Residency · Residency · Neurology

Alzheimer Disease: Diagnosis, Biomarkers, and Emerging Therapies

Introduction

Alzheimer disease (AD) is the most common cause of dementia, accounting for 60-80% of cases. The field has undergone a paradigm shift from a purely clinical diagnosis to a biological definition based on biomarkers of amyloid-beta and tau pathology. This transformation has been driven by advances in PET imaging, cerebrospinal fluid analysis, and blood-based biomarkers, and has enabled the development of disease-modifying therapies targeting the amyloid cascade.

Epidemiology and Risk Factors

The prevalence of AD doubles every 5 years after age 65, affecting approximately 10% of individuals over that age. Non-modifiable risk factors include advancing age, the APOE epsilon 4 allele (with heterozygotes facing a 3-fold increased risk and homozygotes an 8-15 fold increase), female sex, family history, and Down syndrome. The 2020 Lancet Commission identified twelve modifiable risk factors: hearing loss, hypertension, obesity, diabetes, physical inactivity, depression, smoking, excessive alcohol, social isolation, air pollution, traumatic brain injury, and low educational attainment. Early-onset AD (before age 65) accounts for approximately 5-10% of cases, and autosomal dominant forms caused by mutations in APP, PSEN1, or PSEN2 should be considered in these patients.

Pathophysiology

The two pathological hallmarks of AD are amyloid-beta (Abeta) plaques and neurofibrillary tangles (NFTs). Abeta plaques are extracellular deposits of misfolded Abeta42 peptide produced by sequential cleavage of amyloid precursor protein (APP) by beta- and gamma-secretase. NFTs are intraneuronal aggregates of hyperphosphorylated tau protein that spread in a stereotyped pattern described by Braak staging, progressing from the entorhinal cortex to the hippocampus and then to the neocortex. Tau pathology correlates more closely with neuronal loss and cognitive decline than amyloid burden. Neuroinflammation, synaptic dysfunction, and neurodegeneration are downstream consequences. The amyloid cascade hypothesis posits that Abeta accumulation is the initiating event, though this remains debated.

Clinical Presentation

Typical Amnestic AD

The classic presentation is an insidious onset of episodic memory impairment, with difficulty learning and retaining new information. Over time, other cognitive domains become involved, including language (word-finding difficulty), visuospatial function, and executive function. Anosognosia (lack of insight) is common. Behavioral and psychological symptoms develop progressively, with apathy being the most common, followed by depression, anxiety, irritability, agitation, and psychosis in later stages. Functional decline progresses from instrumental activities of daily living (finances, medications) to basic ADLs (dressing, bathing).

Atypical Presentations

Posterior cortical atrophy (PCA) presents with visuospatial and visuoperceptual deficits, including simultanagnosia, visual agnosia, and Balint syndrome, and tends to affect younger patients. The logopenic variant of primary progressive aphasia (lvPPA) features word-finding pauses, impaired sentence repetition, and phonological errors. The frontal/dysexecutive variant presents with early executive dysfunction and behavioral changes that may mimic frontotemporal dementia. Corticobasal syndrome with asymmetric apraxia and parkinsonism can also be caused by underlying AD pathology.

Diagnostic Criteria and Biomarker Framework

NIA-AA AT(N) Framework (2018)

The NIA-AA framework biologically defines AD using three biomarker categories. The "A" category (Amyloid) is assessed by amyloid PET (positive), CSF Abeta42 (low), CSF Abeta42/40 ratio (low), or plasma Abeta42/40 (low). The "T" category (Tau) is assessed by tau PET (positive) or CSF phospho-tau levels (p-tau181, p-tau217, p-tau231, which are elevated). The "N" category (Neurodegeneration) is assessed by FDG-PET (showing temporoparietal hypometabolism), MRI (hippocampal and cortical atrophy), CSF total tau (elevated), or plasma NfL (elevated). The biological definition of AD requires A+T+ regardless of N status.

Clinical Evaluation

A comprehensive evaluation includes a thorough history from both the patient and an informant, cognitive testing using tools such as the Montreal Cognitive Assessment (MoCA), Mini-Mental State Examination (MMSE), or a detailed neuropsychological battery, and a neurological examination to exclude other causes. Laboratory screening should include CBC, CMP, TSH, vitamin B12, and folate, with RPR, HIV, and heavy metals considered based on clinical context.

Biomarkers

Neuroimaging Biomarkers

Amyloid PET using tracers such as florbetapir, florbetaben, or flutemetamol detects cortical amyloid deposition, which becomes positive 15-20 years before symptom onset. Tau PET (flortaucipir) maps regional tau burden, correlates with clinical severity, and predicts progression. FDG-PET shows the characteristic pattern of temporoparietal and posterior cingulate hypometabolism. MRI demonstrates hippocampal atrophy (graded by medial temporal lobe atrophy scales), parietal and posterior cortical atrophy, and helps exclude structural causes.

CSF Biomarkers

CSF Abeta42 is decreased in AD because the peptide is sequestered in plaques; the CSF Abeta42/40 ratio improves diagnostic accuracy. CSF p-tau181 and p-tau217 are elevated and reflect tau pathology, correlating with tau PET findings. CSF total tau is elevated as a marker of neurodegeneration but is not specific to AD.

Blood-Based Biomarkers (Transforming the Field)

Plasma p-tau217 has the highest diagnostic accuracy among blood biomarkers, reflecting both amyloid and tau pathology. Plasma p-tau181 is elevated in AD and can distinguish it from non-AD dementias. The plasma Abeta42/40 ratio is decreased in AD with moderate accuracy. Plasma neurofilament light (NfL) is a non-specific marker of neurodegeneration but is useful for monitoring. Blood-based biomarkers are poised to replace invasive and expensive CSF and PET testing for initial screening and diagnosis.

Treatment

Symptomatic Therapies

Cholinesterase inhibitors, including donepezil (5-10 mg daily), rivastigmine (oral or transdermal), and galantamine, provide modest symptomatic benefit in mild-to-moderate AD. Memantine, an NMDA receptor antagonist, is used for moderate-to-severe AD and can be combined with cholinesterase inhibitors. These therapies do not alter disease progression.

Disease-Modifying Anti-Amyloid Therapies

Lecanemab (Leqembi) is a humanized monoclonal antibody targeting soluble Abeta protofibrils that was FDA approved in 2023 after the CLARITY-AD trial demonstrated 27% slowing of cognitive decline over 18 months. Donanemab, a monoclonal antibody targeting N-terminal pyroglutamate Abeta, showed 35% slowing of decline in the TRAILBLAZER-ALZ 2 trial and was approved in 2024.

The most important safety concern with these agents is ARIA (Amyloid-Related Imaging Abnormalities). ARIA-E presents as sulcal effusion and parenchymal edema, while ARIA-H manifests as microhemorrhages and superficial siderosis. APOE epsilon 4 homozygosity confers the highest risk, and anticoagulant use is an additional risk factor. Monitoring requires serial MRI at baseline and at regular intervals during treatment. Patient selection is limited to early AD (MCI or mild dementia) with confirmed amyloid positivity, and APOE genotyping is recommended before initiating treatment.

Non-Pharmacological Interventions

Aerobic exercise may slow cognitive decline. Cognitive stimulation, social engagement, and management of cardiovascular risk factors are all important. Caregiver support and education should be prioritized, and advance care planning should be initiated early in the disease course.

Clinical Pearls

AD is now defined biologically by the presence of amyloid and tau biomarkers, not just clinically, and biomarker confirmation is required before initiating anti-amyloid therapy. Plasma p-tau217 is emerging as a highly accurate blood-based biomarker that can identify AD pathology with performance approaching CSF and PET measures. APOE genotyping should be performed before starting anti-amyloid immunotherapy because APOE epsilon 4 homozygotes have substantially higher risk of ARIA. Atypical AD presentations such as posterior cortical atrophy and logopenic PPA often affect younger patients and may be initially misdiagnosed, making biomarker testing essential when the clinical picture is atypical. Disease-modifying therapies show modest but statistically significant slowing of decline, and the clinical meaningfulness of the effect size remains an area of active discussion.

References

1. Jack CR Jr, Bennett DA, Blennow K, et al. NIA-AA Research Framework: toward a biological definition of Alzheimer's disease. Alzheimers Dement. 2018;14(4):535-562.
2. van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in early Alzheimer's disease. N Engl J Med. 2023;388(1):9-21.
3. Sims JR, Zimmer JA, Evans CD, et al. Donanemab in early symptomatic Alzheimer disease: the TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA. 2023;330(6):512-527.
4. Livingston G, Huntley J, Sommerlad A, et al. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet. 2020;396(10248):413-446.

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