**2.5 Diagnosis**

The criteria for a clinical diagnosis of AD were established in 1984 and have remained unchanged for the past 27 years (McKhann *et al.,* 1984). The diagnosis of AD is currently based on clinical examination and neuropsychological testing although a definitive diagnosis can only made by postmortem examination. However, the latter is uncommon outside a research setting. A diagnosis of 'Probable AD' is made when there is worsening memory function, particularly episodic memory, accompanied by deficits in two or more other cognitive domains such as executive function, attention, language or visuospatial skills.

A diagnosis of AD would be supported by a positive family history, a normal electroencephalogram, normal cerebrospinal fluid (CSF) analysis and atrophy on computerassisted tomography (CAT) imaging (the only neuroimaging modality available in 1984). An alternative diagnosis of 'possible AD' was suggested when there was a general dementia syndrome but with variations in onset and clinical course (McKhann *et al.,* 1984). Exclusion criteria for AD included the rapid onset of dementia, an early prominence of gait abnormalities or a focal neurological deficit.

In 2011, these criteria were updated, prompted by some inconsistent clinical-pathological correlations and a need to incorporate the likely prodromal periods of AD and biomarkers (biological markers) (Jack et al., 2011). The new criteria propose a continuum of impairment but also delineate three stages along this spectrum: preclinical AD, mild cognitive impairment (MCI) and clinical AD. The basis for these stages is that the pathophysiological process of AD can be reliably represented by biomarkers. The existing 'probable' and 'possible' categories are now expanded to (1) Probable AD dementia, (2) Possible AD dementia, and (3) Dementia with evidence of the AD pathophysiological process. An example of the latter would be an individual with a less typical clinical presentation but with AD-like biomarkers on their neuroimaging or CSF analysis (McKhann *et al.,* 2011). However, biomarkers continue to only support a clinical diagnosis of AD while definitive diagnosis still requires a postmortem examination.

The differentiation of AD from MCI rests on the determination of whether or not there is significant interference in the ability to function at work or in usual daily activities (Albert *et al.,* 2011). MCI is not a definite stage on the progression to AD because some individuals will never develop dementia or will develop other forms such as VaD. However, pathological studies suggest that the majority of individuals with MCI have typical AD pathology, but just in a lesser amount to those who become clinically demented (Haroutunian *et al.,* 2009).

The definition of preclinical AD remains a research-only paradigm based on the promise that biomarkers faithfully reflect the underlying pathophysiological processes (Sperling *et al.,* 2011). As will be discussed below this preclinical diagnostic paradigm is firmly based on one, albeit prominent, working hypothesis for AD pathogenesis.

#### **2.6 Clinical heterogeneity**

392 Neuroscience – Dealing with Frontiers

with Lewy bodies (DLB). Dementia is a progressive decline in cognition that impairs social and/or occupational function. The deficits in a particular individual will reflect the regions

AD sufferers will usually present to a general physician because of their own concern about deteriorating cognition or the concerns of an informant (often their spouse or work colleague). A general physician may refer the patient to a specialist geriatrician or neurologist but many patients remain under the primary care of their general practitioners. The loss of short-term memory is often the earliest cognitive phenotype for AD (Dubois and

The criteria for a clinical diagnosis of AD were established in 1984 and have remained unchanged for the past 27 years (McKhann *et al.,* 1984). The diagnosis of AD is currently based on clinical examination and neuropsychological testing although a definitive diagnosis can only made by postmortem examination. However, the latter is uncommon outside a research setting. A diagnosis of 'Probable AD' is made when there is worsening memory function, particularly episodic memory, accompanied by deficits in two or more other cognitive domains such as executive function, attention, language or visuospatial

A diagnosis of AD would be supported by a positive family history, a normal electroencephalogram, normal cerebrospinal fluid (CSF) analysis and atrophy on computerassisted tomography (CAT) imaging (the only neuroimaging modality available in 1984). An alternative diagnosis of 'possible AD' was suggested when there was a general dementia syndrome but with variations in onset and clinical course (McKhann *et al.,* 1984). Exclusion criteria for AD included the rapid onset of dementia, an early prominence of gait

In 2011, these criteria were updated, prompted by some inconsistent clinical-pathological correlations and a need to incorporate the likely prodromal periods of AD and biomarkers (biological markers) (Jack et al., 2011). The new criteria propose a continuum of impairment but also delineate three stages along this spectrum: preclinical AD, mild cognitive impairment (MCI) and clinical AD. The basis for these stages is that the pathophysiological process of AD can be reliably represented by biomarkers. The existing 'probable' and 'possible' categories are now expanded to (1) Probable AD dementia, (2) Possible AD dementia, and (3) Dementia with evidence of the AD pathophysiological process. An example of the latter would be an individual with a less typical clinical presentation but with AD-like biomarkers on their neuroimaging or CSF analysis (McKhann *et al.,* 2011). However, biomarkers continue to only support a clinical diagnosis of AD while definitive

The differentiation of AD from MCI rests on the determination of whether or not there is significant interference in the ability to function at work or in usual daily activities (Albert *et al.,* 2011). MCI is not a definite stage on the progression to AD because some individuals will never develop dementia or will develop other forms such as VaD. However, pathological studies suggest that the majority of individuals with MCI have typical AD pathology, but just in a lesser amount to those who become clinically demented (Haroutunian *et al.,* 2009).

in which neuronal loss occurs.

abnormalities or a focal neurological deficit.

diagnosis still requires a postmortem examination.

Albert, 2004).

**2.5 Diagnosis** 

skills.

The review of the clinical diagnostic criteria was prompted in part by increasing reports of variations in the classic presentation of AD. It has even been suggested that the term Alzheimer's syndrome is more appropriate than AD (Zellner *et al.,* 2009). In addition to the classic amnestic presentation of AD described above, a "visual variant" of AD, often called posterior cortical atrophy, a "language variant" called logopenic/phonological aphasia (Gorno-Tempini *et al.,* 2011) and a frontal/behavioural variant are occasionally observed (Johnson *et al.,* 1999). The latter two are also considered sub-categories of frontotemporal dementia hinting that there might be considerable overlap in clinicopathological correlates between the current clinical dementia categories. This is supported by a recent study that found AD to be the primary pathological diagnosis in a range of focal cortical syndromes including 50% of corticobasal disease and 44% progressive non-fluent aphasia, another language variant of frontotemoporal dementia (Alladi *et al.,* 2007). This clinical or phenotypic heterogeneity in AD suggests variation in both aetiology and pathogenesis and the potential ramifications of this will be discussed in greater detail below.

#### **2.7 Current treatment options**

There are two classes of drugs that are currently used to treat moderate to severe cases of AD. They are the acetylcholinesterases inhibitors (ChEIs) and glutaminergic receptor antagonists. The cholinergic (acetylcholine producing) neurons of the basal forebrain nuclei such as the nucleus basalis of Meynert are among the earliest lost in AD (Cullen and Halliday, 1998). These neurons synapse in the prefrontal cortex and the hippocampus where they release acetylcholine to modulate circuits involved in learning and memory (Gold, 2003).

Acetylcholinesterases are enzymes responsible for the rapid breakdown of acetylcholine in the synaptic cleft. ChEIs are postulated to maximise the residual acetylcholine modulating these memory circuits in the AD brain and there are three types in current use donepezil, rivastigmine and galantamine. Meta-analyses of randomised control trials for the three ChEIs suggest that all show moderate improvements in cognitive function over placebo but the incidence of adverse events is lowest for donepezil (Birks, 2006; Hansen *et al.*, 2008)

The other drug in common use is called memantine, a low affinity glutamate NMDA receptor antagonist. The postulated mechanism of action for memantine is the prevention of glutamate-mediated excitatory neurotoxicity (McShane *et al.,* 2006). As with the ChEIs, meta-analyses report a significant but marginal improvement (Raina *et al.,* 2008) with particular attenuation of behavioural symptoms (Gauthier *et al.,* 2008). Memantine is less efficacious in mild to moderate compared to severe AD (MMSE >15) (McShane *et al.,* 2006; Schneider *et al.,* 2011).

Unfortunately there is no evidence that either of these treatments significantly alters disease progression (Golde *et al.,* 2011). Hence there is enormous research effort aimed at finding alternative treatment strategies, some of which have already reached Phase II and III human clinical trials. These potential treatments are discussed below.

Alzheimer's Disease: Approaches to Pathogenesis in the Genomic Age 395

Fig. 1. The neuropathological features of Alzheimer's disease. A series of macro-and

debris, magnification = 200x.

microscopic images show the pathological features of Alzheimer's disease (a) A lateral view of the right cerebral hemisphere shows extensive atrophy of the temporal and frontal lobes. There are also regions spared in this case including the precentral (Pr) and and postcentral (Po) gyri and the occipital pole (O), size bar = 2cm (b) A coronal view at the level of the lateral geniculate body demonstrates the severe atrophy in the temporal lobe including the hippocampus (h), along with enlargement of the Sylvian fissure, and third and lateral ventricles, size bar = 2cm (c) A modified Bielschowsky's silver stain shows neurofibrillary tangles in two cortical pyramidal neurons, magnification = 400x and (d) a cored plaque, with its dense amyloid core surrounded by diffuse amyloid, dystrophic neurites and cellular
