Alzheimer disease

The brains of people with AD have an excess of interneuronal amyloid (Abeta) peptides, due to overproduction or diminished clearance of beta-amyloid. This leads to the formation of dense amyloid oligomers, which are deposited as diffuse plaques. These oligomers and plaques cause an inflammatory process through microglial activation, cytokine formation, and activation of the complement cascade. Inflammation leads to the formation of neuritic plaques, causing synaptic and neuritic injury and cell death. However, interventions aimed at preventing Abeta accumulation have failed to demonstrate clinical efficacy in preventing or slowing AD progression.[14]

The amyloid precursor protein and proteins from the presenilin 1 and presenilin 2 genes are involved in the formation of Abeta; missense mutations of these genes are responsible for most cases of early onset AD.[15]

Aggregation of the abnormally phosphorylated tau protein, a microtubule-associated protein that stabilizes microtubules in the cell, is also observed in the brains of people with AD. Tau accumulates into intraneuronal masses known as neurofibrillary tangles and as dystrophic neurites.

There is a long phase of preclinical AD when biomarkers are measurable (e.g., amyloid plaque on imaging, cerebrospinal fluid Abeta and phosphorylated tau, or neuronal degeneration), which is followed by a period of mild symptoms, and then by fully symptomatic disease.[16][17][18][19][20] In this model, people with positive biomarkers and normal cognition have AD even in the absence of symptoms. This is clinically problematic, as a subset of people remain in the prodromal phase for extended periods without cognitive decline. Thus this concept is applied only in a research setting as a way to identify people at greater risk of cognitive decline and to help evaluate and target therapies for this at-risk group.

Lifestyle factors such as smoking, midlife obesity, a diet high in saturated fats, abstinence from alcohol in midlife, and consumption of >14 units of alcohol/per week have been associated with an increased risk for the development of AD.[21][22][23][24] Moderate alcohol consumption (1-14 units/week) may protect against dementia.[21][24]

Various other potential risk factors for the development of AD have been reported, including traumatic brain injury, hearing loss, increased serum cholesterol, elevated serum homocysteine, and regular anticonvulsant drug use.[23][25][26][27][28][29]

Gross examination of brains from people with AD reveals reduced brain weight: typically 100-200 g less than average, or more depending on disease severity. Cortical atrophy is apparent in the temporal, frontal, and parietal areas, whereas the thalamus, brainstem, cerebellar hemispheres, and basal ganglia usually appear normal in size and weight.

On microscopic exam, senile plaques and neurofibrillary tangles are the characteristic histopathologic features postmortem. Plaques are made up of beta-amyloid and are extracellular, whereas neurofibrillary tangles are intracellular and composed of cytoskeletal filaments of hyperphosphorylated tau. These changes are usually present in the hippocampus, amygdala, cortex, and nucleus basalis. The abundance of tangles is roughly proportional to the severity of clinical disease and cognitive decline.

Possible mechanisms by which beta-amyloid induces injury to brain cells include intracellular calcium deposition, production of oxygen radicals and nitric oxide, and inflammatory processes.[30][31][32] Cholinergic neurons are damaged in the basal forebrain, which results in decreased levels of cholinergic neurotransmission. Other findings include degeneration of the locus caeruleus and raphi nuclei, with subsequent neurotransmitter deficiencies in serotonin, corticotropin-releasing factor, glutamate, and norepinephrine.

Diagnostic and Statistical Manual of Mental Disorders, 5th ed, text revision (DSM-5-TR) classification of major and mild neurocognitive disorders[3][4]

DSM-5-TR defines major and mild neurocognitive disorders as being due to:

Alzheimer disease
Frontotemporal degeneration
Lewy body disease
Vascular disease
Traumatic brain injury
Substance/medication use
HIV infection
Prion disease
Parkinson disease
Huntington disease
Another medical condition
Multiple etiologies
Unknown etiology.

Severity is defined for major neurocognitive disorders as mild, moderate, or severe; and the presence or absence of behavioral and psychological symptoms is also specified.

Specific criteria relating to major and or mild neurocognitive disorder due to Alzheimer disease are given in Diagnostic criteria.

Pathophysiology

Classification

Diagnostic and Statistical Manual of Mental Disorders, 5th ed, text revision (DSM-5-TR) classification of major and mild neurocognitive disorders[3][4]