid. Memantine is a low-to-moderate affinity noncompetitive N-methyl-D-aspartic acid (NMDA) receptor antagonist. It inhibits the prolonged influx of Ca2+ ions that forms the basis of neuronal excitotoxicity that may be involved in AD. It should be noted that memantine is approved only for the treatment of moderate-to-severe AD. Ketone bodies are an efficient fuel for cells and may provide an alternative additional energy source for neurons in patients with AD. | Galvin J. E. (2012). OPTIMIZING DIAGNOSIS AND MANANGEMENT IN MILD-TO-MODERATE ALZHEIMER’S DISEASE. Neurodegenerative disease management, 2(3), 291–304. https://doi.org/10.2217/nmt.12.21

Estrogen replacement therapy: Treatment of cognitive disturbance

Exert effect in brain by enhancing transcription and mediation of nongenomic events. It has been suggested that the abrupt decline of estrogen production in postmenopausal women increases the risk for these women developing AD; men, in contrast, have an intrinsic supply of estrogen by aromatizing testosterone in the brain.

Anti-inflammatory agents: Treatment of cognitive disturbance

Help in modulating the course of the disease.
  • Nonsteroidal anti-inflammatory drugs (NSAIDS): Indomethacin, ibuprofen, diclofenac, naproxen
  • Steroids: Low-dose prednisone
  • Other anti-inflammatory agents: Hydroxychloroquine, colchicine

Antioxidant agents: Treatment of cognitive disturbance

Increase in free-radical formation may occur in AD and have a direct toxic effect. The brain may be vulnerable to the damaging effects of oxidative stress because of an abundance of catecholamines and a relatively low concentration of antioxidative enzymes (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase). Furthermore, Aβ has been implicated in increased free-radical formation.
  • Selegiline
  • Vitamin E

Antidepressant therapy: Treatment of behavioral disturbance

Depression in patients with AD should be treated aggressively, with careful monitoring of cognitive function. Sufficient dosage and duration of treatment arc needed for clinical response in depressed patients without dementia. The depressed elderly may take up to 6 weeks to respond to antidepressant medication and patients with AD should be expected to take as long.
  • Reversible MAO inhibitors: Brofaromine and moclobemide
  • Tricyclic antidepressants (TCAs): Nortriptyline and desipramine (only these 2 TCAs, since they have fewer anticholinergic properties than their parent compounds amitriptylinc and imipramine)
  • Newer antidepressants: Fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, nefazodone, bupropion, mirtazapine, and venlafaxine

Summary:

Alzheimer's disease
Alzheimer’s disease is a neurodegenerative disorder associated with extracellular accumulation of amyloid-β in plaques and aggregation of the microtubule protein tau in neurons. | Alzheimer’s disease. Nat Rev Dis Primers 1, 15059 (2015). https://doi.org/10.1038/nrdp.2015.59

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