Alzheimer's Disease

The following are all symptoms that are common to the early stages of Alzheimer's disease:

• Short-term memory dysfunction occurs from hippocampal degeneration.
• Word-finding and naming issues arise from temporal lobe degradation (the temporal lobe is essential for language processing and production).
• Task-sequencing and visuospatial disturbances from parietal lobe degeneration that can produce significant apraxias.

As degeneration worsens and other areas of the brain are affected, the following symptoms occur (note that they likely have diffuse originations):

• Remote memory degenerates: remote memory involves storage and retrieval throughout the brain.
• Neuropsychiatric symptoms become prominent. Apathy, depression, and emotional irritability tend to occur first, followed by personality changes and hallucinations in later stages.
• Visuospatial dysfunction becomes common and prominent. It manifests with spatial disorientation (eg, trouble staying in a lane when driving, finding a parked car, getting lost (wandering)).

When non-memory symptoms predominate, they may ultimately be categorized as having an Alzheimer variant. Indicate that these variants include:

• Primary progressive aphasia (logopenic variant), which involves language dysfunction, especially anomia. On exam, patients struggle with verbal fluency tests out-of-proportion to other deficits. Look for temporal lobe degeneration.
• Frontal variant, which manifests with behavioral dysfunction early-on. Look for frontal lobe degeneration more so than parietal lobe involvement.
• Posterior cortical atrophy, which manifests with visuospatial dysfunction early-on. Look for early, pronounced parietal lobe degeneration.

Note that primary progressive aphasia and behavioral dysfunction are key phenotypes of frontotemporal dementia (which we discuss elsewhere), as well. Generally, the temporal and parietal lobes are affected before the other cerebral lobes. This finding correlates well with some of the key symptoms of Alzheimer's: memory loss and language dysfunction out of the temporal lobes and visuospatial dysfunction due to involvement in the parietal lobe. In Alzheimer's disease, there is severe degeneration of the hippocampal formation. There is degeneration of especially: CA1 (cornu ammonis 1), the entorhinal cortex, and subiculum. As well. there is atrophy of the amygdala and parahippocampal gyrus, which results in dilatation of the temporal horn of the lateral ventricle. Ultimately, as we see, there is gyral shrinkage and sulcal widening as atrophy progresses. Amyloid beta plaques (senile plaques), are extracellular aggregates of fibrillar amyloid beta peptide. The term senile plaque stems from the notion that these plaques were observed in autopsies of elderly patients with dementia.

• Importantly, they stain red with Congo red staining – the classic amyloid stain – they are found both extracellularly and also in blood vessel walls, as we'll discuss further later. The major cleavage products of amyloid plaques include amyloid-beta 42 and amyloid-beta 40.

Tau neurofibrillary tangles comprise intracellular conglomerations of hyperphosphorylated tau (a microtubule stabilizing protein); they are the cornerstone to a great deal of neurodegenerative diseases.

• Tau is a microtubule-stabilizing protein. Hyperphosphorylation of tau weakens the affinity of tau for microtubules, so detached tau proteins aggregate, and form paired helical filaments that conglomerate as densely compacted neurofibrillary tangles. They are insoluble aggregates that crowd the neuronal cell body and extend into the apical dendrite.
• On histopathology, the neurofibrillary tangles have an ill-defined basophilic appearance on H&E but silver impregnation stains (eg, the modified Bielschowsky stain) and immunohistochemistry making it easier to visualize them.

Hirano bodies are intracellular eosinophilic rod (or almond) shaped structures that comprise a lattice of multi-layered actin filaments and actin-binding proteins; they reside within the CA1 sector, most notably. Finally, let's address some of the best-known genetic factors in Alzheimer's disease. The best-established genetic risk factor in Alzheimer's involves the Apolipoprotein E (APOE) gene. The APOEE4 allele INCREASES the risk of Alzheimer's.

• One mutation increases the Alzheimer's risk ~ 3-fold.
• Two mutations will increase the Alzheimer's risk ~ 10-fold.

Whereas, the APOEE2 allele DECREASES the risk. The following are 3 key mutations linked to autosomal dominant early-onset Alzheimer's disease (onset younger than 65 years-old), all of which increase amyloid production.

• Amyloid Precursor Protein (APP) mutation
• Presenilin 1 (PSEN1) mutation
• Presenilin 2 (PSEN2) mutation

In trisomy 21, there is APP gene triplication (there are 3 copies of the APP gene), which increases the risk of early-onset Alzheimer's disease. The core AD CSF biomarkers include total tau (T-tau), phosphorylated tau (P-tau) and the 42 amino acid isoform (Ab42) of b-amyloid as well as Amyloid-PET (18F-flutemetamol amyloid PET) detects amyloid load (burden). FDG-PET (18F-2-fluoro-2-deoxy-D-glucose PET) detects hypometabolism and is also used but is not considered a core biomarker because it is less specific than Amyloid-PET. Amyloid-PET is particularly helpful in distinguishing AD from frontotemporal dementia (FTD) or multi-infarct dementia but, unfortunately, amyloid plaques are found in normal individuals so it struggles to distinguish AD from normal amyloid build-up. Let's address some key aspects of Alzheimer's dementia treatment. There are two main classes of symptomatic management, both of which produce small but real improvements in cognitive performance: First, indicate Cholinesterase Inhibitors, which increase cholinergic activity. As we might predict, these cholinergic effects, commonly cause GI hypermotility (loose stools or diarrhea). We need to look-out for potential bradycardia or cardiac conduction abnormalities and the risk of COPD or asthma exacerbations.

• Donepezil
• Rivastigmine
• Galantamine

• Note that in a 2001 study, donepezil was shown to definitively impact disease progression.
• Winblad B, Engedal K, Soininen H, et al. A 1-year, randomized, placebo-controlled study of donepezil in patients with mild to moderate AD. Neurology 2001;57:489–495.
• Recent studies have shown broader class benefit for the cholinesterase inhibitors in the reduction of cognitive decline and mortality. Galantamine, specifically, was shown to reduce progression to severe dementia.
• Xu, Hong, Sara Garcia-Ptacek, Linus Jönsson, Anders Wimo, Peter Nordström, and Maria Eriksdotter. "Long-Term Effects of Cholinesterase Inhibitors on Cognitive Decline and Mortality." Neurology 96, no. 17 (April 27, 2021): e2220–30. https://doi.org/10.1212/WNL.0000000000011832.

Next, indicate that memantine is an NMDA antagonist: it reduces glutamate excitotoxicity. Although it was originally designated for only moderate to advanced Alzheimer's disease, in practice it is used at all stages of the disease. Paradoxically, it can induce confusion and hallucinations (both of which are already problematic in patients with dementia).

• Note that although memantine is commonly described as being neuroprotective, it still has not been shown to actually slow the progression of the disease (making it a symptomatic management (despite this designation of being neuroprotective)).
• Areosa SA, Sherriff F, McShane R. Memantine for dementia. The Cochrane Database of Systematic Reviews. 2005 Jul(3):CD003154. DOI: 10.1002/14651858.cd003154.pub4. PMID: 16034889.
• Folch J, Busquets O, Ettcheto M, Sánchez-López E, Castro-Torres RD, Verdaguer E, Garcia ML, Olloquequi J, Casadesús G, Beas-Zarate C, Pelegri C, Vilaplana J, Auladell C, Camins A. Memantine for the Treatment of Dementia: A Review on its Current and Future Applications. J Alzheimers Dis. 2018;62(3):1223-1240. doi: 10.3233/JAD-170672. PMID: 29254093; PMCID: PMC5870028.

As far as disease-altering medications are concerned, there have been many advancements in amyloid plaque clearance but as of 2023, there have not been definitive substantive advancements in the ability to medications to slow the progression of the disease. Although the amyloid cascade hypothesis is no longer widely accepted (in part due to failure of medications that specifically clear amyloid plaques), it is still the most universally understood theory and will still provide us with a solid foundation for the science of Alzheimer's disease. Amyloid precusor protein (APP) is the physiologic precursor for the toxic amyloid byproducts that we'll introduce. It is a cell surface protein. A series of secretases: alpha, beta, and gamma splice the APP into various pieces. Normally, amyloid-beta is removed from APP and degraded outside of the cell. In Alzheimer's pathology, however, amyloid-beta peptides accumulate, instead. The following are toxic amyloid peptide components:

• Amyloid-beta-42 oligomers are a 42-residue amyloid beta-protein fragment. Amyloid-beta-42 is considered a particularly "sticky", soluble form of amyloid peptide and, thus, in pathologically high concentrations, it aggregates.
• It lies intraneuronally and also outside of the cell.
• Amyloid fibrils are larger, less soluble aggregation of amyloid-beta peptide.
• Amyloid-beta plaques are called senile or neuritic plaques. They comprise deposits of numerous, aggregated amyloid fibrils. When broken down, the major cleavage products include amyloid-beta 42 and amyloid-beta 40. Show that amyloid-beta plaques are extracellular – they lie outside of the neuron; they are even less soluble than the amyloid fibrils.

The pathophysiology of tau neurofibrillary tangle formation lies within the site of the microtubules in the axons and dendrites. Hyperphosphorylation of tau weakens the affinity of tau for the microtubules. Detached tau proteins aggregate and form paired helical filaments: they have a double-helix pattern (or "twisted ribbon" appearance, per more modern accounts). These paired helical filaments conglomerate as densely compacted neurofibrillary tangles. They are insoluble aggregates that crowd the neuronal cell body and extend into the apical dendrite.

• See the "Alzheimer's Disease" Tutorial.