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Alzheimer's disease may be the most common dementia, but amyloid-beta (Aβ) plaques and tau tangles don't tell the whole story of its complex pathobiology.

The disease is defined in part by two biopathological characteristics:

• Diffuse and neuritic plaques of Aβ deposited in extracellular spaces
• Hyperphosphorylated tau protein aggregated into neurofibrillary tangles and threads inside neurons

Amyloid-beta is released by neurons in response to synaptic activity, but its peptides are prone to aggregate into fibrils. Amyloid-beta can create these structures if 'seeded' in a prion-like manner by the presence of small assemblies of misfolded beta-sheet-containing Aβ seeds that template the formation of larger amyloid aggregates," as a describes.

Injecting mice with minute amounts of misfolded Aβ can start cerebral amyloidosis, and rare cases of apparent human transmission have also been documented in patients getting cadaver-derived human growth hormone treatments for pituitary insufficiency.

The amyloid cascade hypothesis that deposition of Aβ in the brain initiates Alzheimer's disease pathogenesis, "leading to subsequent tau deposition, neuron and synaptic loss, and cognitive decline," has remained a key part of the explanation for decades, the review notes. Recent successes with anti-amyloid monoclonal antibodies in treating early Alzheimer's disease have shored up amyloid's role.

However, evidence has accrued to show that amyloid accumulation is "necessary but not sufficient" to kick-start the disease, the review added. Other downstream events such as neuroinflammation and tau accumulation may be the main drivers of neurodegeneration.

Once amyloid pathology is underway, it predicts intracellular accumulation of hyperphosphorylated tau as neurofibrillary tangles and that, in turn, . Tau plays important roles in microtubule assembly and transport regulation as well as stabilization of neuronal axons.

Hyperphosphorylated tau can impair synaptic function. The same kind of prion-like seeding and spreading may be how that pathological tau propagates into the neocortex in Alzheimer's disease. Cognitive impairment in is only noted when tau spreads from the entorhinal cortex into the in .

Additional Processes

Other critical cellular and molecular processes likely play a role as well, as Aβ may also lead to cognitive impairment via synapse damage and from capillary constriction and reduced cerebral blood flow.

Activation of immune mediators appears to be a critical regulator of Alzheimer's disease pathology, including reactive astrogliosis and microgliosis. Interactions between the gut microbiome and the central nervous system's innate immune system (gut-brain axis) may modulate Alzheimer's disease pathogenesis as well via the microglia, the review in Cell explained.

An underlying infectious basis for the disease has long been speculated, with certain pathogens infecting the brain and kick-starting Aβ fibrillization as an antimicrobial defense mechanism which then seeds further deposition. One , for example, showed that herpes simplex virus-1 catalyzes aggregation of Aβ in vitro via contact with the viral surface.

Sleep impairment and deprivation have also been shown to stimulate higher Aβ and tau levels in human cerebrospinal fluid and animal model brains. is slower during wakefulness versus sleep, and increased synaptic Aβ release due to elevated neuronal metabolism and/or activity during wakefulness versus sleep is

Genetic Factors

ApoE protein is a lipid-binding protein expressed at the highest levels in the liver and brain, where it binds directly to Aβ present in plaques. Of the three common APOE gene alleles, the one encoding ApoE4 is the strongest genetic predictor of Alzheimer's disease risk. It is found in 40-60% of Alzheimer's patients.

After a long debate, a working group convened by the Alzheimer's Disease Sequencing Project came to consensus that the APOE4 gene is definitively toxic. ApoE4 may mediate Alzheimer's disease risk by modulating immune and microglial responses.

A single inherited copy of the APOE4 allele increases Alzheimer's risk approximately three- to four-fold, while two inherited copies increase risk by some 12-fold. In one , APOE4 carriers had 5.65 times higher odds (95% CI 1.52-20.98) of rapid progression from amyloid-beta positive status with mild cognitive impairment to diagnosis with Alzheimer's disease within 3 years, which 40% of the carriers did. Another study suggested that people with homozygous APOE4 may have a distinct, genetically determined form of Alzheimer's disease.

The genetic alterations of also mean elevated risk for Alzheimer's disease. With an extra copy of chromosome 21 comes an extra copy of the gene for amyloid precursor protein and thus higher production of Aβ peptides, leading to Alzheimer's pathology in nearly all and clinical disease in 40-80% of patients before age 60 or 70.

Uncommon Variants in Early-Onset Disease

Autosomal dominant Alzheimer's disease accounts for only a small percentage of cases (5-10%) but results in disease for nearly all who inherit mutations in one of three genes:

• Amyloid precursor protein (AAP) on chromosome 21, which leads to increased production and accumulation of Aβ
• Presenilin 2 (PSEN2) on chromosome 1, which interferes with gamma-secretase processing that would keep amyloid-beta from aggregating in the brain
• Presenilin 1 (PSEN1) on chromosome 14, the most common (around 5% of all Alzheimer's disease) and which interferes with gamma-secretase processing as well

All three are strongly associated with early-onset forms of the disease, with clinical symptoms appearing before age 65.

Read Part 1 of this series: Defining Alzheimer's Disease

Up next: Making the Alzheimer's Disease Diagnosis