Alzheimer's disease (AD) is only definitively diagnosed upon autopsy examination. At autopsy the brains of AD patients exhibit atrophy and neuronal loss.¹ They also demonstrate two pathological hallmarks, which together help confirm the disease: senile (neuritic) plaques and neurofibrillary tangles. Senile plaques consist of a core of ß-amyloid protein (formed from Aß₄₂ protein), glial processes, and dystrophic neurites. Neurofibrillary tangles are intraneuronal structures formed from paired helical filaments, which are composed of abnormally phosphorylated tau proteins, wound together in a double helix.¹

Because senile plaques and neurofibrillary tangles are composed of Aß₄₂ and tau, the levels of these proteins in the cerebrospinal fluid (CSF) provide insight into the presence of a patient's disease. Elevated levels of tau protein and low levels of Aß₄₂ protein found in the CSF of AD patients supports the use of these proteins to help identify individuals with the disease.^2,3

Amyloid precursor protein (APP) is a membrane-bound glycoprotein found in the central nervous system that is cleaved by , ß, and -secretases to form amyloid beta 40 (Aß₄₀) and amyloid beta 42 (Aß₄₂).^1,4 These products are then secreted into the extracellular space, a space that is continuous with CSF. Aß₄₀, the most abundant type of Aß, is thought less likely to form ß-amyloid fibrils, which are precursors to senile plaques. Conversely, Aß₄₂ is more likely to accumulate and form ß-amyloid fibrils.^1,5

The interaction between ß-amyloid and ApoE may explain some of the pathology seen in AD. ApoE4 has been observed to bind with greater affinity to ß-amyloid than ApoE3.⁶ The presence of ApoE4 results in more Aß₄₂ protein in CSF, which accumulates at an accelerated rate⁷ to help form senile plaques in the brain.⁴ This process leaves lower levels of Aß₄₂ in the CSF. "Elderly patients with 1 or 2 4 alleles have more Aß deposits in their brains than those lacking 4, even in the absence of (or prior to) clinical AD."⁴

Tau is a brain phosphoprotein that binds to microtubules in neuronal axons to assist in microtubule assembly and stability. As with Aß, binding avidity of ApoE to tau can vary depending on the variant of ApoE involved. Studies have shown that ApoE3 binds with high avidity to tau protein, whereas ApoE4 does not bind to tau.⁸ These studies also explain that ApoE3 binding to tau slows tau phosphorylation and self-assembly into paired helical filaments, which compose neurofibrillary tangles.⁸

Conversely, ApoE4 does not bind to tau. This may more likely result in abnormally hyperphosphorylated tau, which can prevent binding to microtubules.^5,9 Levels of tau become elevated in the CSF, leading to the formation of neurofibrillary tangles and to microtubule destabilization.⁹ The instability of these microtubules is thought to cause dysfunction of axonal transport which is important to neuronal integrity. This process may ultimately be responsible for neuronal death.⁹

While one cannot make a definitive diagnosis of AD without brain histology, tau and Aß₄₂ biomarkers can be used to assist in the determination of the likelihood that an individual has AD. Studies have shown that increased levels of tau and reduced levels of Aß₄₂ are found in the CSF of AD patients.^2,3 Conversely, elevated levels of Aß₄₂ and low levels of tau can help reduce the likelihood of AD.² A study by Galasko et al. revealed that, "[c]ombined analysis of CSF Aß₄₂ and tau levels discriminated patients with AD, including patients with mild dementia, from the NC group [control group], supporting the use of these proteins to identify AD and to distinguish early AD from aging."²  When these two biomarkers are analyzed together, they can potentially help differentiate AD from other forms of dementia, such as frontotemporal dementia, vascular dementia, and Lewy body dementia, especially early in the course of the disease, when the clinical diagnosis is least certain.² According to Galasko et al.,

At this early stage of AD, it is more difficult to document a history of progressive cognitive and functional decline or to demonstrate deficits on cognitive testing . . . measuring CSF Aß₄₂ and tau levels may be helpful in diagnosing very early or mild AD.²

Aß₄₂ and tau are intimately involved with neurodegeneration seen in AD. Aß₄₂ accelerates production of senile plaques, a pathological feature in the AD brain, that cause neurodegeneration. In a review of a study by Naslund et al., Dennis Selkoe, MD, an Alzheimer's disease specialist from Harvard Medical School and Brigham and Women's Hospital, states, "Aß accumulation correlates quantitatively with the degree of dementia."⁴ Tau is associated with neurofibrillary tangles and neuronal damage typically seen in Alzheimer's disease.

"The differential diagnosis of AD from other dementias can be difficult, in part because AD abnormalities may coexist with those of other disorders."¹⁰ In patients suspected of AD, but in whom the clinical diagnosis is unsure, these biomarkers, when used in conjunction with a clinical work up, can add confidence to the diagnosis and improve patient management.^2,11