Alzheimer's Disease 2025 (Mendius 10/15/2025)

 A recording of this presentation is available HERE.

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Thanks to Dr. Mendius, SMGR Neurologist, for a practice-changing Grand Rounds presentation on Alzheimer's Disease (AD) in 2025. Dr. Mendius shared that he had updated this presentation from 2022, and whereas in 2022, he was filled cynicism and despair regarding the diagnosis and treatment of AD, just three years later, he is filled (and filled us) with tremendous hope. 

Gosh, don't we all need a little more hope these days?! Well. . .here it is, in the form of GR notes on AD!

Two important primary care practice changers right up front:

• Primary care providers should be ordering a serum blood test  for diagnostics-- Lumipulse G pTau217/ß-Amyloid 1-42 Plasma Ratio -- for patients with cognitive impairment and in whom you suspect Alzheimer's Disease
• Primary care providers should refer ALL patients with cognitive impairment/concern for dementia to neurology for assessment for new anti-amyloid treatments if they meet indications

 Major neurocognitive disorder criteria

• Acquired
• disabling decline from prior level of function (be aware that if you are declining from a relatively high level of function, you may still have a significant dementia)
• single cognitive area sufficient

Cognitive domains

• learning and memory (ability to acquire, store, recall info)
• language (comprehend, repeat, produce in reading/writing/speaking)
• executive function (plan for something, e.g. get to store and back with all the things)
• complex attention (sustained focus/attention on something, divided attention)
• perceptual motor (take a visual, auditory or tactile stimulus and make a complex response)
• social cognition (can you process social cues, appropriateness of their and your own behavior, theory of mind-- understand their processes)

Ddx of Dementia

• Alzheimer 60-80% (most common by far)
• Vascular 15-20% 
• Lewy Body 10%
• Frontotemporal 2-10%
• Parkinson's Dementia 2%
• Mixed 10%
• Other: Huntington, CJD, CTE 

Life Expectancy: at age of 70, 3-10 years at time of diagnosis. Average is 7 in AD, but 6-20 years is what Dr. Mendius quotes to patients. 

"Reversible" Dementias: Alcohol, Depression, Metabolic (Thyroid, Parathyroid, B12/folate), Infectious (HIV, syphilis, long COVID), Structural (NPH, subdural hematoma, tumor)

Top Score=30, 26 is lower limit of normal

Dr. Mendius prefers the MOCA due to combination of executive function, language function, visuospatial function and memory. Formal neuropsych testing costs thousands of dollars and 2 days of work. Comprehensive Dementia Review (CDR) is used a lot in research studies but not used much in clinic. 

A few pearls on Parkinsonism and Dementia

• Parkinson's Disease (PD) has significant dementia component, 40-60% of PD patients "dement" during the course of their disease
• There is an important difference between Lewy Body Dementia and PD Dementia>>stiffness/tremor/slowness/postural instability presents WITH the dementia at time of  onset. Also presents with REM sleep, visual hallucinations, vivid dreams. 
• In PD, dementia presents late, 5-8 years after the onset of tremor/movement disorder

Mild Cognitive Impairment: 20% of population >70 has MCI. Most will remain stable, about 25-40% progress to dementia (10-15% per year). People with MCI presenting with primarily short term memory group is most likely to progress to AD

RF: age, smoking, obesity, lack of exercise

Alzheimer's Disease

Genetic Autosomal Dominant occurs in  <1% of AD, mutation amyloid precursor

Only 7.5% of AD presentation presents <65 years (some genetics, some non-genetics)

Cardinal features of AD:

• Memory impairment-- generally begins with declarative episodic memory (time/place) BEFORE semantic and procedural memories. Anterograde long term episodic amnesia. Trouble laying down new memories. In MOCA task, give 5 words to remember>> if unable to recall words with hints indicate more significant Alzheimer pathology
• Executive functioning-- anosognosia "I don't know I have a problem" (If someone comes in worried about their memory, they usually don't have dementia, if their spouse is worried>> more likely to be a problem)
• Visuospatial impairment: ability to draw cube, numbers on clock
• Language difficulties: "like pruning a tree", language becomes very simple, words to describe things begin to disappear, circumlocution (talk all around a word to describe something)
• Behavioral Symptoms: apathy and social disengagement, irritability/wandering/aggression tend to be late. Capgras phenomenon: "this is not my wife"
• Apraxia: motor tasks, e.g. show me how you brush your teeth, use a razor to shave
• Olfactory dysfunction is typically late
• Sleep disturbance: frequent arousal
• Seizures 10-20% of patients with AD have seizures
• Motor: myoclonus, frontal release signs late in the course

Neuroimaging reveals specific atrophy patterns:

Alzheimer Molecular Biomarkers

• Currently studying and targeting amyloid and tau, microglia
• NEW this year!!!! Lumipulse G pTau217/ß-Amyloid 1-42 Plasma Ratio (17970) is a serum test that is sufficiently diagnostic for AD, some pretty good numbers: 91% positive predictive value and 95% negative predictive value (Palmquist 2025). You can reduce the "indeterminate population" down to about 10%. Seems to be covered by insurance!
• Can be used in the amnestic/MCI population
• This test should not be done on a "normal" (i.e. not cognitively impaired) patient
• Lumipulse is necessary to get into trials for antibody infusions

Amyloid is in the brain for a reason>> part of the innate immune system, involved in synaptic formation and repair, organizing long term memory and synaptic organization, also involved in moving things from cell bodies into dendrite and axons

There are TWO Current anti amyloid antibodies that are available:

1) Lecanemab: against protofibrils, used in MCI and mild AD dementia, 10mg/kg every other week. Infusion reactions are common 26% (need to watch 4 hours after first three infusions). need frequently MRI scans to look for flare/T2 for edema, hemorrhage and hemosiderin (12-17% of patients, most asymptomatic, but 9/900 had significant hemorrhage)

-Efficacy demonstrated in study of  1800 patients, 18 months, outcome: CDR, 30% slowing of decline, marked reduction of amyloid in the brain, improvement best if amyloid reduced to 15-20% of what you expect in AD population. Efficacy is maintained to a couple of years for those who respond. NEW Subq injection (weekly) just approved. 

2) Donanemab: goes against deposited plaques, this is a monthly injection, need frequent MRIs

-Efficacy : similar to Lecanemab -- 30% slowing in decline, side effects: 24% edema, hemorrhage/hemosiderin in 30% (vs. 13% in placebo arm)

FUTURE????

Tau seems like major target we will be treating in the future>> tau stabilizes microtubule bundles (internal cytoskeleton of the neuron). Also involved in transport functions. Functional tau has a specific distribution, pathologic tau clumps and destabilizes the microtubule>> neurofibrillary tangle. Stages of AD seem related to Tau.

Microglia also seems like future possibility>> microglia is brain's immune system (lymphocyte infiltrated into the tissue)

170 drugs in various stages of development!

Lifetime interventions for dementia prevention: see the Lancet image below: ~30-40% of dementia is preventable over a lifetime.

2024 Lancet standing commission

Methamphetamine Associated Heart Failure (Gordon, 10/8/25)

 A recording of this presentation is available HERE.

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Thanks so much to Dr. Lily Gordon for a really impactful presentation on Methamphetamine Associate Heart Failure. We see SO much of this condition in the hospital, and at times it can literally feel like the Wild West. Having a structured presentation helped me to understand where to focus my medical an advocacy efforts, as well as contextualizing the problem within our current times. 

Epidemiology and Trends

For example, it was helpful for me to hear that methamphetamine use rates have increased significantly in the last decade (see graph below), that the entire west coast is experiencing an disproportionate burden of meth-induced heart disease (see map below), and that patients with meth-induced heart failures have a documented longer length of stay and higher cost and disease burden. 

My lived experience as a hospital-based family doctor was confirmed that patients with this disease carry a high burden of social determinants of health, including housing instability and low SES, as well as disease occurring at a younger age and male-gender predominant.  

I was fascinated to revisit the physiology and pathophysiology of meth-induced heart failure to be able to understand that there are two dominant pathways through which methamphetamine impacts cardiac output, leading to heart failure: 1) direct myocyte toxicity as well as 2) sympathetic activation. 

Interestingly, for patients who use methamphetamine, binge pattern of use (leading to higher rates of inflammation), co-use with alcohol (even in low and moderate range), and an as-of-yet undiagnosed genetic predisposition are associated with meth-induced HF, whereas route of use (IV vs. smoke vs. snort) and duration. This has also been my experience-- that some patients can use for decades and not develop cardiomyopathy, whereas others can use in binge-like fashion for a relatively short period of time (less than a year) and develop heart failure. 

Diagnosis and Treatment

A reminder from Dr. Gordon that Meth-associated Heart Failure is a diagnosis of exclusion. There are no consensus guidelines on diagnostic criteria. In point of advocacy, patients with a new diagnosis of heart failure AND concomitant meth use tend to have a longer delay in getting an ischemic evaluation, as shown in the data from this 2024 paper from Kersey, et al (see below). A reminder that most patients with a new HF diagnosis should get an ischemic evaluation as part of their diagnosis.

Another important clinical pearl is that something like 33% of patients with meth-associated HF have an LV thrombus, and transthoracic echocardiogram is only 21-35% sensitive in detecting these. For patients with otherwise unexplained worsening of symptoms and/or diagnosis, some professional organizations recommend cardiac MRI vs. contrast-assisted ultrasound in order to properly diagnose LV thrombi. 

 

Three patient-centered questions:

1) Is the damage from methamphetamine permanent?

answer: limited data from Germany (Schurer, 2017) found that the ejection fraction in patients with hear failure OFTEN improves significantly with meth cessation (as compared with continued use). This, in my opinion, may offer our patients some true HOPE. 

2) Are there treatment options to help me stop meth?

answer: there is good data that CONTINGENCY management (i.e. payment/gift cards and/or rewards) is the most effective intervention to decrease methamphetamine use and get to sustained cessation. 

Non-FDA approved (but evidence based) interventions that can be effective in helping with meth cessation include naltrexone+ bupropion (contraindicated with concomitant opioid use), mirtazapine (ideal for co-treating depression), and psychostimulants (in case of underlying ADHD).

3) What if I cannot stop?
answer: GDMT is still indicated and can improve outcomes. Patients with ongoing methamphetamine use should still be offered full GDMT. We could do better! Active meth use is not reason to withhold lifesaving treatment. The chart below shows evidence that we can be more diligent about providing full GDMT for these patients.