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Alzheimer Disease & Dementia

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Dementia is defined as a chronic neurocognitive disorder leading to a progressive decline in executive cognitive abilities such as memory, speech, and attention, while maintaining clear consciousness.

Alzheimer's disease (AD) is the most common form of dementia, with age as the most significant risk factor, affecting 50% of those over 85. Early-onset Alzheimer’s often manifests before 40, and is associated with Down syndrome as the amyloid precursor protein (APP), a precursor for amyloid beta, resides on chromosome 21. Mutations in presenilin 1 (chromosome 14) and presenilin 2 (chromosome 1) may also increase amyloid beta production and contribute to early-onset AD. Notably, individuals homozygous for the ApoE4 allele (chromosome 19) possess a ten-fold heightened risk for late-onset AD.

The pathogenesis of Alzheimer’s is associated with the misfolded amyloid beta proteins aggregate to form neuritic (senile) plaques, predominantly in the medial temporal lobe, causing neuronal dysfunction and apoptosis. Additionally, hyperphosphorylated tau protein accumulates intracellularly to create neurofibrillary tangles. Neurodegeneration in AD typically manifests as cortical mass loss, resulting in hydrocephalus ex vacuo. Brain atrophy is most prominent in the hippocampus and can be seen on MRI in early disease. AD is also associated with low acetylcholine levels due to decreased activity of choline acetyltransferase choline acetyltransferase (ChAT) activity. The nucleus basalis of Meynert, important for memory and cognition, is particularly susceptible to acetylcholine deficiency. Clinically, AD is characterized by memory dysfunction, executive cognitive issues, and visuospatial impairments.

Frontotemporal dementia (FTD) primarily affects the frontal and temporal lobes and usually begins in the fifth and sixth decades of life, whereas Alzheimer's typically starts in the eighth decade. FTD has a notable genetic component, with up to 25% of cases inherited in an autosomal dominant fashion. The predominant subtype arises due to hyperphosphorylated tau protein inclusions, presenting histologically as Pick bodies. In fact, FTD is associated with ALS, as most patients with ALS show TDP-43 intracellular neuronal inclusions. Another common subtype of FTD is caused by abnormally ubiquitinated TDP-43 RNA binding protein. FTD presents with two variants: the behavioral variant of FTD leads to early personality and behavior changes, while the primary progressive aphasia variant induces severe language deficits.

Dementia with Lewy bodies (DLB) is caused by the intracellular accumulation of alpha-synuclein, forming eosinophilic inclusions. Patients with DLB typically develop Parkinsonism, as Lewy bodies are also present in Parkinson’s disease. Unlike Parkinson’s, DLB often triggers visual hallucinations early in its progression.

Vascular dementia presents a unique stepwise deterioration in cognition: stable cognitive function intermittently disrupted by episodes of acute, permanent decline. This pattern stems from the cumulative effect of cerebrovascular events, such as strokes, evident as infarcts of varying ages on MRI scans.

HIV-associated dementia occurs in advanced HIV-AIDS patients, particularly those with CD4 counts below 200. This dementia subtype is marked by the inflammatory activation of microglia and macrophages. These activated immune cells release proinflammatory cytokines, resulting in the formation of microglial nodules with associated necrosis and multinucleated giant cells.

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How symptoms typically arise in Alzheimer’s disease?

Alzheimer's disease primarily manifests as memory dysfunction, especially concerning recent events. Other notable symptoms include executive cognitive dysfunction, such as challenges in planning or organizing tasks. Additionally, individuals may experience visuospatial impairment, where they become disoriented or lost in familiar surroundings.

How is down syndrome linked to early-onset Alzheimer's disease?

Down syndrome is associated with an increased risk of early-onset Alzheimer's disease as the amyloid precursor protein (APP) is encoded on chromosome 21. Patients with trisomy 21 may produce more APP, leading to an accumulation of amyloid-beta proteins—a hallmark of Alzheimer's disease.

What genetic factors increase the risk of late-onset Alzheimer's disease?

A significant genetic risk factor for late-onset Alzheimer's disease is the presence of two copies of the ApoE4 allele on chromosome 19. This genetic variant increases the risk of developing the disease by approximately tenfold.

How do frontotemporal dementia and Alzheimer's disease differ?

Frontotemporal dementia (FTD) primarily affects the frontal and temporal lobes and usually begins in the fifth and sixth decades of life, whereas Alzheimer's typically starts in the eighth decade. FTD has a notable genetic component, with up to 25% of cases being inherited. The most prevalent subtype of FTD is linked with tau protein inclusions, while the pathogenesis of Alzheimer's disease is associated with extracellular amyloid-beta plaques and intracellular neurofibrillary tangles formed by hyperphosphorylated tau protein.

How can HIV-AIDS lead to dementia?

Advanced HIV-AIDS, particularly when CD4 counts are below 200, can result in cognitive decline and dementia. HIV-associated dementia is attributed to the inflammatory activation of microglia and macrophages, which release cytokines that cause inflammation, forming microglial nodules with necrosis and multinucleated giant cells.